Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:15]=[N:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:17][O:16][C:10]1[CH:9]=[C:8]2[C:13]([N:14]=[CH:15][C:6]([S:1][CH2:2][CH2:3][OH:4])=[N:7]2)=[CH:12][CH:11]=1
Reactant: OCCS
Reactant: COc1ccc2ncc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(SCCO)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
2-Mercaptoethanol (2.5 g, 32.06 mmol, 1.2 eq) is added at room temperature to a stirred solution of 2-chloro-7-methoxy-quinoxaline (5.2 g, 26.72 mmol, 1.0 eq) in N,N-dimethylformamide (160 mL), followed by potassium carbonate (7.4 g, 53.44 mol, 2.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×150 mL) and water (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: ethyl acetate:hexane, 1:2, v/v) to afford 2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethanol as a pale yellow solid (6.22 g, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:31]=[CH:30][C:17]4[O:18][CH2:19][C:20]5[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[C:35]([CH2:34][CH2:33][S:32][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]#[N:29])[C:20]=2[CH2:19][O:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:37])=[O:36]
Reactant: O=C(O)CCS
Reactant: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2O
Product: N#Cc1cccc2c1COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-7-cyano-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[C:10]([C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31](O)=[O:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])[NH2:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:1]1([S:4]([NH:7][C:31]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:11])=[O:12])[CH2:28][C:27]3([CH3:30])[CH3:29])=[O:32])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.1 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (200 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A34. A solution of 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B34. Solution B34 was added to Solution A34 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-cyclopropanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzamide (10 mg, 24%) as a white solid: MS (ESI) M+1=428.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Li]CCCC>C1COCC1>[CH2:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:10]([CH3:12])[CH3:11])[N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1cc(C)nc(N(C)C)n1
Reactant: CCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 1.06 g (6.34 mmol) of 4-methoxy-N,N,6-trimethylpyrimidin-2-amine and 1.32 g (6.34 mmol) of 1-bromononane in 20 mL of anhydrous THF were added 5.15 mL (8.34 mmol) of 1.6 M n-BuLi in hexanes. The reaction mixture was stirred at 23° C. for 20 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and poured into 100 mL of water. The compound was extracted with two 80-mL portions of ethyl acetate. The combined organic layer was washed with one 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 9:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 1.22 g (66%); silica gel TLC Rf 0.7 (9:1 hexanes-ethyl acetate); 1H-NMR (CDCl3) δ 0.85 (t, 3H, J=6.8 Hz), 1.28-1.23 (br m, 14H), 1.82 (quint, 2H, J=7.2 Hz), 2.46 (dd, 2H, J=7.6, 7.6 Hz), 3.14 (s, 6H), 3.85 (s, 3H) and 5.77 (s, 1H); 13C NMR (CDCl3) δ 14.09, 22.66, 28.46, 29.31, 29.32, 29.48, 29.54, 29.59, 31.88, 36.78, 37.83, 37.83, 52.75, 93.03, 162.29, 170.25 and 173.93.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][N:29]([S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH2:30][CH2:31]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl}boronic acid (47 mg, 0.254 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. (This run was aborted prior to 30 min due to excessive pressure build-up). The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 60° C. to give 8.8 mg of the title compound (10%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl.N1C=CC=CC=1>[C:23]([O:22][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 43.4 %

Procedure:
The procedure is as in Example 30, but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.4 g) in methylene chloride (320 cc), pyridine (48 cc) and butyryl chloride (12.8 g). After one recrystallization in isopropyl ether followed by two recrystallizations in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl butyrate (3.4 g), m.p. 140° C., is obtained.
Reaction SMILES: C1(C([NH:14][CH:15]([P:23]([OH:25])[OH:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C2C=CC=CC=2)C=CC=CC=1>Br>[NH2:14][CH:15]([P:23]([OH:25])[OH:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OP(O)C(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Agent: Br
Product: NC(Cc1ccccc1)P(O)O
Reaction time: 8 h

Procedure:
9.9 g (0.028 mol) of 1-diphenylmethylamino-2-phenylethylphosphonous acid are heated, at 100°-105° C. for 2 h, in 50 ml of 40% hydrobromic acid. The reaction solution is then evaporated to dryness i.V. and the residue is taken up in 50 ml of water. The aqueous solution is washed several times with diethyl ether and evaporated to dryness. The residue is dissolved in 60 ml of ethanol and propylene oxide is added to the solution until the product precipitates out. After the mixture has been left to stand overnight, the precipitate is filtered off with suction, washed with ethanol/diethyl ether and dried.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccc(F)c2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(2,3-difluorophenyl)thiazole-4-carboxylic acid (Example 25) gave 324. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.07 (dd, J=8.3, 6.5 Hz, 1H), 7.87 (s, 1H), 7.52 (s, 2H), 7.48-7.38 (m, 1H), 7.31-7.22 (m, 1H), 4.87-4.80 (m, 1H), 4.56-4.38 (m, 1H), 4.36-4.23 (m, 1H), 4.16-3.99 (m, 1H), 3.76 (s, 3H), 2.09-2.01 (m, 1H), 1.87-1.66 (m, 5H). LCMS (ES+) m/z 467 (M+1).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][N:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:19].C(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[CH3:6][N:7]1[C:11]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:19]
Reactant: Cc1nc2ccc([N+](=O)[O-])cc2n1C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2ccc(N)cc2n1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of tin (II) chloride dihydrate (4.7 g) in concentrated hydrochloric acid (15 ml) was added 1,2-dimethyl-6-nitro-1H-benzimidazole (1 g) (J. Chem. Soc.,1931, 1143-1153), and the mixture was stirred at room temperature for 6 h. The mixture was poured onto ice and chloroform, and basified to pH 10 by the addition of 10M sodium hydroxide solution. The mixture was extracted several times with chloroform and the combined organic extracts dried and concentrated in vacuo to give a brown solid. This was crystallised from ethanol to give the title compound.
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCC1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH2:29][C:30]1[C:31]([C:46](=O)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:32]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[S:36]>>[NH2:29][C:30]1[C:31]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:32]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[S:36]
Reactant: Nc1cc(C(O)=S)cc(Cc2ccccc2)c1C(=O)c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Product: Nc1cc(C(O)=S)cc(Cc2ccccc2)c1Cc1ccccc1

Procedure:
By replacing in Example 24, step A, 4-benzoyl-3-benzyloxy-5-nitrobenzoic acid with 5-amino-4-benzoyl-3-benzylthiobenzoic acid and following the procedure described, 5-amino-4-benzyl-3-benzylthiobenzoic acid is obtained with a melting point of 256°-257° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[CH:10](O)=[O:11].S(S([O-])=O)([O-])=O.[Na+].[Na+].C>C(N)=O.O>[CH:10]([NH:1][C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11]
Reactant: O=[N+]([O-])c1ncccn1
Reactant: O=CO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: O=CNc1ncccn1
Reaction time: 0.29 h

Procedure:
The crude nitropyrimidine (25.32 g) from above was suspended in formamide (150 ml) and 90% formic acid (50 ml) and the suspension was warmed to 70° C. in a water bath. Sodium dithionite was carefully added to the warm suspension and then boiled for 15-20 minutes. The reaction mixture was diluted with hot water (300 ml), treated with charcoal and then boiled for an additional 20-25 minutes, filtered through celite, cooled and concentrated under reduced pressure to give formamido-pyrimidine which was collected by filtration, washed with acetone, and dried under vacuum at 56° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([Cl:27])[CH:18]=4)[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(O)CCC>[Cl:27][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH:5]=[CH:4][N:3]=[C:2]4[N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]3)[N:16]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH:24]([CH3:25])[CH3:26]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Solvent: CCCCO
Product: CCOC(=O)C1CCN(c2nccc3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1

Procedure:
1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol), ethyl 4-piperidinecarboxylate (available from Fluorochem; 0.077 ml, 0.500 mmol) and n-butanol (0.75 ml) were heated under microwave irradiation at 175° C. for 2 h. The reaction mixture was filtered to give the title compound as an off white solid (35 mg).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3ccc(NC(=O)c4ccccc4)cc32)n1)c1ccccc1
Yield: 76.7 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (50 mg, 0.15 mmol) and benzoyl chloride (21 mg, 0.15 mmol) furnished the product (50 mg, 76%) after chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.N1(CCCN[C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[S:29](=[O:44])(=[O:43])[NH:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)=[O:22])CCCCC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[S:29](=[O:43])(=[O:44])[NH:30][C:31]2[CH:32]=[C:33]([O:41][CH3:42])[C:34]([O:39][CH3:40])=[C:35]([O:37][CH3:38])[CH:36]=2)=[O:22])[CH:2]=1
Reactant: COc1cc(NS(=O)(=O)N2CCCC[C@H]2C(=O)NCCCN2CCCCC2)cc(OC)c1OC
Reactant: NCCCc1cccnc1
Product: COc1cc(NS(=O)(=O)N2CCCC[C@H]2C(=O)NCCCc2cccnc2)cc(OC)c1OC

Procedure:
Compound 93 was prepared from the carboxylic acid (compound 39) and 3-pyridin-3-yl-propylamine by a synthetic method analogous to the synthesis of compound 91. An 8.5% yield was obtained for the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][C:14]=3[CH3:21])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].P(Br)(Br)([Br:28])=O>C(Cl)Cl.CCOC(C)=O>[Br:28][CH2:19][C:17]1[CH:16]=[CH:15][C:14]([CH3:21])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:22])[C:5](=[O:23])[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:12]3=[CH:11][CH:10]=2)[CH:18]=1
Reactant: Cc1ccc(CO)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: O=P(Br)(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(CBr)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 51-1 (150 mg, 0.44 mmol) in DCM (2 mL) at 0° C. was added phosphorus oxybromide (126 mg, 0.46 mmol). After 4 hours, the reaction was diluted with EtOAc, and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give product as a white foam. MS (M+H)+: observed=402.0/404.0, calculated=402.3/404.3.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:21])[CH:17]=[CH:18][O:19][CH3:20])[NH:13][C:12]1=[O:22])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:23][CH:24](O)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26]>C(N(CC)CC)C.C1C=CC=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:21])[CH:17]=[CH:18][O:19][CH3:20])[N:13]([CH:24]([OH:23])[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[O:26])[C:12]1=[O:22])[CH3:10])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)C(O)O)cc1
Reactant: COC=CC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC=CC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc(OC)cc1
Yield: 92.3 %

Procedure:
A mixture of (3S ,4R) 3-((1R)-1-(tert-butyldimethylsilyloxy)ethyl)-4-(4-methoxy-2-oxobut-3-en-1-yl)azetidin-2-one (100 mg, 0.3 mM), 4-methoxybenzyl dihydroxyacetate (72 mg, 0.33 mM) and 2 drops of triethylamine in benzene (5 ml) was heated at reflux for 1 hour. The solvent was evaporated and the product purified by subjecting to chromatography on silica, eluting with ether to give 4-methoxybenzyl 2-[(3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)-ethyl]-4-[4-methoxy-2-oxobut-3-en-1-yl]-2-azetidinone-1-yl]-2-hydroxy-acetate (147 mg, 93%). IR (film, NaCl) 3310, 1745.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COC(=O)CBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)cc1C=O
Yield: 99.4 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (35 g, 220 mmol), bromo-acetic acid methyl ester (43 g, 282 mmol), K2CO3 (60 g, 434 mmol) and in DMF (300 mL) was heated at 140° C. for 10 min. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water 4 times, dried over anhydrous Na2SO4, concentrated to give crude product as yellow solid (50 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:30]>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[CH:33][CH:34]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-chloro-phenyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-chloro-phenyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 564.2 [M]+.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[H][H]>[Pd].C(O)C>[S:1]1(=[O:10])(=[O:11])[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=S1(=O)C=Cc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=S1(=O)CCc2ccccc21
Yield: 100 %

Procedure:
In a Parr shaker bottle was placed benzo[b]thiophene 1,1-dioxide (5.0 g, 30.08 mmol), palladium on activated carbon (500 mg) and ethanol (100 mL). The bottle was placed on a Parr shaker and charged with 50 psi of hydrogen for 1 h. The reaction mixture was removed from the Parr shaker and filtered through a plug of celite and concentrated in vacuo to afford 2,3-dihydro-benzo[b]thiophene 1,1-dioxide (5.06 g, 100%) as a white solid.
Reaction SMILES: [NH:1]([C:25]([O:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1)=[O:26])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:24])([CH3:23])[CH2:7]1)=[O:4].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>>[N:2]([C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([CH3:23])([CH3:24])[CH2:7]1)=[O:4])=[N:1][C:25]([O:27][CH:28]1[CH2:29][C:30]([CH3:46])([CH3:45])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:32]([CH3:34])([CH3:35])[CH2:33]1)=[O:26]
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The procedure of Example 4 is repeated using 4.6 g of bis(1-octyloxy-2,2,6,6-tetra-methylpiperidin-4-yl) hydrazine-1,2-dicarboxylate and 2.3 g of iodobenzene diacetate to afford 3.3 gg of the title compound as a pale yellow oil. NMR, IR and mass spectra analyses are consistent with the desired structure.