Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=O.[CH3:4][C:5]([S:22][S:23][CH3:24])([CH3:21])[CH2:6][NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[CH:12]=1.[OH-].[Na+]>C=O>[CH3:1][N:7]([CH2:6][C:5]([CH3:4])([S:22][S:23][CH3:24])[CH3:21])[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][OH:20])[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=1
Reactant: CSSC(C)(C)CNCCOc1cc(CO)nc(CO)c1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CSSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Temperature: 100 °C

Procedure:
365 μl of formic acid are added to a suspension, cooled to 0° C., of 322 mg of 4-[2-(2-methyl-2-(methyldisulphanyl)propylamino)ethoxy]-2,6-bis(hydroxymethyl)pyridine in 262 μl of formaldehyde. The mixture is heated at 100° C. for 1¼ hours. After returning to ambient temperature, the mixture is hydrolysed and then a 5N aqueous sodium hydroxide solution is added until a pH=12 is obtained. The aqueous phase is extracted 3× with AcOEt and the combined organic phases are dried over MgSO4 and concentrated under RP. 310 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5]C(=O)OCC1C=CC=CC=1.[H][H]>CO>[NH2:5][CH2:4][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)NC(CO)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl tert-butyl (3-hydroxypropane-1,2-diyl)biscarbamate (400 mg, 1.23 mmol) was dissolved in methanol (12.3 mL) and put under a hydrogen atmosphere with 3 cycles of evacuation and hydrogen balloon flushing. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours, and then filtered through CELITE. The filtrate was concentrated under reduced pressure to afford tert-butyl 1-amino-3-hydroxypropan-2-ylcarbamate. MS ESI calcd. for C8H19N2O3 [M+H]+ 191. found 191. 1H NMR (500 MHz, CDCl3) δ 5.25 (s, 1H), 3.87 (d, J=10.0 Hz, 1H), 3.71 (d, J=10.5 Hz, 1H), 3.59-3.63 (m, 1H), 3.08 (d, J=10.6 Hz, 1H), 2.90 (d, J=10.1 Hz, 1H), 1.84 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][C:3]=1[F:13].C([O-])(=[O:16])C.[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:16])=[CH:4][C:3]=1[F:13]
Reactant: CC(=O)[O-]
Reactant: Fc1cc2ccnc(Cl)c2cc1Br
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(F)c(Br)cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
12.9 g (49.5 mmol) 7-bromo-1-chloro-6-fluoro-isoquinoline (94) were dissolved in 250 ml of acetic acid. After addition of 38.7 g (0.5 mol) of ammonium acetate, the solution is stirred at 100° C. After 3 h, the solvent was removed under reduced pressure and the residue was poured into water. The precipitate is filtered and dried to yield 9.91 g (83%) of the title compound. Rt=1.15 min (Method C). Detected mass: 242.2/244.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[F:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[F:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.66 g, 47%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 5.07 mmol) and 4-fluorophthalic anhydride (0.80 g, 5.07 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Li+].[OH-].C1COCC1.CO.Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(COC(=O)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccco3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 36.5 %

Procedure:
4-Methoxybenzyl 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-2a) (750 mg, 1.4 mmol) was stirred a 2/2/1 mixture of aqueous 2N LiOH/THF/MeOH (45 mL) at ambient temperature for 3 hours. The solution was acidified with aqueous 1N aq HCl to a pH of ˜3 (ca. 100 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (9 mL) and purified by reverse phased HPLC (5-95% ACN in H2O gradient:40 minutes) in three-3 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in absolute ethanol and evaporated (4×, 20 mL) to provide pure 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (205 mg, 36%) as a white solid. M.p. 151-152° C. 1H NMR (DMSO-d6, 400 MHz): 3.71 (s, 3H), 4.24 (s, 2H), 4.27 (s, 2H), 6.14 (d, 1H, J=3.2 Hz), 6.26 (m, 1H), 6.87 (d, 2H, J=9.2 Hz), 7.14 (d, 2H, J=8.8 Hz), 7.41 (s, 1H), 7.89 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8.4 Hz), 13.48 (bs, 1H). MS 400 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:24]#[N:25])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>Cl.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([CH2:24][NH2:25])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(C#N)n3)cc(C)c21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(CN)n3)cc(C)c21
Yield: 11.7 %

Procedure:
A solution of [6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.35 g, 3.82 mmol), 10% Pd/C (1.35 g) and 6M HCl (2 drops) in EtOH (60 mL) was hydrogenated at 40 psi for 1 hour. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-aminomethyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.16 g, 11.7%). 1H NMR (400 MHz, DMSO-d δ 8.42 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 7.00 (m, 1H), 5.58 (m, 1H), 3.80 (s, 2H), 3.18 (m, 1H), 2.38 (m, 4H), 1.17 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[NH:9][C:8]2=O)=[CH:3][CH:2]=1>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[NH:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2SC1c1ccncc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCC(c1ccncc1)S2
Temperature: 80 °C
Yield: 53.2 %

Procedure:
To a solution of 2-(pyridin-4-yl)-2H-benzo[b][1,4]thiazin-3(4H)-one (0.6 g, 0.00247 mol) in THF (60 mL) was added borane-dimethyl sulfide complex solution under nitrogen atmosphere. The reaction mixture was heated at 80° C. for 3 h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to RT and quenched with 1N hydrochloric acid (100 mL). The mixture was then basified with 10% sodium hydroxide solution (50 mL), extracted with EtOAc (3×100 mL), and the organic layer concentrated under reduced pressure. The crude product was purified by column chromatography (70% EtOAc:hexane in silica 100-200 mesh, diameter of column—5 cm, height of silica—approx. inch) to provide the desired compound as a yellow colored solid (0.3 g, 53% yield).
Reaction SMILES: C1([O:7][C:8](=S)[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:7])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Yield: 70 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH:25]=O>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][NH:6][CH3:5]
Reactant: Cn1cc(C=O)c2cc(Cl)ccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Product: CNCc1cn(C)c2ccc(Cl)cc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 5-chloro-1-methyl-1H-indole-3-carboxaldehyde for the ,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.1 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[CH:26]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn(C)c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1-Methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=485.4.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Product: CN(C)CCN(C(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and benzoyl chloride
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].CCOCC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Yield: 99.2 %

Procedure:
10 g of 6-bromo-2-naphthol, 13.4 g of imidazole and 15 g of t-butyldimethylchlorosilane were stirred at room temperature in 75 ml of dimethylformamide for 18 hrs. Thereafter, 500 ml of ether were added thereto and the organic phase was washed 5 times with 100 ml of water each time. The organic phases were concentrated and the residue was dried in a high vacuum. 15.0 g of 6-bromo-2-t-butyl-dimethylsilyloxy-naphthaline were isolated as a yellowish solid. Yield: 99%. Mass spectrum (ISP): peaks inter alia at m/e: 338 and 336 (M+, in each case 34%), 281 (100%), 279 (98%), 200 (98%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.CCCCCC.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]([OH:43])[CH2:1][C:2]2[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:40][CH:39]=1
Reactant: CC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CC(O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a cold (−70° C.) solution of 2-methyl-cis-4,5-diphenyl-4,5-dihydro-imidazole-1-carboxylic acid, tert-butyl ester (253) (3.36 g, 10.0 mmol) in THF is added 1.6M n-butyl lithium in hexane (6.9 mL, 11.0 mmol), and the mixture is stirred for 1 h at −70° C. To the reaction mixture is added 4-fluorobenzaldehyde (1.18 mL, 11.0 mmol), and the mixture is stirred for 1 h at −70° C. and 1 h at RT. To the reaction mixture is added ammonium chloride solution, EtOAc, and the organic layer is separated, and washed with brine, dried (MgSO4), and filtered. The filtrate is rotary evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane: EtOAc (9:1) gives 2.11 g of the product 256. 1H NMR (CDCl3) δ 7.60-7.45 (m, 2H), 7.15-6.90 (m, 10H), 6.85-6.60 (m, 2H), 5.70-5.20 (m, 4H), 3.60-3.10 (m, 2H), 1.18 (s, 9H); MS: m/z 461 (M++1).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: COc1ccccc1CC(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COc1ccccc1CC(=O)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-methoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].Cl.[CH2:8]([NH2:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>CN(C)C=O>[CH2:8]([NH:17][C:4](=[O:5])[CH2:3][CH2:2][Br:1])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(Cl)CCBr
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CCBr)NCC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
3-Bromopropionyl chloride (25 g; 0.146 mole) was added slowly to a stirred suspension of phenacylamine hydrochloride (17.15 g; 0.1 mole) in dry dimethylformamide (50 ml) at room temperature. The internal temperature rose to ca. 40° C. The mixture was stirred for 2 hours and the DMF removed under vacuum. The residue was diluted with water (200 ml) and the crystalline solid collected, washed with water and dried. Weight of product = 9.49 g (35%), m.p. 114° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[S:21])[OH:20].C(Cl)Cl.O>C(O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]([S:21][CH2:13][CH:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4])=[O:20]
Reactant: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: OC(=S)c1ccco1
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(CSC(=O)c1ccco1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.4 g (2S)-1-(2- methyl-2-propenoyl)-2-pyrrolidine carboxylic acid are dissolved in 16.5 ml ethanol and 10 g furan-2-thiocarboxylic acid are added dropwise over 15 minutes. The reaction mixture is stirred overnight at room temperature, and methylene chloride and water (9:1) are then added. The so obtained organic phase is decanted and extracted with 0.5 N NaOH. The combined aqueous phases are adjusted to pH 4 and then twice extracted with 0.5 l CH2Cl2. The combined organic phases are dried over MgSO4, filtered and the solvent is evaporated. The residue is dissolved in CH2Cl2 /ether (1:4) and 6 ml tert-butylamine dissolved in ether are added; the tert-butyl ammonium salt of the title compound precipitates (M.P. 132°-140°) ([α]D20 =-67.3°; c=2.2 in H2O).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 81.3 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-isobutyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.0 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-galactopyranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CNCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (9 g, 40 mmol), sarcosine (3.6 g, 40 mmol), and potassium carbonate (5.5 g, 40 mmol) in ethanol (100 ml) and water (40 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with 1N aqueous HCl solution. The yellow precipitate was collected, washed with water and dried in vacuo to obtain crude [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid (10 g, 87%). A portion of the crude sample was recrystallized from EtOAc/hexane to afford the pure [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid: mp 152-155° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 4.00 (s, 2H), 7.06 (dd, 1H, J=8.79, 1.98 Hz), 7.22 (d, 1H, J=1.98 Hz), 7.69 (d, 1H, J=8.79 Hz), 12.8 (s, 1H); MS (+APCI) m/z 289/291 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 1-(2-methoxyphenyl)-piperazine hydrochloride (5.0 g, 20 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (200 mL). The crude solid product was collected by filtration, air dried, and purified by trituration with CHCl3 (1.3 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].[CH3:17]O>Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH3:16])[C:13]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: Cl
Product: COC(=O)C(C)c1cc(F)c([N+](=O)[O-])cc1F
Yield: 90 %

Procedure:
Compound (27a) (6.2 g, 26.8 mmol) was dissolved in a solution of a catalytic amount of concentrated hydrochloric acid (0.24 mL) in methanol (123 mL) and treated in the same manner as in (c) in Production Example 1 to give 5.9 g (90%) of compound (28a) as pale yellow oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][C:16]1[CH:20]=[CH:19][N:18]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](C2C=CC(N3C=CC(CC(O)=O)=C3)=CC=2)=[CH:33][CH:32]=1)#[N:30].C([C@H]1COC(=O)N1)C1C=CC=CC=1.CCOC(C)=O>CCOC(C)=O.CC(OC)(C)C.C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][C:16]1[CH:20]=[CH:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(-n3ccc(CC(=O)O)c3)cc2)cc1
Reactant: O=C(Cc1ccn(-c2ccc(F)cc2)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C1N[C@@H](Cc2ccccc2)CO1
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(-n3ccc(CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c3)cc2)cc1
Yield: 59 %

Procedure:
As in Example 14(a) for 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone, 2-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid and 4(S)-benzyl-2-oxazolidinone were coupled. Flash column chromatography with 10-25% EtOAc/hex to CH2Cl2 stepwise gradient eluant and subsequent trituration with EtOAc/MTBE/hex provided in 59% yield 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone as a pale yellow amorphous solid. 1H NMR: δ 7.75 (d, 2H, J=8.8 Hz), 7.70 (d, 2H, J=8.5 Hz), 7.65 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.32-7.25 (m, 3H), 7.17-7.15 (m, 3H), 7.12 (t, 1H, J=2.8 Hz), 6.40 (dd, 1H, J=1.7, 2.8 Hz), 4.74-4.68 (m, 1H), 4.31-4.16 (m, 4H), 3.29 (dd, 1H, J=2.9, 13.6 Hz), 2.80 (dd, 1H J=9.4, 13.4 Hz). Anal. Calculated for C29H23N3O3 : C, 75.47; H, 5.02; N, 9.11. Found: C, 75.36; H, 5.08; N, 9.15.