Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:30]=[CH:29][C:22]4[N:23]([CH3:28])[C:24](=[O:27])[CH2:25]S[C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:31])[C:9]1=[O:32].OO[S:35]([O-:37])=O.[K+].[CH3:39]O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:30]=[CH:29][C:22]4[N:23]([CH3:28])[C:24]([O:25][CH3:39])=[CH:27][S:35](=[O:37])[C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:31])[C:9]1=[O:32]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CN1C(=O)CSc2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3ccccc3Br)C4)ccc21
Agent: [K+]
Product: COC1=CS(=O)c2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3ccccc3Br)C4)ccc2N1C

Procedure:
100 mg of the compound from example 9 and 108 mg oxone were stirred in 2 ml MeOH at room temperature for 17 hrs. The mixture was filtered and the residue washed with THF. The combined filtrates were concentrated and purified by preparative HPLC-MS to yield 10 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[F:16][CH:17]([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24]([SH:26])=[N:25][C:21]=2[CH:20]=1>>[F:29][CH:17]([F:16])[O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24]([S:26][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:25][C:21]=2[CH:20]=1
Reactant: FC(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(Sc2nc3cc(OC(F)F)ccc3[nH]2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-difluoromethoxy-1H-benzoimidazole-2-thiol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:29]([O:31][CH3:32])=[O:30])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:23](Cl)=[O:24])[C@@H:10]([CH:26]2[CH2:28][CH2:27]2)[CH2:9]1.[CH:42]([OH:45])([CH3:44])[CH3:43]>>[CH:42]([O:45][C:23]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[Br:22])[C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=2)[C:29]([O:31][CH3:32])=[O:30])[CH2:9][C@@H:10]1[CH:26]1[CH2:28][CH2:27]1)=[O:24])([CH3:44])[CH3:43]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2c(Br)cc(C(F)(F)F)cc21
Reactant: CC(C)O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2c(Br)cc(C(F)(F)F)cc21

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonyl chloride (Example 100D) (1.5 g) in isopropanol was heated to reflux for 48 h. The reaction was cooled and concentrated, and the residue was chromatographed (5-10% EtOAc/hexane) to afford the title product (1.0 g). MS m/z 705.4 (M+); 1H NMR (CDCl3) δ 3.8 (s, 3H), 7.1 (s, 1 H), 7.8 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+].O>CN(C=O)C>[CH3:10][S:11][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: O=Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
In DMF (5.0 mL) was dissolved 6-chloronicotinaldehyde (300 mg, 2.12 mmol). Sodium thiomethoxide (178 mg, 2.54 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 6-(methylthio)nicotinaldehyde (239 mg, 74%).
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([C:14]1[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=1)=[C:7]2[C:11]([OH:13])=[O:12].O.C(=O)(O)[O-].[Na+].[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>CC(C)=O>[C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[C:14]1[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=1)[CH:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)[C:9]2=[O:10])([OH:13])=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Reactant: O=C(Cl)Cc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(c3cnc(-c4ccccc4)s3)CSC12
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-2-carboxy-8-oxo-3-(2-phenylthiazol-5-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) in a mixture of distilled water (35 cc) and acetone (24 cc) containing sodium bicarbonate (2 g) is cooled to -10° C. and then treated with a solution of (thien-2-yl)-acetyl chloride (0.86 cc) in acetone (10 cc), which is added dropwise in 8 minutes. The reaction mixture is stirred for 30 minutes at -10° C. and then for 3 hours at 20° C. The acetone is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. and ethyl acetate (150 cc) and a saturated sodium bicarbonate solution (100 cc) are added. The aqueous layer is extracted with ethyl acetate (100 cc), then treated with decolorising charcoal (1 g) and a filtration aid (diatomaceous earth powder) (5 g), and filtered on the filtration aid, rinsing with distilled water (2×50 cc). The combined filtrates are acidified to pH 2 with 4N hydrochloric acid. The precipitate is filtered off, washed with ethyl acetate (50 cc) and then triturated with isopropyl ether (100 cc) and dried. 2-Carboxy-8-oxo-3-(2-phenyl-thiazol-5-yl)-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.8 g) is obtained in the form of a cream-coloured solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>CCCCO>[Br:16][C:17]1[C:18]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[C:19]2[C:25]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Solvent: CCCCO
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
(R)-tert-Butyl methyl(piperidin-3-yl)carbamate (384 mg, 1.79 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg, 0.597 mmol, Example 1, Step I) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness. The residue was then purified by chromatography (Biotage SP4, C-18 25M+ column, 10-90% CH3CN/water gradient, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate as a solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[C:12]1([CH3:33])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([NH:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.O>C1COCC1>[C:12]1([CH3:33])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:19]=[C:20]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]([OH:30])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:31][CH:32]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccccc1-c1cccc(Nc2ccc(C=O)cc2)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCC(O)c1ccc(Nc2cccc(-c3ccccc3C)c2)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (28.5 mL of a 2.5 M hexane solution, 71.3 mmol) was added dropwise to a slurry of 2,5-bis(triphenylmethylenephosphonium)-1,4-dimethoxybenzene (26.8 g, 35.2 mmol) in dry THF (450 mL) at −78° C.; the reaction mixture immediately became very dark. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 2 h before recooling to −78° C. and adding a solution 4-(m-tolylphenylamino)benzaldehyde (21.2 g, 73.8 mmol) in dry tetrahydrofuran (100 mL) dropwise. The reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 2 h before cautiously adding water (300 mL). The mixture was extracted with diethyl ether until the extracts were almost colorless and the combined ether layers were dried on magnesium sulfate. After filtration silica gel was added and the solvent removed under reduced pressure leaving the product absorbed onto the silica. The crude product was transferred to the top of a silica gel column which was eluted with toluene. The first fraction was found to be an approximately statistical mixture of the geometric isomers of 3,5-bis[4-(m-tolylphenylamino)styryl]-1,4-dimethoxybenzene. Further elution gave a trace of an unidentified material, possibly impure 1-[4-(m-tolylphenylamino)phenyl]-pentan-1-ol on the basis of its 1H NMR spectrum, and then 4-(m-tolylphenylamino)benzaldehyde. The mixed isomers were dissolved in toluene (1 L) and heated under nitrogen with a few crystals of iodine. After 48 h, the solution was passed through a silica plug. The solvent was removed under reduced pressure and the solids were recrystallized from hot toluene to afford the pure E,E isomer as a bright yellow powder (12.82 g, 18.2 mmol, 52%). 1H NMR (CD2Cl2) δ 7.43 (d, J=8.6 Hz, 4H), 7.36 (d, J=16.5 Hz, 2H), 7.27 (t, J=ca. 8 Hz, 4H), 7.19-7.00 (m, ca. 16H), 6.94 (br s, 2H), 6.91-6. (br m, 4H) 3.91 (s, 6H), 2.27 (s, 6H); 13C NMR (75 MHz, CD2Cl2) δ 151.7, 148.0, 147.8, 147.7, 139.6, 132.2, 129.5, 129.4, 128.5, 127.6, 126.7, 125.7, 124.7, 124.4, 123.7, 123.2, 122.2, 121.6, 109.0, 56.6, 21.5; UV (THF) λmax 305 (ε305 37000), 426 (ε426 84000) nm; m.p 254° C.; High resolution EIMS calcd. for C50H44N2O2 M+ 704.3403. found 704.3404. Anal. calcd for C50H44N2O2: C, 85.20; H, 6.29; N, 3.97. Found: C, 85.44; H, 6.40; N, 3.86.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:33][N:32]=[N:31][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 96 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxymethylbenzimidazole (0.4 g), sodium azide (0.98 g) and ammonium chloride (0.8 g) in DMF (4 ml) was stirred for 4 days at 110-120° C. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried. After removal of the solvent, the residue was crystallized from ethyl acetate-methanol to give colorless needles, m.p. 152-153° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.Cl[C:45](OC(C)=C)=[O:46].[NH:51]1[CH2:56][CH2:55][S:54](=[O:58])(=[O:57])[CH2:53][CH2:52]1>C1COCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:45]([N:51]3[CH2:56][CH2:55][S:54](=[O:58])(=[O:57])[CH2:53][CH2:52]3)=[O:46])=[CH:35][CH:36]=2)=[N:4]1)[CH3:2]
Reactant: C=C(C)OC(=O)Cl
Reactant: O=S1(=O)CCNCC1
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)N3CCS(=O)(=O)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)aniline (0.25 mmol) in anhydrous THF (2 mL) cooled to 5° C., was added triethylamine (4 mmol) and isopropenyl chloroformate (0.5 mmol). The reaction mixture was stirred overnight at room temperature. Thiomorpholine 1,1-dioxide (2.5 mmol) was added and the reaction heated at 50° C. for three days. The crude reaction was purified by reverse phase chromatography to give the title product (30%). ESMS [M+H]+: 640.0.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]1([C:20]2[C:29]([CH3:30])=[CH:28][C:27]3[C:22](=[C:23]([C@H:31]([OH:34])[CH2:32][OH:33])[CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[C:14]1([C:20]2[C:29]([CH3:30])=[CH:28][C:27]3[C:22](=[C:23]([C@H:31]([OH:34])[CH2:32][O:33][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc2cccc([C@H](O)CO)c2nc1-c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cccc([C@H](O)CO[Si](C)(C)C(C)(C)C)c2nc1-c1ccccc1
Reaction time: 16 h
Yield: 92 %

Procedure:
3.7 g (24.3 mmol) of tert-butyldimethylsilyl chloride and 3.4 g of (50 mmol) of imidazole are added at ambient temperature to a solution of 6.5 g (23.2 mmol) of 2-phenyl-3-methyl-8-(1-(S),2-dihydroxyethyl)-quinoline in 200 ml of dimethylformamide. The reaction medium is stirred for 16 hours. After addition of 200 ml of distilled water, the reaction mixture is extracted with 3×200 ml of ethyl acetate. The organic phases are combined, washed with 300 ml of distilled water, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane to provide 8.4 g of 2-phenyl-3-methyl-8-(1-(S)-hydroxy-2-[tert-butyldimethylsilyloxy]ethyl)quinoline in the form of a colorless oil. (Yield: 85%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=2[CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][CH2:18][C:19]=3[CH:24]=2)[CH:8]=1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 2,3-dihydro-benzofuran-5-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 4H), 7.07 (m, 2H), 6.73 (d, 1H), 4.54 (t, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.66 (s, 3H), 3.18 (t, 2H), 2.94 (t, 2H), 2.63 (t, 2H); MS 326 (M+1). Step B: Amide Formation
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([O:4][CH:1]([OH:5])[C:2]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: O=CC(=O)O
Reactant: CCCCO
Solvent: O
Product: CCCCOC(=O)C(O)OCCCC
Temperature: 82.5 °C

Procedure:
In a suitable reactor flask equipped with stirrer, heating mantle, Dean Stark trap, condenser, nitrogen inlet, vacuum take off and dropping funnel were added 1980 grams (13.0 moles) of 50% glyoxylic acid in water and 1215 grams (16.4 moles) of n-butanol. The contents of the flask were heated to 80-85° C. under nitrogen sparge and vacuum to remove approximately 760 grams of an n-butanol/water azeotrope. Thereafter, an additional 1210 grams of n-butanol were added and strip distillation continued until no water was seen in the azeotrope. An additioral 810 grams of n-butanol were then added and the mixture refluxed for two hours at 80-85° C. under vacuum, followed by vacuum stripping of excess n-butanol. Product weight was 2850 grams.
Reaction SMILES: O.C(OC([NH:9][C@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([C:42]([NH2:44])=[O:43])[CH3:41])=[O:38])[CH2:33][C:34](=[O:36])[OH:35])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O)(C)(C)C.C(O)(=O)C.SCCO.[ClH:53]>O1CCOCC1>[ClH:53].[NH2:9][C@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([C:42]([NH2:44])=[O:43])[CH3:41])=[O:38])[CH2:33][C:34](=[O:35])[OH:36])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Agent: OCCS
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Reaction time: 0.08 h

Procedure:
to a solution of N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine amide hydrate in 11.6 parts by volume glacial acetic acid and 0.12 part by volume 2-mercaptoethanol is added 5.8 parts by volume of a 6.04 M solution of hydrochloric acid in dioxane. After stirring for approximately five minutes, the solvent is removed under reduced pressure. The residue is triturated with ethyl ether, filtered and vacuum-dried to afford L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine amide hydrochloride. This compound is represented by the following formula.
Reaction SMILES: [OH:1][CH:2]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23](Br)([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.ClCCl.[Ag-]=O>[C:23]([O:1][CH:2]([C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(O)c1cc2ccccc2n1-c1ccccc1
Reactant: CC(C)(C)Br
Agent: O=[Ag-]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1cc2ccccc2n1-c1ccccc1
Reaction time: 24 h
Yield: 33.5 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(1-phenyl-1H-indol-2-yl)acetate (5b) (50 mg, 0.17 mmol), silver (I) oxide (130 mg, 0.56 mmol) and tertbutylbromide (114 μL, 1.02 mmol) in cyclohexane (4 mL) and dichloromethane (2 mL) was vigorously stirred for 24 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired ether oxide (5c) as a white solid (20 mg, 0.057 mmol, 33%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([NH2:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH3:13][CH:14]([NH:21][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CCCCCCC(C)N
Product: CCCCCCC(C)NC(=O)CCCc1ccccc1

Procedure:
4-Phenylbutyryl chloride was reacted with 1-methylheptylamine to provide N-(1-methylheptyl)-4-phenylbutyramide, which, when reduced by reaction with diborane in tetrahydrofuran, provided N-(1-methylheptyl)-4-phenylbutylamine. The amine so formed was reacted with formic acid and formaldehyde to give N-methyl-N-(1-methylheptyl)-4-phenylbutylamine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].FOBOF.Br.Br.[CH2:32]([N:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH2:41][NH:42]2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CS(C)=O>[F:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:42]1[CH2:41][CH:40]3[CH2:45][CH:43]1[CH2:44][N:39]3[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[N:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])[CH:8]=[C:7]([C:20]([OH:22])=[O:21])[C:6]2=[O:23]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Agent: Br
Agent: FOBOF
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CC4CC3CN4Cc3ccccc3)c(F)cc2c1=O
Yield: 39 %

Procedure:
Analogous to example 6 but utilizing 5.56 g (13.85 m Mol) of the mixed anhydride of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)1,4-dihydro-4-oxoquinoline-3-carboxylic acid and difluoroboronic acid, 5.82 g (16.62 m Mol) 2-benzyl-2,5-diazabicyclo(2.2.1)heptane dihydrobromide and 11.58 ml (83 m Mol)triethylamine in 50 ml dry DMSO yielded 2.73 g (39%) of the product, mp 233° C.-238° C. dec.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(NC(C)C)(C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)#[CH:18]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]#[C:17][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(I)n1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
4-Iodo-2-(methylthio)pyrimidine (39.7 g, 0.157 mol) and diisopropylamine (44.2 mL, 0.315 mol) are dissolved in dry THF (720 mL) and argon gas is bubbled through the solution for 20 min. Copper(I) iodide (2.99 g, 14.3 mmol) and bis(triphenylphosphine)palladium dichloride (5.51 g, 7.85 mmol) are added and then 1-ethynyl-3-nitrobenzene (25.4 g, 0.173 mol) in dry THF (100 mL) is added dropwise over about 30 min with the temperature being maintained at about 25° C. Following complete addition, the mixture is stirred at rt for overnight. The mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure. The residue is washed with EtOAc/MeOH to give pale-yellow solid (42 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:48]([Cl:50])[Cl:49]>C(O)(=O)C>[NH3:1].[CH2:48]([Cl:50])[Cl:49].[C:19]1([C:25]2([OH:31])[CH2:30][CH2:29][N:28]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:27][CH2:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N
Product: OC1(c2ccccc2)CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (210 mg), 4-Phenyl-piperidin-4-ol (150 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (225 mg). 1H NMR (400 MHz, CDCl3): 7.54–7.49 (m, 2H), 7.37–7.33 (m, 2H), 7.28–7.23 (m, 3H), 6.88–6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.51 (s, 2H), 2.78 (m, 2H), 2.50–2.36 (m, 8H), 2.15 (m, 2H), 1.97 (m, 2H), 1.73 (m, 2H), 1.63–1.55 (m, 4H), 1.47–1.40 (m, 2H).