Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([Si:6]([CH3:17])([CH3:16])[O:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:27][C:28]([O:31][C:32]([N:34]1C(C2C=CC(C#N)=CC=2)O1)=[O:33])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:31][C:32](=[O:33])[NH:34][N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][O:7][Si:6]([C:2]([CH3:3])([CH3:5])[CH3:4])([CH3:17])[CH3:16])[CH2:11][CH2:12]1)([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CCC(CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
4-[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-piperidine hydrochloride (1:1) (300 mg, 1.07 mmol) was combined with dichloromethane (15 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (166 mg, 225 μl, 1.29 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (238 mg, 965 μmol) in dichloromethane (10 mL) was added during 20 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 10 g, ethyl acetetate/n-heptane 1/1) to give the title compound (0.23 g, 60%) as a white solid; LC-MS (ESI) 94.9%, 359.2710 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=1>>[N+:38]([C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2cccc([N+](=O)[O-])c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-nitro-benzene following the procedure of Example 478: MS (ESI) m/z529.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=O.Cl.[NH2:19][OH:20].CN(C)CCO>C(O)C>[ClH:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:19][OH:20]
Reactant: O=C(c1ccc(F)cc1F)C1CCNCC1
Reactant: NO
Agent: CN(C)CCO
Agent: Cl
Solvent: CCO
Product: ON=C(c1ccc(F)cc1F)C1CCNCC1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
30 g of 2,4-difluorophenyl(4-piperidinyl)methanone hydrochloride obtained in step B) and 30 g of hydroxylamine hydrochloride were added to 50 ml of ethanol. 29.5 ml of N,N-dimethylethanolamine was added thereto dropwise while stirring at room temperature, and then the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered and dried to obtain 26.4 g of the title compound as a white crystal (yield: 96%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:32](O)(=[O:37])[CH:33]([CH2:35][OH:36])[OH:34].ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:35](=[O:36])[CH:33]([CH2:32][OH:37])[OH:34])=[CH:30][CH:31]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)C(O)CO
Reactant: CCCCCCCOc1ccc(CN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CNC(=O)C(O)CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
Dicyclohexylcarbodiimide (160 mg) was added to a solution of 200 mg of p-heptyloxybenzylamine, 150 mg of glyceric acid (65% aqueous solution) and 110 mg of 1-hydroxybenzotriazole in 2 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate, washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography to give 80 mg of N-(p-heptyloxybenzyl)glyceramide.
Reaction SMILES: OC1C2C(=CC=CC=2)C(N[S:13]([C:16]2SC=CC=2)(=O)=O)=CC=1SCC(O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([N:36]=[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[C:39](Cl)=[CH:38]2)(=[O:35])=[O:34])[S:30][C:31]=1[Cl:32].S[CH2:50][C:51]([O:53][CH2:54]C)=[O:52]>CCOC(C)=O>[CH3:54][O:53][C:51](=[O:52])[CH2:50][CH2:16][S:13][C:39]1[CH:38]=[C:37]([NH:36][S:33]([C:29]2[S:30][C:31]([Cl:32])=[C:27]([Cl:26])[CH:28]=2)(=[O:35])=[O:34])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]=1[OH:47]
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: CCOC(=O)CS
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1cc(NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc2c1O

Procedure:
5.2.55 Methyl-3-(4-(4,5-dichlorothiophene-2-sulfonamido)-1-hydroxynaphthalen-2-ylthio)propanoate (14m) was prepared according to the procedure of procedure B for 10a except using 4,5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and ethyl mercaptoacetate, which afforded the title compound 16.1 mg (33%) as a grey solid after flash chromatography (Hex/EtOAc), m.p.: ° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@@H:5]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[NH2:30][CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([OH:45])=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[OH:33]>>[OH:33][C@H:32]([C:34]1[CH:35]=[CH:36][C:37]([OH:45])=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[CH2:31][NH:30][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C@@H:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:3][CH2:1][CH3:2])=[O:29])=[O:28])=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanedioic acid diethyl ester (which was obtained in Example 157) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp>75° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.18 (t, J=7.1 Hz, 3 H), 1.19 (t, J=7.1 Hz, 3 H), 1.20–1.45 (m, 2 H), 1.80–2.10 (m, 4 H), 2.41 (t, J=7.4 Hz, 2 H), 2.50–2.95 (m, 5 H), 2.93 (s, 3 H), 3.75–3.85 (m, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 4.35–4.45 (m, 1 H), 4.45–4.55 (m, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 6.94 (d, J=8.9 Hz, 2 H), 7.01 (dd, J=8.3, 2.0 Hz, 1 H), 7.18 (d, J=2.0 Hz, 1 H), 7.74 (d, J=8.9 Hz, 2 H), 8.38 (d, J=7.5 Hz, 1 H); MS (ES) m/z: 635.1 (MH+); HRMS Calcd. for C30H43N4O9S (MH+): 635.2745. Found: 635.2735.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[CH3:18][O-:19].[Na+]>O>[C:8]1([CH:6]=[CH:6][C:8]2[CH:17]=[CH:16][C:11]([C:18]([O:5][CH3:4])=[O:19])=[CH:10][CH:9]=2)[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1
Reactant: C[O-]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(C=Cc2ccc(C(=O)OC)cc2)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
DMF (100 mL) and methyl 4-formylbenzoate (13.9 g, 0.13 mole) are added to the product solution from step (3) at a temperature of 25° to 28° C. Sodium methoxide (7 g) is added to the solution while maintaining the temperature at 25° to 35° C. by means of a water bath. The reaction mixture is heated at 25° to 35° C. for an additional 4 hours and then water (100 mL) is slowly added at 25° to 35° C. (with water bath cooling as necessary) to precipitate the product. After stirring for 1 hour, the product, dimethyl 4,4'-stilbenedicarboxylate, is collected by filtration, washed with water until the filtrate has a pH of 5 to 7 and then washed with methanol (2×50 mL). After drying at 60° C. under vacuum, dimethyl 4,4'-stilbenedicarboxylate is obtained in a 65% yield based on the amount of methyl 4-(hydroxymethyl)benzoate employed.
Reaction SMILES: Cl.[CH:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.FC(F)(F)S([O-])(=O)=O.[N:18]1([S:23](N2C=C[NH+](C)C2)(=[O:25])=[O:24])[CH:22]=[CH:21][N:20]=[CH:19]1>>[N:18]1([S:23]([N:4]2[CH2:3][CH:2]3[O:9][CH:6]([CH2:7][CH2:8]3)[CH2:5]2)(=[O:25])=[O:24])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CC2CCC(C1)O2)n1ccnc1

Procedure:
3-(Imidazole-1-sulfonyl)-8-oxa-3-aza-bicyclo[3.2.1]octane was prepared in accordance with step A of the general method described in example 76 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=244.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[N+:19]([O-])=O)(=[O:10])=[O:9])[CH:7]=1.[Sn](Cl)Cl.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[NH2:19])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1ccc(F)cc1N
Temperature: 25 °C
Yield: 61.3 %

Procedure:
The nitro intermediate (0.5 mmol) above was dissolved in EtOH (10 mL) and was treated with tin(II) chloride (2.5 mmol). The reaction mixture was heated to reflux for 12 h. The contents were cooled to RT and treated with 1 M aqueous NaOH until the pH of the reaction mixture was between 8-9 which resulted in formation of a precipate. The precipitate was then filtered, washed with methanol (10 mL) and DCM (10 mL). The combined filtrate was concentrated in vacuo and the residue obtained was purified by column chromatography eluting with DCM/ethyl acetate as eluant to give 115 mg of 5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][F:16])[CH2:12][CH2:11][N:10]2C(OCC2C=CC=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][F:16])[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](CF)C[C@@H]1c1ccc(F)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC[C@H]1CCN[C@@H](c2ccc(F)c(F)c2)C1
Yield: 74 %

Procedure:
A mixture of (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(fluoromethyl)piperidine-1-carboxylate (85 mg, 0.23 mmol), 10% palladium on carbon (85 mg) and ethyl acetate (5 mL) in a 100 mL flask was stirred under 1 atmosphere of hydrogen at room temperature for three days. The mixture was filtered and the filtrate concentrated and dried to give (±)-(2R,4S)-2-(3,4-difluorophenyl)-4-(fluoromethyl)piperidine (39 mg, 73% yield), MS (EI) for C12H14F3N: 230 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]=[C:8]1[C@@H:14]([N:15](C)[C:16](=O)C(F)(F)F)[CH2:13][CH2:12][S:11][C@H:10]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:27]([O:29][CH3:30])=[O:28])[N:9]12>O.CO>[CH3:16][NH:15][C@H:14]1[CH2:13][CH2:12][S:11][C@H:10]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:27]([O:29][CH3:30])=[O:28])[N:9]2[C:8]1=[O:7]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N(C)C(=O)C(F)(F)F)C(=O)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of K2CO3 (18.8 mg, 0.136 mmol) in water (0.16 mL) was added to a solution of (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoro-N-methylacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (45.6 mg, 0.124 mmol) in MeOH (0.4 mL). The reaction mixture was stirred at rt for 2 hr. After a total of 3 hr, a stream of nitrogen gas was used to partially evaporate the MeOH. The residue was then partitioned between CHCl3 and saturated aqueous NaCl. The aqueous layer was isolated and extracted once again with CHCl3. All organic phases were combined, dried over MgSO4 and concentrated to give (4S,7S,10aS)-methyl 4-(methylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (34 mg, 0.12 mmol, 100% yield) of a yellow oil. Anal. Calcd. for C12H20N2O3S m/z 272.3. found: 273.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:28][NH:29][C:43]([CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:44])=[O:27])=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C2(c3ccc(C(=O)NNC(=O)C4CCC4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide (0.7 g, 1.69 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.35 mL, 2.5 mmol) was catalytic DMAP (20 mg) and cyclobutane carbonyl chloride (0.19 mL, 1.69 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The solution was washed with brine (5 mL), dried (MgSO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (6:4) afforded 0.63 g (75% yield) of cyclobutanecarboxylic acid N′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide. 1HNMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.67 (d, 2H), 7.41-7.08 (comp, 8H), 6.82-6.61 (comp, 3H), 3.79 (s, 3H), 2.41 (s, 2H), 3.09-3.02 (m, 1H), 2.41-2.23 (comp, 8H), 2.19-1.67 (comp, 6H); MS (M+1) 498.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)[CH:27]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]1[C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1cncc(C2CCCCN2)c1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2c2cccnc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-3-yl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.99 minutes; C27H25Cl2N5O2 (522.43); mass spectrum: (M−H)−=521/523/525 (chlorine isotope).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[N:5]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[C:6]=[S:7]>O1CCCC1>[CH2:1]([NH:4][C:6](=[S:7])[NH:5][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: COC(=O)c1ccsc1N=C=S
Solvent: C1CCOC1
Product: CCCNC(=S)Nc1sccc1C(=O)OC
Reaction time: 4 h
Yield: 597.2 %

Procedure:
In a sulfonation flask, 13.5 g (0.023 mol) of n-propylamine are added dropwise to 350 ml of tetrahydrofurane and 41.3 g (0.021 mol) of methyl 2-isothiocyanatothiophene-3-carboxylate, such that the internal temperature does not arise above 40° C. The reaction mixture is then stirred for 4 hours at reflux temperature and then the tetrahydrofurane is removed in a water-jet vacuum. The residue is taken up in ethyl acetate and extracted three times with water. The organic phase is then dried over sodium sulfate and the solvent is removed in the water-jet vacuum, giving the crude product, which is purified by column chromatography over silica gel (eluant: ethyl acetate/hexane=1:3). 32.4 g of methyl 2-(3-propylthioureido)thiophene-3-carboxylate are obtained in the form of a beige powder having a melting point of 123-126° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:30][NH:29][C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[N:1]1([CH:7]2[CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:10]3=[N:11][C:12]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC(N2CCCCC2)C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC(N2CCCCC2)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 7-(piperidin-1-yl)-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (step 7) (62 mg, 0.156 mmol) in DCE (5 ml) under nitrogen, was treated with ethyl 7-oxoheptanoate (53.6 mg, 0.311 mmol) and stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (132 mg, 0.622 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (20 ml) and washed with water. The organic portion was passed through a phase separating column and concentrated under reduced pressure. Purification of the crude material by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][NH:10][C:9](=[O:22])[C:8]=2[CH:23]=1.[CH3:24]I.O>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:24])[C:9](=[O:22])[C:8]=2[CH:23]=1
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1cc(F)ccc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.1 g (2 mmol) of sodium hydride (55 percent oil dispersion) are suspended in 10 ml of dry dimethylformamide and treated with 0.5 g (1.7 mmol) of ethyl 8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate. After completion of the gas evolution, 0.13 ml (2 mmol) of methyl iodide is added and the mixture is stirred at room temperature for 2 hours. The mixture is poured into ca 60 ml of water and extracted three times with 30 ml of chloroform each time. The combined chloroform extracts are washed with ca 30 ml of water, dried over magnesium sulphate and evaporated. After recrystallisation from ethyl acetate, there is obtained ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 196°-197° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([C@H:58]3[CH2:62][C@H:61]([O:63][N+:64]([O-:66])=[O:65])[C@@H:60]([O:67][CH3:68])[CH2:59]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([C@H:58]3[CH2:62][C@H:61]([O:63][N+:64]([O-:66])=[O:65])[C@@H:60]([O:67][CH3:68])[CH2:59]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)[C@@H]3C[C@H](OC)[C@@H](O[N+](=O)[O-])C3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)[C@@H]3C[C@H](OC)[C@@H](O[N+](=O)[O-])C3)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A methanol (20 mL) solution of 1-({[(1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentyl]carbonyl}oxy)ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (1420 mg, 1.62 mmol) was heated to 70° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography, eluting with 0/100→10/90 methanol/dichloromethane to give the title compound as a white solid. Chromatography of the diasteromeric mixture over Chiralpak IC column, eluting with methanol/carbon dioxide, afforded the separate disastereomers D1 and D2.
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: CCO
Solvent: CC(C)O
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: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)CCC(=O)c1cc(Cl)ccc1O
Reactant: BrCC1CO1
Product: COC(=O)CCC(=O)c1cc(Cl)ccc1OCC1CO1
Yield: 53 %

Procedure:
Methyl 3-(5-chloro-2-hydroxybenzoyl)propionate was reacted with epibromohydrin in a similar manner to the procedure described in Example 1 (ii) to give methyl 3-[5-chloro-2-(2,3-epoxypropoxy)benzoyl]propionate as an oil (53%).