Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:16]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]>O1CCOCC1.C1(C)C=CC=CC=1>[ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2=CCNCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Hydrogen chloride (20 mL of a 4N solution in dioxane) was added dropwise to a solution of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g; 9.86 mmol; 1.0 eq.) in toluene (15 mL). The reaction mixture was stirred at RT for 3 h. The formed suspension was filtered, washed with toluene (10 mL) and dried under vacuum to give the title compound as a white solid (1.96 g, 97%). UPLC/MS: (MS+) 205.3.
Reaction SMILES: CS/[C:3](/[NH:12][C:13](=O)OC(C)(C)C)=[N:4]\[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27]([NH2:32])C(N)=[CH:29][CH:30]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:22]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:13]2[N:12]=[C:3]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[NH:32][C:27]=2[CH:26]=1
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Reactant: CS/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Yield: 67.8 %

Procedure:
add 615 mg of bis(1,1-dimethylethyl) [(Z)-(methylsulphanyl)methylylidene]biscarbamate to a solution of 600 mg of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in a mixture of 30 cm3 of methanol and 127 mg of pure acetic acid. The mixture is refluxed for about 3 hours then concentrated under reduced pressure (0.2 kPa). The residue is taken up in 20 cm3 of a saturated aqueous solution of potassium carbonate and the mixture is extracted three times with 100 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, then filtered and evaporated under reduced pressure. After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (98/2 by volume)], we obtain 586 mg of 1,1-dimethylethyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate in the form of an orange resin, which has the following characteristics:
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CN.C[CH2:27][N:28](C(C)C)C(C)C>CS(C)=O.C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([NH:28][CH3:27])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Agent: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reaction time: 72 h

Procedure:
A suspension of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (12.0 g, 32 mmol) in DMSO (48 mL) was treated with methyl amine (48 mL of a 2M solution in THF, 96 mmol) and Hunig's base (11.1 mL, 86 mmol). The vessel was purged with argon, sealed and stirred at 135C for 3 days. The reaction was cooled, quenched with water (280 mL) and the pH adjusted to 5 by the addition of acetic acid. The reaction was stirred at room temperature for 1 hr and filtered. The solids were washed with water (100 mL) and then EtOAc (50 mL), and dried in vacuo to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:23](=[O:37])[C@@H:24]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:23](=[O:37])[C@@H:24]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: c1ccc(COCn2ccnc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1nccn1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg, 3.75 mmol) in THF (4 mL) at −78° C. under N2, was added n-Butyllithium (2.3 mL of a 1.6 M solution in hexanes). The mixture was stirred at −78° C. for 30 min. To a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200 mg, 0.75 mmol) in THF (2 mL) under N2 at −15° C., was added isopropylmagnesium chloride (375 μL of a 2.0 M solution in THF). The resulting mixture was stirred at −15° C. for 15 min. This mixture was then added, by cannula to the solution above at −78° C. The mixture stirred at −78° C. for about 3 h, then warmed up gradually to room temperature and stirred overnight. The mixture was quenched with saturated NH4Cl. The aqueous layer was extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamate contaminated with about 30% of the unreacted starting material benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. The mixture was carried forward to the next step without further purification. LCMS calc.=394.18; found=394.2 (M+1)+.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])CC2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)CCN(CCCCc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CCNCCCCc1ccccc1

Procedure:
27.13 g (0.085 mol) of this hydrochloride are hydrogenated in 300 ml of ethanol over 3 g of 5% palladium-on-charcoal catalyst at 20°-25° under normal pressure until the uptake of hydrogen has ended. The catalyst is filtered off with suction, the filtrate is evaporated and the residue is crystallized from acetone. 3-[N-(4-Phenylbutyl)-amino]-propionic acid hydrochloride is obtained, melting point 135°-137°.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Li+].[C:5]([O:9][C:10]([NH:12][C@H:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=1)[C:14](OC)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>C(O)C.O1CCCC1>[OH:15][CH2:14][C@H:13]([NH:12][C:10](=[O:11])[O:9][C:5]([CH3:6])([CH3:8])[CH3:7])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=1
Reactant: CCCC(C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
To a suspension of sodium borohydride (1.346 g, 35.6 mmol) in ethanol (50 mL) at 0° C. was added lithium chloride (1.508 g, 35.6 mmol). The mixture was stirred at 0° C. for 10 min. A solution of (2R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)acetate (5.00 g, 13.68 mmol) in tetrahydrofuran (50.0 mL) was then added via cannula. The reaction mixture was warmed up to room temperature and was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and was quenched by the slow addition of saturated aqueous NH4Cl solution (30 mL). The reaction mixture was transferred to a separatory funnel containing water (50 mL). The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30%→45% ethyl acetate in hexanes) to afford t-butyl (1R)-2-hydroxy-1-(4-(2-methylpentyloxy)phenyl)ethylcarbamate (4.24 g, 92% yield) as a colorless solid: 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 4.72 (t, J=5.8 Hz, 1H), 4.44 (q, J=6.8 Hz, 1H), 3.79 (dd, J=9.3, 5.8 Hz, 1H), 3.70 (dd, J=9.3, 6.5 Hz, 1H), 3.37-3.49 (m, 2H), 1.80-1.92 (m, 1H), 1.36 (s, 9H), 1.23-1.47 (m, 3H), 1.13-1.21 (m, 1 H), 0.95 (d, J=6.5 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 338.2 [(M+H)+, calcd for C19H32NO4 338.2].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][C:12]3([CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[O:11][CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.ClCCl.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][C:12]3([CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[O:11][CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCC3(CC2)CN(c2cccc(F)c2)C(=O)CO3)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1COC2(CCN(c3ccc(O)cc3)CC2)CN1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The methoxy compound (205 mg, 0.553 mmol) obtained in (a) was dissolved in chloroform, and at 0° C., 1.0 M boron tribromide/dichloromethane solution (2.2 ml, 2.2 mmol) was dropwise added thereto, and this was stirred overnight at room temperature. At 0° C., the reaction solution was neutralized by adding aqueous 2 N sodium hydroxide solution thereto, and extracted with chloroform, and the organic layer was washed with saturated saline. The organic layer was dried with sodium sulfate, and the solvent was evaporated off under reduced pressure to obtain the phenol compound as a crude product (165 mg, 84%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[Na+].[I-:24].CN[C@@H]1CCCC[C@H]1NC.O1CCOCC1>N.[Cu]I.O>[I:24][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Brc1cccc(-c2nnc(-c3ccc4ccccc4c3)o2)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: Ic1cccc(-c2nnc(-c3ccc4ccccc4c3)o2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 2-(3-bromophenyl)-5-(2-naphthyl)-1,3,4-oxadiazole (352 mg, 1.00 mmol), NaI (300 mg, 2.00 mmol), briefly evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The resulting light green-gray suspension was allowed to reach room temperature, diluted with 30% aq ammonia (5 mL), poured into water (20 mL), and extracted with dichloromethane (3×15 mL). The combined organic phases were dried (Na2SO4), concentrated to ca. 2 mL volume. The product was allowed to crystallize at room temperature. After 15 min, hexane (20 mL) was added, the mixture was kept at room temperature for 15 h, and finally filtered to provide 382 mg (96% yield) of 2-(3-iodophenyl)-5-(2-naphthyl)-1,3,4-oxadiazole as white, fine needles. Mp: 156-158° C. 1H NMR (400 MHz, CDC13): δ 8.64 (s, I H), 8.53 (t, J=1.8 Hz, 1H), 8.22 (dd, J=8.6, 1.8 Hz, 1H), 8.18 (dt, J=7.9, 1.2 Hz, 1H), 8.03-7.93 (m, 2H), 7.95-7.88 (m, 2H), 7.65-7.53 (m, 2H), 7.30 (t, J=7.9 Hz, 1H). 13C NMR (100 MHz, CDC13): δ 165.1, 163.2, 140.6, 135.5, 134.8, 132.8, 130.7, 129.1, 128.9, 128.1, 128.0, 127.5, 127.2, 126.1, 125.8, 123.2, 120.8, 94.4. IR (neat, cm−1): 1558, 1540, 753, 731. Anal. Calcd. for C18H11IN20: C, 54.29; H, 2.78. Found: C, 54.29; H, 2.74.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:25][CH:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:35]([CH2:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH:54]([CH3:59])[CH2:53]1)=[C:34]2[C:60]([NH:62][C@H:63]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:64]([F:67])([F:66])[F:65])=[O:61])(=[O:30])=[O:29])[CH3:27]>ClCCl.O>[CH3:27][CH:26]([S:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)[C:35]([CH2:51][N:52]1[CH2:57][CH2:56][CH:55]([N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:54]([CH3:59])[CH2:53]1)=[C:34]2[C:60]([NH:62][C@H:63]([C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)[C:64]([F:67])([F:65])[F:66])=[O:61])(=[O:29])=[O:30])[CH3:25]
Reactant: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CCC1=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CCC1N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
Acetic acid (9.73 μL, 0.170 mmol), morpholine (0.030 g, 0.340 mmol), and sodium triacetoxyborohydride (0.048 g, 0.227 mmol) were added to a suspension of 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.080 g, 0.113 mmol) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 3 d. The solution was diluted with water (3 mL) and methylene chloride (5 mL) and poured into a hydrophobic frit to separate the phases. The organic phase was concentrated and the residue was purified via HPLC (Waters, Sunfire C18, 30×100 mm, 35-69% CH3CN/H2O with 0.1% TFA) to afford 6-[(1-methylethyl)sulfonyl]-3-{[3-methyl-4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.040 g, 45% yield) as a mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) δ10.1250=4 Hz, 0.5H), 10.045 (br d, J=4 Hz, 0.5H), 8.38 (m, 2H), 8.14 (m, 2H), 7.97 (m, 2 H), 7.84 (d, J=8 Hz, 1H), 7.73 (m, 1H), 7.63 (m, 2H), 7.45 (br s, 2H), 6.24 (apparent q, J=6.8 Hz, 1H), 3.50 (m, 4H), 3.17 (m, 1H), 2.40-2.05 (m, 5H), 1.95-0.75 (m, 14H), 0.410 (d, J=6 Hz, 1.7H), 0.295 (br d, J=4 Hz, 1.3H). MS (m/z) 777.3 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-])=O.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC#N>[N:23]1([CH2:22][CH2:21][N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([NH2:7])[CH:18]=3)[CH:14]=[CH:15]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2ccn(CCN3CCOCC3)c2c1
Temperature: 25 °C

Procedure:
K2CO3 (5.08 g, 36.726 mmol) was added to a slurry of 6-nitroindole (1.985 g, 12.242 mmol), 4-(2-chloroethyl) morpholine HCl (2.278 g, 12.242 mmol), and CH3CN (100 ml). The mix was heated to reflux for 18 h, then cooled to RT, filtered, and concentrated in vacuo. The crude was eluted through a silica gel column with a gradient of 3:97 to 5:95 and finally 8:92 MeOH/CH2Cl2, to yield upon drying the desired intermediate which was hydrogenated under conditions previously described.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:75])([F:74])[C:23]1[CH:24]=[C:25]([CH:67]=[C:68]([C:70]([F:73])([F:72])[F:71])[CH:69]=1)[C:26]([N:28]1[CH2:32][C@@:31]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][C:45]3([C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[CH2:49][C@@H:48]3[O:56][CH2:57][C:58]([N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][NH:64][CH3:65])=[O:59])[CH2:44][CH2:43]2)([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[O:30][CH2:29]1)=[O:27]>>[F:73][C:70]([F:71])([F:72])[C:68]1[CH:67]=[C:25]([CH:24]=[C:23]([C:22]([F:21])([F:75])[F:74])[CH:69]=1)[C:26]([N:28]1[CH2:32][C@@:31]([CH2:40][CH2:41][N:42]2[CH2:43][CH2:44][C:45]3([C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[CH2:49][C@@H:48]3[O:56][CH2:57][C:58]([N:60]([CH3:66])[CH2:61][CH2:62][CH2:63][N:64]([CH3:65])[C:15]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]([CH3:20])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:19][CH:18]=3)=[O:17])=[O:59])[CH2:46][CH2:47]2)([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[O:30][CH2:29]1)=[O:27]
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CN(CCc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Product: CN(CCCN(C)C(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Yield: 61.4 %

Procedure:
The compound (140 mg, 0.501 mmol) obtained in Example 50a and the compound (260 mg, 334 mol) obtained in Example 1k were used to give the title compound (320 mg; yield, 92%) as a white solid according to the method described in Example 41a.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>O1CCOCC1.Cl.CN(C)CC(O)=O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1ccc(I)cc1
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(Oc2ccc(C)cc2)cc1
Yield: 177.4 %

Procedure:
Following the general procedure for Example 11 (step 1), N,N-dimethylglycine hydrochloride (0.03 g, 0.22 mmol), cesium carbonate (1.59 g, 4.88 mmol) and Cu(I) iodide (0.02 g, 0.09 mmol) were added to a solution of 4-iodotoluene (0.8 g, 3.67 mmol) and 4-methoxyphenol (0.3 g, 2.42 mmol) in dioxane (10 mL) to afford the title compound (0.92 g, 100%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]2[CH:16](OCC)[O:17]CC)=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)C1CC(C)(C)CCC1(O)c1ccc(Cl)cc1
Agent: Cl
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 1-(4-chlorophenyl)-2-(diethoxymethyl)-4,4-dimethylcyclohexanol and aqueous hydrochloric acid at about 50° C. to 80° C. to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[S:23]>C(O)C.C(OCC)(=O)C>[C:21]([C:22]1[S:23][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:24]=1)([CH3:26])([CH3:25])[CH3:20]
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CC(C)(C)C(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2sc(C(C)(C)C)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (Example 1, Step 3) (0.196 g, 0.578 mmol) in ethanol (6 mL) in a 25 mL round bottom flask was added 2,2-dimethylthiopropionamide from Step 1 (0.071 g, 0.606 mmol) and the mixture heated to reflux overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and this solution washed successively with Na2CO3 (10% solution) and brine, dried over Na2SO4, filtered and concentrated in vacuo yielding 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole as a pale yellow oil (0.162 g, 78%): 1H NMR (CDCl3) 300 mHz δ7.56-7.51 (m, 2H), 7.24 (d, J=8.48 Hz, 2H), 7.20 (d, J=8.48 Hz, 2H), 6.98 (t, J=8.85 Hz, 2H), 2.49 (s, 3H), 1.52 (s, 9H). MS (EI): m/e 357 (M+). HRMS Δ=0.1 mmu.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.Br[C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)(Br)C(N)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(C)(C)C(N)=O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 530 was alkylated by 2-bromo-2-methyl-propionamide to give 531. LCMS m/z: 259.7 (2M+H+)
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[NH:15][C:16]2[N:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)C)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:9][NH:11][CH2:13][C:14]1[NH:15][C:16]2[N:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: CN(Cc1nc2cccnc2[nH]1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCc1nc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.4 %

Procedure:
2-[[N-(Benzyloxycarbonyl)-N-methylamino]methyl]4-azabenzimidazole (385.5 mg, 1.30 mmol) was dissolved in MeOH, and 10% Pd/C was added. The mixture was stirred at RT under H2 (balloon pressure) for 4 h, then the catalyst was removed by filtration through a bed of Celite®. The clear, colorless filtrate was evaporated under vacuum to afford the title compound (237.0 mg, 100%): 1H NMR (250 MHz, CDCl3 /CD3OD) δ 2.48 (s, 3H), 4.06 (s, 2H), 5.38 (br s, 1H), 7.15-8.35 (m, 4H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:30][C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)(=[O:21])=[O:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=480.1 (M+H)+