Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(#N)C>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])=[CH:7][CH:6]=3)=[O:4])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CBr)cc2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-(2-[4-bromoacetylphenyl]ethyl)-4-methylphenylsulphonamide (485 mg) in acetonitrile (10 ml) was added to a stirred solution of l-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture was stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction crystallisation occured. These crystals on filtration and washing with dichloromethane gave the title compound, 230 mg, as an off-white solid: m.p. 133°-135° C.; NMR (d6DMSO) δ 8.14(2H,bd), 7.90(2H,d), 7.65(2H,d), 7.59(1H,t), 7.35(2H,d), 7.29(2H,d), 6.81(2H,d), 3.37(2H,s), 3.33(4H,t), 2.98(2H,q), 2.76(2H,t), 2.63(4H,t), 2.38(3H,s); m/e 479(M+H)+ ; calculated for C26H30N4O3S: C, 65.2; H, 6.3; N, 11.7; found. C 65.0; H, 6.3; N, 11.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[C:20]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.Cl>C(O)C.Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][C:20]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:30])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)c2[nH]c(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)nc2-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone (15 mg, 21.5 mmol) in ethanol (1 mL) was added 5 drops of 2N HCl. The solution was stirred at room temperature for 18 hours. A solution of 1 M HCl in ether (0.5 mL) was then added and the reaction mixture was heated to 70° C. for 2 hours. The volatile components were then removed under reduced pressure. Flash silica gel chromatography (2:1 hexane/ethyl acetate to 1:1 hexane/ethyl acetate to ethyl acetate to 4:1 ethyl acetate/methanol) afforded the product [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1H-imidazol-2-yl]-methanone as a yellow powder (12 mg, 98%). 1H NMR (CDCl3) δ 2.3 (s, 3H), 5.3 (s, 2H), 7.0 (d, 2H, J=7), 7.1–7.3 (m, 9H), 7.8 (t, 1H, J=7), 7.9 (d, 2H, J=7), 8.4 (d, 1H, J=7), 8.6 (s, 1H), 8.7 (d, 1H, J=7), 8.85 (s, 1H). ESMS calcd for (C31H23ClN4O3S): 566.2; found: 567.2 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][N:29]=[C:21]([Br:20])[CH:22]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
3-(3,4-Dimethoxyphenyl)-L-alanine ethyl ester hydrochloride (66 g), triethylamine (33.3 ml), 2-bromoisonicotinic acid (50.6 g), 1-hydroxybenzotriazole monohydrate (38.4 g) and 1,3-dicyclohexylcarbodiimide (51.7 g) are added to methylene chloride (660 ml), and the mixture is stirred at room temperature for four hours. The reaction mixture is washed, dried, and concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=10:1) to give N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)-L-alanine ethyl ester (93.5 g).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[C:4]2([CH2:7][CH2:6][CH2:5]2)[CH2:3]1.[C:17](=O)([O:19]C1C=CC=CC=1)N.[NH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][N:32]=[CH:33]2>>[O:15]=[S:8]1(=[O:16])[C:4]2([CH2:5][CH2:6][CH2:7]2)[CH2:3][CH:2]([NH:1][C:17]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][N:32]=[CH:33]3)=[O:19])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=2
Reactant: Nc1cccc2cnccc12
Reactant: NC1CC2(CCC2)S(=O)(=O)c2ccccc21
Reactant: NC(=O)Oc1ccccc1
Product: O=C(Nc1cccc2cnccc12)NC1CC2(CCC2)S(=O)(=O)c2ccccc21

Procedure:
This compound was prepared in the same manner from above (±) 4-Amino-3,4-dihydro-1,1-dioxo-spiro[2H-1-benzothiopyran-2,1′-cyclobutane] and phenyl carbamate of 5-aminoisoquinoline as in step 1V of example 1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc(N)nc1N
Reactant: CCCCOc1cccc(CC(Cl)=NO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1cccc(Cc2cc(-c3ccc(N)nc3N)on2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 65-1-4 and 3-ethynyl-pyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (216 μL, 1.55 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1˜ethyl acetate) to obtain the title compound (43 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH2:32][C:33]([OH:35])=[O:34]>O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:32][C:33]([OH:35])=[O:34])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:17][CH3:18])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:19])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2
Reactant: O=C(O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Temperature: 50 °C

Procedure:
5,6-Dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (Example 1, Step C) (15 gm., 0.048 mole), potassium carbonate (13.3 gm., 0.096 mole), dimethylformamide (100 ml.) and iodoacetic acid (10.6 gm., 0.057 mole) is stirred at room temperature for 24 hours. The reaction mixture is poured into water (150 ml.), stirred, warmed to 50° C., filtered and the filtrate acidified with 6 N hydrochloric acid to obtain [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid, which after recrystallization from acetic acid, melts at 237° C.-238° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13]Br)=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15].[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]>O1CCOCC1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][N:19]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17][CH3:18])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15]
Reactant: CCCNCCC
Reactant: CN1C(=O)COc2cc(CCBr)ccc21
Solvent: C1COCCO1
Product: CCCN(CCC)CCc1ccc2c(c1)OCC(=O)N2C
Reaction time: 96 h

Procedure:
5.4 g of 4-methyl-7-(2-bromoethyl)2,3-dihydro 3-oxo 1,4-benzoxazine, dissolved beforehand in 120 cm3 of dioxane and 6 cm3 of (0.044 mol) of dipropyl-amine, are introduced into a 250 cm3 round-necked flask equipped with a reflux condendser. The mixture is heated to reflux with magnetic stirring for 4 days. After cooling, the reaction mixture is filtered and the filtrate is then evaporated on a water bath under vacuum. The residue is ground with distilled water and extracted with ethyl acetate. The organic phase is recovered and evaporated to dryness and the residue is taken up with 5% HCl solution. The acidic aqueous phase is washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with ethyl acetate and the organic phase is washed with distilled water and then dried over potassium carbonate. The solvent is evaporated off on a water bath under vacuum. The residue is taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The residue is ground in toluene or ether, then drained and dried. The product is recrystallized in anhydrous acetone.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH2:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[N:15]=2)[N:4]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:31][C:32]1[CH:37]=[CH:36][N:35]2[C:38]([C:41](OC)=[O:42])=[CH:39][N:40]=[C:34]2[CH:33]=1>C1COCC1.CO.C(Cl)Cl>[Br:31][C:32]1[CH:37]=[CH:36][N:35]2[C:38]([C:41]([NH:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]4[C:11]=3[C:3]([CH2:1][CH3:2])=[N:4][N:5]4[CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[N:15]=3)=[O:42])=[CH:39][N:40]=[C:34]2[CH:33]=1
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a solution 3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (328 mg, 1.22 mmol) in anhydrous THF (3 mL) was added under a nitrogen atmosphere at ambient temperature lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.15 mL). The resulting mixture was stirred at ambient temperature for 10 minutes, then added dropwise to a chilled (ice-water bath) solution of methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (140 mg, 0.55 mmol) in anhydrous THF (3 mL). The cold bath was removed, and the reaction mixture was allowed to warm to ambient temperature, and quenched with water. The resulting suspension was extracted thoroughly with DCM, the combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH-DCM as eluent to afford 219 mg of desired product as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:30]([C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]2[C:41]([CH2:42][OH:43])=[C:40]([Cl:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:34][CH:33]=1)=O.C[O-].[Na+]>CN(C)C=O.O>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1/[CH:2]=[CH:30]/[C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[C:41]([CH2:42][OH:43])=[C:40]([Cl:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:49][CH:50]=1)#[N:10]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C=O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(/C=C/c2ccccc2C#N)cc1
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a solution of 0.98 g of α-bromo-o-tolunitrile in 25 mL of dimethylformamide at 25° was added 1.40 g of triphenylphosphine. The mixture was stirred at 80° for 3 hours, then treated with 1.53 g of 1-(4-formylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole, followed immediately by 0.54 g of sodium methoxide, and the mixture was diluted with water and extracted with benzene. The organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) afforded 0.45 g of 1-[(2'-cyano-trans-stilben-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ8.01 (d, 1h); 7.85 (d, 1h); 7.73 (t, 1h); 7.47 (t, 1h); 7.44 (AB, 2H, J=16.3); 7.38 (A2B2, 4H); 5.28 (s, 2H); 5.24 (t, 1H); 4.34 (d, 2H); 2.49 (t, 2H); 1.47 (quint., 2H); 1.24 (sext., 2H); 0.79 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH2:15][N:14]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([OH:24])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:12][C@H:11]2[C@@H:10]([OH:9])[CH2:15][N:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:13]2)=[O:24])=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3c(o2)CN(C2CCCCC2)C3)cc1
Reactant: CCO
Product: O=C(N[C@@H]1CN(C2CCCCC2)C[C@@H]1O)c1ccc(Cl)cc1

Procedure:
Forty-one grams of 2-(4-chlorophenyl)-5-cyclohexyl-5,6-dihydro-4H-pyrrolo-[3,4-d]oxazole was dissolved in 500 ml. of 95% ethanol and the solution was heated at reflux for one hour. The solvent was evaporated under vacuum and replaced with methylene chloride. The methyl chloride was washed with dilute sodium hydroxide, dried and evaporated. The product was crystallized from benzene. Yield was 33.2 g (94.5%); m.p. 158°-160° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[CH:18][C:17]([S:30]([C:33]1[CH:34]=[C:35]([CH:55]=[CH:56][CH:57]=1)[C:36]([NH:38][C:39]1[CH:54]=[CH:53][C:42]([CH2:43][CH2:44][NH:45]C(=O)OC(C)(C)C)=[CH:41][CH:40]=1)=[O:37])(=[O:32])=[O:31])=[CH:16][C:15]=2[CH3:58])(=[O:10])[NH2:9]>C(Cl)Cl>[NH2:45][CH2:44][CH2:43][C:42]1[CH:53]=[CH:54][C:39]([NH:38][C:36]([C:35]2[CH:34]=[C:33]([S:30]([C:17]3[CH:18]=[C:19]4[C:14](=[C:15]([CH3:58])[CH:16]=3)[N:13]=[CH:12][C:11]([C:8]([NH2:9])=[O:10])=[C:20]4[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)(=[O:31])=[O:32])[CH:57]=[CH:56][CH:55]=2)=[O:37])=[CH:40][CH:41]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC(=O)OC(C)(C)C)cc5)c4)cc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCN)cc5)c4)cc23)c1
Reaction time: 5 h

Procedure:
TFA (0.5 mL) was added dropwise to a suspension of Intermediate 82 (382 mg, 0.538 mmol) in CH2Cl2 (5 mL) at rt. After stirring for 5 h, the reaction was concentrated in vacuo to give a brown residue. A portion was treated with silica-carbonate resin and used in the following step without further purification. ES/MS calcd. for C33H32N5O5S+ 610.2. Found m/z=610.2 (M+H)+.
Reaction SMILES: C(OC(N[C@H:9]([CH2:15]C1C=CC=CC=1)[CH:10](O)[C:11](O)=[O:12])=O)(C)(C)C.[CH2:22]([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:34])[C@H:31]([CH3:33])[NH:32][C:11](=[O:12])[CH2:10][CH2:9][CH3:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(O)C(=O)O
Product: CCCC(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
The product of example 20A and L-alanine benzyl ester were processed as in examples 1E to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester. 0.5 g of the above product was hydrogenated in 2 mL of isopropyl alcohol in the presence of 20 mg of 10%-palladium on charcoal to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine (0.4 g).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:9]([C:12]1[CH:13]=[C:14]([C:22]([OH:24])=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)(=[O:11])=[O:10]>O>[CH:1]1([NH:7][S:9]([C:12]2[CH:13]=[C:14]([C:22]([OH:24])=[O:23])[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
250 ml of water and 300 ml of cyclohexylamine were put into a 1-liter balloon flask. 139 g of moist 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added by fractions, the temperature being maintained at from 20°-30° C. The mixture was stirred at room temperature for three hours and then the solution was treated with 30 g of black carbon 3S. After filtration, 300 ml of hydrochloric acid (d=1.18) were added. The precipitate was recrystallized, washed with water and dried. 92 g of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 150° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH3:15])=O.CNC(C1CC2C(C=1C)=CC=CC=2)=O>>[CH3:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1ccc2ccccc2c1C
Agent: CNC(=O)C1=C(C)c2ccccc2C1
Product: CNCc1ccc2ccccc2c1C
Yield: 36 %

Procedure:
According to the procedure of Preparation 20 (b), except substituting N, 1-dimethylnaphthalene-2-carboxamide (0.3 g, 1.5 mmole) for the N,3-dimethylindene-2-carboxamide, the title compound (0.1 g, 36%) was prepared as a colorless oil: MS (ES) m/e 186 (M+H)+.
Reaction SMILES: OC(C1C=CC=C(C2C=C3[C:20]([C:21]4C=C[CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[CH:19][N:18](S(C4C=CC(C)=CC=4)(=O)=O)C3=NC=2)C=1)C(O)=O.CNCC1CCC[O:43]1.C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[O:27]1[CH2:28][CH2:24][CH2:23][CH:22]1[CH2:21][CH2:20][C:19]([NH2:18])=[O:43]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Reactant: CNCC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)CCC1CCCO1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
A mixture of hydroxyl-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl}-acetic acid (0.2 g, 0.38 mmol), methyl-(tetrahydro-furan-2-ylmethyl)-amine (0.7 g, 0.57 mmol), diisopropylethylamine (DIEA, 200 μl, 1.14 mmol), N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 216 mg, 0.57 mmol) in THF (5 ml) was stirred at 60° C. until no solid remained. The reaction mixture was taken up in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica chromatography. The resulting material was dissolved in 3 ml of methanol and aqueous NaOH (1 ml, 2 N in H2O) was added and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue neutralized with 500 μl of 1N HCl. The resulting crude was directly purified by mass-triggered reverse phase HPLC to afford 2-hydroxyl-2{3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl-acetamide as an off-white powder (51 mg, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.35-1.45 (m, 1H), 1.61-1.79 (m, 3H), 2.89-2.92 (d, 3H), 3.14-3.68 (m, 4H), 3.84 (s, 3H), 3.92-3.98 (m, 1H), 5.47 (d, 1H), 7.05 (m, 1H, 7.15 (d, 1H), 7.31 (m, 1H), 7.36 (m, 1H), 7.45-7.48 (m, 1H), 7.56-7.59 (m, 1H), 7.63-7.70 (m, 2H), 7.73 (m, 1H), 8.14 (m, 1H), 8.52 (m, 1H). MS: m/z 472.2 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>CCOCC>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CC)CO
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
2-Ethylhexanol (50.51 g, 0.384 mol) and pyridine (260 mL) are combined in a flask fitted with a condenser, internal thermometer, mechanical stirrer and argon inlet. The solution is cooled to -5° C. and to it is added p-toluenesulfonyl chloride (89.63 g, 0.416 mol) in portions via Gooch tubing so as to maintain the reaction temperature -5°-5° C. After 3 h, water (40 mL) is added in portions so as to keep the temperature of the reaction below 5° C. The reaction mixture is warmed to room temperature and then poured into a separatory funnel containing 540 mL of ether. The layers are separated and the organic layer is washed with 5M H2SO4 (2×140 mL), saturated CuSO4 solution (140 mL), water (2×140 mL) and saturated NaHCO3 solution (140 mL). After drying over MgSO4, the organic layer is filtered, and concentrated to leave a light yellow liquid as 2-ethyhexanyl p-toluenesulfonate. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.C[O-].[Na+].CN(C)C=O.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>O.C1(C)C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=2[C:7]([C:13]2[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=2[F:19])=[N:8][CH2:9][C:10]1=[O:12]
Reactant: COC(=O)CBr
Reactant: O=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Reaction time: 6 h

Procedure:
A mixture of 0.1 mole of 7-chloro-1,3-dihydro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl bromoacetate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 7-chloro-2,3-dihydro-2-oxo-5-(2,6-difluorophenyl)-1H-1,4-benzodiazepin-1-acetic acid methyl ester.