Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[O:17][CH2:16]1)[C:5](=[O:15])[N:6]2[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[F:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35].ClCCl>C1(C)C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:19]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=3[O:17][CH2:16]1)[C:5](=[O:15])[N:6]2[CH2:11][C:12]([NH:35][C:34]1[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=1[F:32])=[O:14]
Reactant: O=C(O)CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21
Reactant: Nc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of (4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.24 g, 0.59 mmol) and oxalyl chloride (0.15 mL, 1.76 mmol) in toluene (7.00 mL) was added one drop of DMF and the resulted mixture was stirred at ambient temperature overnight. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (5.00 mL) and 2-fluoroaniline (0.18 mL, 1.89 mmol) was added at ambient temperature. The mixture was stirred at ambient temperature for one hour. More dichloromethane (100 mL) was added. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.23 g, 76%): 1H NMR (300 MHz, CDCl3) δ 8.20 (t, 1H), 7.80 (br, 1H), 7.27-7.17 (m, 2H), 7.16-7.03 (m, 3H), 6.97-6.88 (m, 1H), 6.78-6.60 (m, 2H), 5.08 (d, 1H), 4.93 (d, 1H), 4.68 (d, 1H), 4.49 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 177.1, 163.9, 157.8, 143.6, 131.0, 128.8, 128.1, 124.7, 121.8, 120.0, 115.0, 111.6, 108.1, 99.8, 77.5, 59.2, 44.7; MS (ES+) m/z 503.4 (M+1), 505.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27]/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[CH3:33][O:32][C:30](=[O:31])[CH:29]=[CH:28][CH2:27][N:10]([CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: COC(=O)/C=C/CBr
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C=CCN(CCNC(=O)OC(C)(C)C)Cc1ccc(F)cc1
Yield: 89.2 %

Procedure:
[2-(4-Fluoro-benzylamino)-ethyl]-carbamic acid tert-butyl ester (7.0 g, 26.1 mmol) and potassium carbonate (7.2 g, 52.2 mmol) were stirred in acetone (150 mL). A mixture of methyl 4-bromocrotonate (4.7 g, 26.1 mmol, 3.1 mL) in acetone (50 mL) was added to this solution dropwise using an addition funnel. After 18 h the solution was filtered, concentrated and chromatographed on silica gel to yield the title compound as a yellow oil (8.53 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1>CN(C)C=O>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Temperature: 0 °C
Yield: 44 %

Procedure:
The 3-Nitro-1H-pyrazole (prepared in example 3, 1.18 g, 10.44 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL) and a 60% dispersion of sodium hydride in mineral oil (500 mg, 12.53 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and the 4-bromomethyl-benzoic acid methyl ester (2.63 g, 11.48 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The solution was poured into ice water; a white precipitate formed and was collected by in vacuo filtration and dried in vacuo for 16 h. Recrystallization from 20% ethyl acetate/hexanes afforded 4-(3-nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.20 g, 44%), as a white powder upon collection and drying in vacuo: H1-NMR (400 MHz, CDCl3) δ 3.93 (3H, s), 5.43 (2H, s), 6.93 (1H, d, J=2.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.42 (1H, d, J=2.8 Hz), 8.05 (2H, d, J=8.4 Hz).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[I:9]Cl>CO>[I:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: ClI
Reactant: O=c1cc[nH]c(=O)[nH]1
Solvent: CO
Product: O=c1[nH]cc(I)c(=O)[nH]1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A mixture of uracil (28.6 mmol, 3.2 g) and iodine monochloride (49.2 mmol, 7.988 g) in methanol (120 mL) was refluxed for 40 hr. The solvent was removed under vacuum and the residue was crystallized from ethanol:water (1:1, 150 mL) and stored in the refrigerator for 3 h. The resulting needles were collected by filtration and were washed with ethanol:water (1:1 mixture, 50 mL), water (30 mL), hexane (30 mL) and then dried in air to obtain 5.47 g (80%) of 5-iodo uracil as a white needles (mp 278-282° C., Lit. 274-276° C., Synthetic communication 1988, 18, 855-867). EI-HRMS m/e calcd for C4H3IN2O2 (M+) 237.9239, found 237.9244.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)=O.[H-].[Na+].[N:25]#[C:26]Br>O1CCCC1.O.CC(C)=O>[NH2:25][C:26]1[N:11]2[C:12]3[N:13]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH2:10]2)[N:14]=[CH:15][C:16]=3[C:17](=[O:18])[N:19]=1
Reactant: N#CBr
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
To a stirred suspension of 5.0 g of 7-(3-fluorophenyl)-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 6) in 250 ml of dry tetrahydrofuran, cooled to -78° C. (dry-ice, acetone) was added 1.70 g of sodium hydride (60% dispersion in mineral oil) in one portion. The reaction mixture was stirred at -78° C. for 30 minutes then 2.05 g of cyanogen bromide was added and the mixture was stirred for an additional 2 hours at -78° C., then slowly allowed to warm to room temperature over 16 hours. The reaction mixture was diluted with water and the solid was collected by filtration, washed with water, then ether to give 376 mg of the desired product as a white solid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CC#N
Solvent: c1ccccc1
Product: N#CCCN1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of acrylonitrile (5.6 ml/85.1 mmol) and benzylpiperazine (5.0 g/28.3 mmol) in benzene (28 ml) was refluxed for 10 hours. After cooling down, the mixture was concentrated in vacuo and the residue was purified by column chromatography (NH2 gel/200-350 mesh/100 g/dichloromethane) to give a pale brown oil (5.5 g/85%).
Reaction SMILES: [CH:1]([N:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:12])[CH2:7][CH2:6]1)[CH3:4])=[O:2].[OH-].[Na+]>O1CCCC1.CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=3)=[O:28])=[C:14]([NH:13][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([N:3]([CH:1]=[O:2])[CH3:4])[CH2:6][CH2:7]3)=[O:12])[C:18]=2[CH:19]=1)([OH:25])=[O:24]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C=O)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C=O)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-3-[4-(N-formyl-N-methylamino)cyclohexylcarbonylamino]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.90 g) obtained in Example 234 is suspended in tetrahydrofuran/methanol (1:1, 50 ml), and thereto is added 4N aqueous sodium hydroxide solution (5 ml) under ice-cooling. The mixture is warmed to room temperature, and stirred for 17 hours. The reaction solution is concentrated under reduced pressure, and to the residue is poured ice-water, and the mixture is neutralized with 10% hydrochloric acid. The precipitates are collected by filtration, washed successively with water and tetrahydrofuran, and dried to give the title compound (1.59 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[CH3:12][O:11][C:3]1[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: O=S(=O)(O)Cl
Reactant: COc1c(C)c(C)cc(C)c1C
Solvent: ClCCl
Product: COc1c(C)c(C)c(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In 600 ml of dichloromethane was dissolved 10.0 g of 2,3,5,6-tetramethylanisole, followed by addition of a solution (400 ml) of 12 ml of chlorosulfonic acid in dichloromethane at -5°~-10° C. The mixture was kept stirred for 2 hours and the reaction mixture was poured into ice-5% aqueous NaHCO3. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from n-hexane and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[O-].[Na+].[OH:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]2[C:24]3=[C:25]([CH2:27][C:28]([CH3:30])([CH3:29])[N:23]3[CH:22]=[C:21]([C:31](OCC)=[O:32])[C:20]2=[O:36])[CH:26]=1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:31]([C:21]2[C:20](=[O:36])[C:19]3[C:24]4=[C:25]([CH2:27][C:28]([CH3:30])([CH3:29])[N:23]4[CH:22]=2)[CH:26]=[C:17]([C:16]#[C:15][CH2:14][OH:13])[CH:18]=3)=[O:32])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn2c3c(cc(C#CCO)cc3c1=O)CC2(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2cc(C#CCO)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 50 °C

Procedure:
4-Chlorobenzylamine (110 μL) and sodium methoxide (25 mg) are added to a solution of ethyl 8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (Preparation 14, 153 mg) in methanol (12 mL). The reaction is warmed to 50° C. for 48 hours. The reaction mixture is cooled in a freezer and the resulting white precipitate is filtered and washed with cold methanol, hexane, and ether to give 150 mg of the title compound as white crystals. Physical characteristics: M.p. 228° C. (dec); 1H NMR (DMSO-d6) δ10.43, 8.98, 7.90, 7.66, 7.40, 5.39, 4.54, 4.34, 3.44, 1.66; IR (diffuse reflectance) 2226, 1907, 1646, 1618, 1568, 1538, 1510, 1493, 1434, 1318, 1307, 1223, 1033, 1012, 808 cm−1; MS (EI) m/z 420 (M+); HRMS (FAB) 421.1332 (C24H21ClN2O3+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18](F)(F)F)[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>>[CH2:26]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10]1)[CH:25]=[CH2:24]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 19.4 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and allylbromide (0.086 mL, 1.0 mmol) to give the title compound (0.027 g) as a white solid. Used as is without further characterization.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:9][CH:8]=1)([O-])=O>O.C(O)C.[Zn]>[NH2:4][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][NH:16][S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(NCCNS(=O)(=O)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
A mixture of zinc powder (2 g) and ammonium chloride (0.2 g) in 22 ml of a water/ethanol mixture (1/1) was refluxed in a boiling-water bath. The derivative N-{2-[(4nitrophenyl)amino]ethyl}benzenesulfonamide (2) (3 g, 9 mmol) was added in portions and heating was continued until the reaction medium decolorized. The mixture was filtered while hot and the zinc was rinsed with ethanol/water solution (50/50). The filtrate crystallized rapidly. After cooling to 0° C., the solid was filtered off and then washed with water. After drying, 2.27 g of crude product with a melting point of 144° C. were obtained. 0.77 g of this crude product was recrystallized from 20 mL of water/ethanol (1/1), and the crystals obtained were dried over P2O5 and microanalysed.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:25][C@@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)cc1

Procedure:
[1,1′-Biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:13][C:12]([SH:14])=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:19]([C:24]#[N:25])=[N:20][CH:21]=[CH:22][N:23]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:8][C:9]1[S:13][C:12]([S:14][C:18]2[C:19]([C:24]#[N:25])=[N:20][CH:21]=[CH:22][N:23]=2)=[N:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nnc(SCc2ccccc2)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1nccnc1Sc1nnc(SCc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(benzylthio)-1,3,4-thiadiazole-2-thiol (240 mg, 1.00 mmol) in DMF and benzene (4 ml, 1/1) was added NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol) slowly at 0° C. under a nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added 3-chloropyrazine-2-carbonitrile (140 mg, 1.00 mmol). The reaction was stirred at room temperature for 2 hr. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4. Removal of the solvent gave the crude product which was purified by chromatography to give the title compound as off-white solid.
Reaction SMILES: [CH2:1]=O.[CH2:3]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:23])=[C:17]2[OH:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:11][C:12]2[C:21]3=[C:16]([C:17](=[O:33])[C:18]([C:22]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[O:23])=[CH:19][N:20]3[CH2:1]1)[CH:15]=[C:14]([CH2:34][N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)[CH:13]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(CNCc3ccccc3)cc(CN3CCOCC3)cc2c1O
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)CN(Cc1ccccc1)C2

Procedure:
Aqueous formaldehyde (0.25 ml, 37% solution) is added to a solution of 8-((benzylamino)methyl)-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 29, 60 mg) in methanol (2.5 mL) at 50° C. The solution is allowed to cool and the resulting precipitate is filtered and washed with methanol to give 38 mg of the title compound. Physical characteristics: M.p. 203-205° C.; 1H NMR (DMSO-d6) δ2.38, 3.57, 3.73, 4.20, 4.57, 5.29, 7.2-7.4, 7.51, 8.08, 8.74, 10.4. Anal. Found: C, 68.50; H, 5.72; N, 10.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=O)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[C:36]3[C:34](=[O:35])[NH:33][C:31](=[O:32])[NH:30]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Reactant: O=C1CNC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=C3NC(=O)NC3=O)cn2)cc1Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (prepared as in Example 18, 217 mg, 0.5 mmol), hydantoin (75 mg, 0.75 mmol), piperidine (10 μL, 0.10 mmol), and benzoic acid (6.1 mg, 0.05 mmol) in anhydrous ethanol (30 mL) was heated under reflux for 2 d. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10%–65% ethyl acetate/hexanes) afforded the 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidin-4-ylidenemethyl)-pyrazin-2-yl]-propionamide (84 mg, 33%) as a white solid: LC-MS m/e 518 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH:25]=[CH:26][Cl:27])[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:9]2[CH:18]=[CH:17][C:16]3[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12][C:11]=3[C:10]=2[CH:25]([CH2:26][Cl:27])[CH2:24]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(Br)c(N(CC=CCl)C(=O)OC(C)(C)C)ccc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: COC(=O)c1ccc2c3c(ccc2c1)N(C(=O)OC(C)(C)C)CC3CCl
Yield: 85.2 %

Procedure:
A mixture of 149 (1.16 g, 2.55 mmol), Bu3SnH (0.69 mL, 2.56 mmol) and AIBN (50 mg, 0.30 mmol) in dry benzene (15 mL) under N2 was stirred at reflux for 2 h, then concentrated under reduced pressure. The residue was triturated with i-Pr2O and the resulting solid was purified by chromatography on silica gel, eluting with CH2Cl2/EtOAc (19:1), to give methyl 3-(tert-butoxycarbonyl)-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indole-7-carboxylate (150) (817 mg, 85%) as a white solid. mp EtOAc) 187-189° C.; 1H NMR [(CD3)2SO] δ 8.60 (d, J=1.2 z, 1H), 8.1 (v br, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.97 (dd, J=8.8, 1.6 Hz, 1H), 4.31-4.23 (m, 1H), 4.20 (t, J=10.4 Hz, 1H), 4.09 (dd, J=11.2, 2.5 Hz, 1H), 4.04 (dd, J=11.1, 3.1 Hz, 1H), 3.96-3.88 (m, 4H), 1.55 (s, 9H). Anal. (C20H22ClNO4) C, H, N.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:24])[C:4]([OH:23])([CH3:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(O)(C)C>C(O)C>[OH:1][NH:2][C:3](=[O:24])[C@:4]([OH:23])([CH3:22])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: CC(O)(CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Solvent: CC(C)O
Solvent: CCO
Product: C[C@](O)(CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Yield: 40.9 %

Procedure:
A solution of N,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]propanamide (20 g) in ethanol (1500 mL) was sequentially injected in 12 mL portions onto a Prochrom column (50 mm I.D., 36 mm bed length) packed with Chiralpak AD. The mobile phase used was 30% isopropyl alcohol/70% heptane. Fractions were collected automatically and pooled. The second eluting peak was collected and the appropriate fractions were combined to provide the title compound (8.176 g). HPLC purity: 92%.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:10]([N:12]2[CH2:19][CH2:18][C@:17]3([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:13]2[CH2:14][C:15]2[C:27]([O:28]C)=[CH:26][CH:25]=[CH:24][C:16]=23)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([C:10]([N:12]2[CH2:19][CH2:18][C@:17]3([CH3:23])[C:20]([CH3:21])([CH3:22])[C@H:13]2[CH2:14][C:15]2[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][C:16]=23)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc2c1C[C@H]1N(C(=O)C3CCCC3)CC[C@]2(C)C1(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (2.8 mL) is added to a solution of cyclopentyl-[(2R,6S)-10-methoxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (280 g) in dichlormethane (10 mL). The resulting solution is stirred at ambient temperature for 2 h and then quenched by the addition of water. The organic phase is separated, washed with water and dried (Na2SO4). Evaporation of the solvent under reduced pressure affords the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:42]/[O:43][C@@H:44]([CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)=[O:46])/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S@:20](=[O:41])[CH2:21][C:22]([CH2:39]Cl)=[C:23]3[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:65].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:42]/[O:43][C@@H:44]([CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)=[O:46])/[C:15]([NH:17][C@@H:18]2[C:25](=[O:26])[N:24]3[C@@H:19]2[S@:20](=[O:41])[CH2:21][C:22]([CH2:39][I:65])=[C:23]3[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)C2=C(CCl)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\O[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc4ccc(OC)cc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)C[S@@](=O)[C@@H]3[C@H](NC(=O)/C(=N\O[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc4ccc(OC)cc4)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To the solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((5R,6R,7R)-3-(chloromethyl)-2-(((4-methoxybenzyl)oxy)carbonyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-2-oxoethylidene)amino)oxy)succinate (1.183 g, 1.25 mmol) in acetone (50 mL) at room temperature was added sodium iodide (0.234 g, 1.563 mmol). The mixture stirred at room temperature for 2 hours. Filtered and evaporated to give (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((5R,6R,7R)-3-(iodomethyl)-2-(((4-methoxybenzyl)oxy)carbonyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-2-oxoethylidene)amino)oxy)succinate (1.1 g, 1.060 mmol, 85% yield). LCMS (M+H)+: 1038.9