Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:6]=1[NH:15]C(=O)CCC.[CH3:23][C:24]([O-:27])([CH3:26])[CH3:25].[K+].O>CN(C=O)C>[C:24]([O:27][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[C:3]([C:2]([CH3:1])([CH3:21])[CH3:22])[NH:15]2)=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])([CH3:26])([CH3:25])[CH3:23]
Reactant: CCCC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C#CC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Oc1cc2[nH]c(C(C)(C)C)cc2cc1[N+](=O)[O-]
Yield: 21.1 %

Procedure:
A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (500 mg, 1.63 mmol) and t-BuOK (0.37 g, 3.26 mmol) in DMF (10 mL) was heated at 70° C. for 2 h. The mixture was poured into water and then extracted with EtOAc (50 mL×3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give 6-tert-butoxy-2-tert-butyl-5-nitro-1H-indole (100 mg, 21%). 1H-NMR (300 MHz, DMSO-d6) δ 11.35 (brs, 1H), 7.99 (s, 1H), 7.08 (s, 1H), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([Li])CCC.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>CCCCCC>[C:12]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCC(=O)N1CCOC1=O

Procedure:
Following the cyclization reaction, the formed oxazolidinone is N-acylated to form the nucleophilic precursor of the molecule. The oxazolidinone is reacted with butyllithium in hexane, to form the conjugate base and then reacted with an acyl halide such as propionyl chloride at -71° C., for 0.5-1 hour to yield the N-propionyloxazolidinone.
Reaction SMILES: Cl.C([O:5][C:6]1[C:7]([CH3:14])=[N:8][CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)(=O)C.Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.N1C=CC=CC=1>[OH:5][C:6]1[C:7]([CH3:14])=[N:8][CH:9]=[C:10]([CH2:12][O:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:11]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(=O)Oc1cc(CO)cnc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ncc(COC(=O)c2ccncc2)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.4 g. of 3-acetoxy-5-hydroxymethyl-2-methylpyridine hydrochloride in 20 ml. of pyridine was added a solution of 2.0 g. of isonicotinoyl chloride hydrochloride in 15 ml. of dimethylformamide under cooling and the resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-water and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give an oily substance. The substance was taken into 25 ml. of 2N HCl and the resulting mixture was stirred at 80°C. for 30 minutes. The mixture was neutralized with sodium bicarbonate, filtered and recrystallized from methanol to give 0.9 g. of the desired product. m. p. 180° - 180.5°C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:28]([N:25]1[CH2:24][CH2:23][N:22]([C:20]([N:11]2[CH2:12][CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([NH:7][CH3:6])[CH2:10]2)=[O:21])[CH2:27][CH2:26]1)(=[O:30])=[O:29]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (640 mg, 1.37 mmol) in CH2Cl2 (10 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 500 mg (99%) of the title product as a white solid. ES-MS m/e: 367.1 (M+H+).
Reaction SMILES: [C@H:1]1([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O.[O-:23][Mn](=O)(=O)=O.[K+]>CC(C)=O>[O:23]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CC[C@@H](N2C(=O)c3ccccc3C2=O)c2ccccc21
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a solution of (R)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)isoindoline-1,3-dione (3.9 g) in acetone (60 mL) at 0° C. was added MgSO4.7H2O (11.5 g) and water (20 mL). Then KMnO4 (11.5 g) was added portionwise over the period of 2 h and stirring continued at room temperature overnight. The brown solid was filtered off and the filtrate treated with saturated sodium metabisulfite, filtered, and extracted with CH2Cl2. The combined organic layer was washed with distilled water and saturated brine, dried over MgSO4, and concentrated in vacuo. The resultant was chromatographed on silica gel (EtOAc/hexane, 25/75) to afford 0.14 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 0 °C
Yield: 89 %

Procedure:
To a solution of 4-bromo-3-hydroxybenzoic acid (30 mmol) in methanol (100 mL) was added concentrated sulfuric acid (2.6 mL). The solution was heated at reflux for 5 hours, cooled to 0° C., and brought to pH 7 by adding saturated. aqueous sodium carbonate. The solution was evaporated to one-third the original volume. Water was added and the product was extracted into ethyl acetate. The organic extracts were washed with water and brine, and dried over anhydrous sodium sulfate. Evaporation gave 6.15 g (89%) of the title compound as a white solid. This was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2([C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:3]=1
Reactant: NC1=NC(c2cncnc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2cc(C3(c4cncnc4)N=C(N)c4c(F)cccc43)ccc2F)c1F
Yield: 18 %

Procedure:
The title compound was synthesized as described for Example 12 in 18% yield, starting from 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyrimidin-5-yl)-1H-isoindol-3-amine (59.6 mg, 0.15 mmol) and 2-fluoro-3-methoxybenzeneboronic acid (59.5 mg, 0.35 mmol); 1H NMR (500 MHz, DMSO-d6)6 ppm 9.08 (s, 1 H) 8.74 (s, 2 H) 7.81 (d, 1 H) 7.53-7.60 (m, 1 H) 7.42-7.49 (m, 1 H) 7.37 (dd, 1 H) 7.25-7.33 (m, 2 H) 7.18-7.25 (m, 2 H) 6.87-6.93 (m, 1 H) 6.77 (br. s., 2 H) 3.85 (s, 3 H). MS (ES−) m/z 445 [M−H]−
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:22](OC)(OC)(OC)[CH2:23][CH2:24][CH3:25]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:23]([C:22]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:24][CH3:25]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Reaction time: 3 h
Yield: 90.2 %

Procedure:
The method described in Part A of Example 10 was used to treat ethyl 5-(3-aminoquinolin-4-ylamino)pentanoate (26.3 g, 91.5 mmol) with trimethyl orthobutyrate (18.3 mL, 114 mmol) and pyridinium p-toluenesulfonate (0.5 g). The reaction was complete in three hours to provide 28 g of ethyl 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate as a brown oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH:10]([NH:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)(=O)[CH3:2].C([OH:32])C.OO.[OH-].[Na+]>O>[CH3:2][C:1]1[NH:15][C:14](=[O:32])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:28][CH:29]=4)[C:11]=3[CH:12]=2)[N:4]=1
Reactant: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 8 (1.33 g, 3.40 mmol), ethanol (15 ml), and water (3.1 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (2.8 ml) was added followed by granulated sodium hydroxide pellets (0.230 g, 5.78 mmol). The reaction mixture was stirred at ˜0° C. for 10 min, then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 40 min. The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜40 ml). The pH of this mixture was adjusted to ˜5 with 1N hydrochloric acid. The white precipitate was collected by filtration, washed with water, dried in vacuo over P2O5, then it was triturated with ether, collected by filtration and dried in vacuo. The title compound 9 was obtained as a white solid 1.11 g (83%), m.p. 277-281° C. (it melts with decomposition), (Found: C, 70.22; H, 6.43; N, 10.65; C23H25N3O3 requires C, 70.57; H, 6.44; N, 10.73%); δH ((CD3)2SO) 1.50 (9H, s, C(CH3)3), 2.31 (3H, s, Me), 1.87, 2.55 (each 1H, m, 7-H), 2.97 (2H, m, 8-H), 5.15 (1H, q, J 7.50, 6-H), 6.77 (2H, d, J 8.6, 3′,5′-H), 6.91 (1H, d, J 8.70, N10—H), 7.44, 7.87 (each 1H, s, 5-H, 9-H), 7.66 (2H, d, J 8.75, 2′,6′-H); m/z ESI) 783 {(2M+H)+, 100%}, 392 {(N+H)+, 30%}, 199 (90).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22](Br)[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:31][OH:32].C[O-].[Na+]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:32][CH3:31])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([Cl:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nn2cc(-c3cc4c(OCc5ccccc5)cc(Cl)cc4o3)nc2s1
Yield: 81.5 %

Procedure:
To a stirred solution of 6-(4-(benzyloxy)-6-chlorobenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Example 37G, 1.18 g, 2.56 mmol) in DCM (40 mL, 622 mmol) and methanol (10 mL, 247 mmol) was added sodium methoxide (1.164 mL, 5.12 mmol). The reaction mixture was stirred at r.t. for 1 h 15 min while monitoring by TLC (7:3 hexanes:EtOAc). The reaction mixture was quenched with 1N HCl and extracted with DCM. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with MeOH (sonication) and the solid material was filtered off, rinsed with MeOH and sucked dry to give the desired compound as a brown solid (859 mg, 2.086 mmol, 81% yield). LC (Method A): 2.478 min. LCMS (APCI) calcd for C20H15ClN3O3S [M+H]+ m/z 412.05. found 412.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.50 (s, 1H), 7.52 (m, 2H), 7.43 (m, 2H), 7.36 (m, 2H), 7.09 (d, J=0.8 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 5.31 (s, 2H), 4.21 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH:28]([C@@H:31]1[C:35]([CH3:37])([CH3:36])[O:34][C:33](=[O:38])[NH:32]1)([CH3:30])[CH3:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:32]3[C@H:31]([CH:28]([CH3:29])[CH3:30])[C:35]([CH3:36])([CH3:37])[O:34][C:33]3=[O:38])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC(C)[C@H]1NC(=O)OC1(C)C
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC(C)(C)[C@H]4C(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 42.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (722 mg) described in Preparation Example 9 and (R)-(+)-4-isopropyl-5,5-dimethyloxazolidin-2-one (250 mg), the title compound (359 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.C1COCC1>C(Cl)Cl>[Br:26][C:17]1[CH:16]=[N:15][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(-n3cccn3)cc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(-n3cc(Br)cn3)cc2)cc1
Yield: 87.1 %

Procedure:
Prepared from INT-85: To a stirring solution of 1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole (309 mg, 1.319 mmol) INT-85 in DCM (4 mL) was added NBS (258 mg, 1.45 mmol). After stirring at room temperature for 1 h additional THF (4 mL) was added and stirring continued. After 18 h the reaction mixture was concentrated in vacuo and slurried in MeCN (4 mL). The solid was collected by filtration and washed with MeCN (2×2 mL) to provide 360 mg (87%) of 4-bromo-1-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-pyrazole INT-86. LCMS-ESI (m/z) calculated for C16H13BrN2: 312; found 313 [M+H]+, tR=3.07 min (Method 5).
Reaction SMILES: [OH:1][C:2]1[C:28]([O:29][CH3:30])=[CH:27][C:5]2[NH:6][C:7](=[O:26])[C:8]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=4)=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH3:30][O:29][C:28]1[C:2]([O:1][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:3][C:4]2[NH:10][C:9]3[CH:11]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=4)[CH:13]=[CH:14][C:8]=3[C:7](=[O:26])[NH:6][C:5]=2[CH:27]=1
Reactant: COc1cc2c(cc1O)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCC1CCCCO1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of Example 476I (40 mg, 0.098 mmol), 2-bromomethyl-tetrahydro-2H-pyran (0.13 mL, 0.98 mmol), K2CO3 (136 mg, 0.98 mmol) and DMF (2 mL) was heated at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel with 49:1 dichloromethane/methanol to provide 23 mg (47%) of the desired product. MS (ESI) m/e 506 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.66 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.35 (dd, J=1.7, 8.5 Hz, 1H), 7.26-7.31 (m, 2H), 6.69 (s, 1H), 6.64 (s, 1H), 4.03 (s, 3H), 3.72-3.94 (m, 3H), 3.67 (s, 3H), 3.60 (m, 1H), 3.39 (m, 1H), 1.82 (m, 1H), 1.64 (m, 1H), 1.41-1.55 (m, 3H), 1.27 (m, 1H).
Reaction SMILES: C([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:19]([C:30]([OH:32])=[O:31])[NH2:18])=[CH:22][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)c1ccc(C[C@H](N)C(=O)O)cc1
Yield: 88 %

Procedure:
Fmoc-p-acetyl-L-phenylalanine was purchased from RSP Amino Acid Analogues, Inc. (Worcester, Mass.). This compound (1.0 g, 2.3 mmol) was stirred with 4 mL of piperidine (20% in dimethyl formamide (DMF)) for 2 hours at room temperature. The solvent was evaporated to obtain white powder. The solid was then resuspended in 10 mL of cold water (0.1% trifluoroacetic acid (TFA)), and the supernatant was collected by filtration. Preparative reverse-phase HPLC (Microsorb C18, Rainin Instrument Co., Inc., Woburn, Mass.) was used to separate the desired product from the reaction mixture (5–30% CH3CN in H2O with 0.1% TFA over 30 min). The eluant (tR=12 min) was lyophilized to obtain a white solid (0.45 g, 88%). 1H NMR (400 MHz D2O): δ 7.85–7.28 (m, 4H), 4.23 (dd, 1H, 5.4 Hz), 3.2 (m, 2H), 2.7 (s, 3H). MS electrospray ionization (ESI): [M+1]+ calcd for C11H13NO3 208.09, found 208.47.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:13]#[N:14])[C:9](=[NH:12])[O:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]#[C:16]N>C1C=CC=CC=1>[C:16]([N:12]=[C:9]([O:10][CH3:11])[CH:8]([C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:15]
Reactant: N#CN
Reactant: COC(=N)C(C#N)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: COC(=NC#N)C(C#N)c1ccccc1
Yield: 76.9 %

Procedure:
4.21 g of methyl α-phenylcyanoacetimidate hydrochloride and 1.26 g of cyanamide were mixed at room temperature and the mixture was made to react for 5 hours. Then, 50 ml of benzene was added to the reaciton mixture to extract the resulting product. The extracted solution was concentrated to dryness in vacuo and 3.06 g of methyl N-cyano-α-phenylcyanoacetimidate was obtained (yield 76.8%).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[C:42]([OH:46])(=[O:45])[CH:43]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:43][C:42]([OH:46])=[O:45])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Reactant: O=CC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CN1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.25 mmol; see Example 88) in methanol (1 mL) was added glyoxylic acid (0.5 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (0.6 mmol), and the stirring was continued at RT for 10 h. To the reaction mixture was then added a few drops of glacial acetic acid, and the mixture was stirred for 30 min. The volatiles were then removed in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford {4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}acetic acid as a white solid. MS: m/z 579 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH:46]=[CH:45][CH2:44]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:42][C@@H:43]1[C:49](=[O:50])[N:48]2[CH2:51][CH2:52][CH2:53][CH2:54][C@@H:47]2[CH:46]=[CH:45][CH2:44]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=C[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((7S,10aR,Z)-6-oxo-1,2,3,4,6,7,8,10a-octahydropyrido[1,2-a]azepin-7-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 53 (4.6 mg, 0.021 mmol) to give a white solid (12 mg, 90% yield). Anal. Calcd. for C41H52N4O6S m/z 728.4. found: 729.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.10 (11H, m), 7.05 (1H, d, J=7.1 Hz), 5.63-5.48 (2H, m), 5.39-5.30 (2H, m), 5.14-5.09 (1H, m), 5.04-4.96 (1H, m), 4.80-4.71 (1H, m), 4.02-3.93 (1H, m), 3.68 (3H, s), 3.21-3.10 (1H, m), 3.05-2.94 (1H, m), 2.87-2.69 (6H, m), 2.50-2.36 (3H, m), 2.31-2.18 (1H, m), 2.07-1.99 (2H, m), 1.89-1.45 (15H, m).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][C:21]([CH3:25])=[CH:22][Mg]Br>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH:20]=[C:21]([CH3:25])[CH3:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)=C[Mg]Br
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=C[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
In an argon atmosphere, 8.44 g (36.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 17 mL of hexane and after adding a (2-methylprop-1-en-1-yl)magnesium bromide tetrahydrofuran solution (0.56 mol/L, 68.0 mL, 38.1 mmol), the resulting solution was stirred at room temperature for 18 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 90° C./3.5×102 Pa) to obtain 1,3-di-tert-butyl-2-(2-methylprop-1-en-1-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CHC(CH3)2) as a yellow liquid (yielded amount: 6.30 g, yield: 69%).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][NH2:10]>>[C:2]1([C:1]2[NH:8][NH:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1ccccc1
Product: c1ccc(C2=NN=C(c3ccccc3)NN2)cc1
Yield: 20.3 %

Procedure:
Benzonitrile (52 ml, 0.5 mole) and anhydrous hydrazine (16 ml, 0.5 mole) were heated at 90°-109° C. for 14 hours under nitrogen gas to give an orange solid. Recrystallization from toluene gave 12 g of orange-pink solid of melting point 177°-178° C. (compared to literature mp of 181° C.).