Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][NH:14][C:15](=O)[CH2:16][CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:48][C:15]([CH2:16][CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1)Cc1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A mixture of tert-butyl ((1R)-4-(2-((3-fluoro-4-nitrophenyl)carbonyl)hydrazino)-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (214 mg, 394 μmol) and Lawesson's reagent (207 mg, 512 μmol) in THF (3 mL) was heated in a Biotage® microwave reactor at 100° C. for 15 minutes. The mixture was concentrated under reduced pressure, and the resulting yellow solid was taken up in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 2% to 6% MeOH/DCM) to provide tert-butyl (R)-4-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (190 mg, 89.1% yield) as a light yellow solid. LCMS (API-ES) m/z: 564.0 (M+Na+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][C:43]1=[O:48]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:45]4[CH2:46][CH2:47][NH:42][C:43](=[O:48])[CH2:44]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:41])[NH:37][S:38]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: O=C1CNCCN1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CCN1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (134 mg, 0.2 mmol) was treated as described in general procedure R using excess piperazin-2-one (200 mg, 2 mmol) to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazin-2-one.
Reaction SMILES: N1(C[N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)CCCC1.C([Li])CCC.[CH:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[NH:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]=[C:8]1[CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:28]
Reactant: c1ccc2c(c1)ncn2CN1CCCC1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1nc2ccccc2[nH]1
Reaction time: 0.25 h

Procedure:
To a solution of 1-pyrrolidin-1-ylmethyl-1H-benzimidazole (5 g) in tetrahydrofurane (20 mL) cooled at a temperature close to −80° C., is added a 2.5M solution of butyl lithium in hexanes (10 mL). The mixture is stirred for 15 minutes. A solution of benzaldehyde (2.64 g) in tetrahydrofurane (20 mL) is added. The mixture is stirred at a temperature close to −80° C. for 1 hour, then at a temperature close to −20° C. for 2 hours. The reaction is quenched by addition of saturated ammonium chloride. The mixture is extracted with ethyl acetate. Pooled extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 90/10) to give (1H-benzimidazol-2-yl)phenylmethanol used without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:25])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([N+:22]([O-])=O)[CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.[Pd]>[C:1]12([NH:11][C:12](=[O:25])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: Nc1ccc(CCC(=O)NC23CC4CC(CC(C4)C2)C3)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCC(=O)NC23CC4CC(CC(C4)C2)C3)cc1N
Reaction time: 2 h
Yield: 46 %

Procedure:
500 mg of N-(1-adamantyl)-3-(3-nitro-4-aminophenyl)propionamide (prepared as described in Example 21) was dissolved in 20 ml of methanol. 200 mg of 10% w/w palladium-on-carbon was added to the solution, which was then catalytically reduced whilst bubbling hydrogen through it, under atmospheric pressure for 120 minutes. The catalyst was then removed by filtration, and the methanol was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using 19:1 ethyl acetate:methanol as the eluent, to afford 0.21 g of the title compound as crystals, melting at 151°-152° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([OH:12])[CH3:11].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(=O)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C(=O)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
2',4'-Difluoro-2-hydroxypropiophenone (2.8 g) was dissolved in methylene chloride (28 ml), to which were added triethylamine (2.5 ml) and methanesulfonyl chloride (1.3 ml) at 0° C. After stirring for 15 minutes, the mixture was washed with water (30 ml), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with methylene chloride. The desired fraction was concentrated, to give 2',4'-difluoro-2-methanesulfonyloxypropiophenone (3.0 g) as a colorless oil. This compound (3.0 g) was dissolved in 30 ml of N,N-dimethylformamide, to which were added 1H-1,2,4-triazole (0.94 g) and then 60% sodium hydride suspension in oil (0.5 g) at -10° C. After stirring at 0° C. for 50 minutes, the reaction mixture was added to a mixture of ethyl acetate (100 ml) and water (200 ml) for extraction. The water layer was extracted with ethyl acetate (100 ml) and the ethyl acetate layers were combined, washed with saturated aqueous solution of sodium chloride (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with ethyl acetate. The desired fraction was concentrated, to give 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)propiophenone (1.5 g) as a colorless oil. This compound (1.24 g) was added to a mixture of dimethyl sulfoxide (30 ml), 60% sodium hydride suspension in oil (0.25 g) and trimethylsulfoxonium iodide (1.38 g) at 10° C. and then the temperature was raised to 25° C. Two hours later, the reaction mixture was added to a mixture of diethyl ether (100 ml) and water (150 ml), diethyl ether layer was separated, and the water layer was extracted with diethyl ether (100 ml×2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with ethyl acetate-hexane (3:1), to give 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane as a colorless oil (0.87 g).
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].CC(C)=[O:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:34]=[O:35])=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[N:22][CH:23]=2)[CH:17]=1>O>[C:29]([CH2:28][CH2:27][NH:26][C:24]([C:21]1[N:22]=[CH:23][C:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[C:34]([OH:35])=[O:9])=[CH:19][CH:20]=1)=[O:25])([OH:31])=[O:30]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)O)cn1
Temperature: 50 °C

Procedure:
Solid KMnO4 (460 mg, 2.9 mmol) was added to an acetone (14 mL) and water (5 mL) solution of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as described in Example 6, (700 mg, 1.9 mmol) and the resulting mixture was heated to 50° C. After 20 h the resulting mixture was cooled, filtered through CELITE and washed with EtOAc. The aqueous phase was extracted with EtOAc and the combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:26]([O:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)(=[O:28])[CH3:27]
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2cc(OC(C)=O)nc(C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (3.11 g, 14.19 mmol) in dry CH2Cl2 (230 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added DIEA (2.46 mL, 14.88 mmol), DMAP (173 mg, 1.42 mmol) and acetic anhydride (1.39 mL, 14.80 mmol) and the reaction mixture was stirred overnight at RT. The organic solution was then washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was finally purified by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) to give 6,7-dimethoxy-1-methylisoquinolin-3-yl acetate SIL 32158 as an off-white solid (3.26 g, 88% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([N+:18]([O-])=O)[CH:5]=1)[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[NH2:18][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCC)c(OCC)cc1N
Yield: 99.9 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of ethyl 4,5-diethoxy-2-nitrobenzoate (7.17 g, 25.3 mmol) and Pd/C (10%, 0.7 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 2-amino-4,5-diethoxybenzoate as a solid (6.401 g, 99%) 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 6.14 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.05 (m, 4H), 1.44 (t, 3H), 1.38 (m, 6H); LC-MS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].II>>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1cccc(F)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Product: OCCNc1cccc(F)c1

Procedure:
Similar procedure as described in example 31a) was used, starting from 3-fluorophenylglycine, sodium borohydride and iodine to give 3-fluoro-Phenylglycinol. LC-MS m/e 156 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=2[N:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(N)cncc2F)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
A mixture of (6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (44.02 g, 126.6 mmol) and tert-butyl 1-(3-amino-5-fluoro-4-pyridyl)piperidine-4-carboxylate 27 (prepared according to Preparation N-15) (34 g, 115.1 mmol) in pyridine (510.0 mL) was heated at 95° C. internally overnight (18 h). Mixture was cooled to room temperature (product precipitated) then added ethanol (340.0 mL) and stirred at room temperature for 10 mins. Collected yellow solid by filtration, washed well with ethanol, dried by suction, then on high vac line for 1 h to leave product 28 as a yellow solid, (32.5 g 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47 (masked signal, 1H), 2.02-1.91 (m, 4H), 1.47 (s, 9H). MS (ES+) 474.2.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=O)C.[CH:26](=O)[CH2:27][CH2:28][CH3:29].C([BH3-])#N.[Na+].Cl>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1
Reactant: CCCC=O
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1.52 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 600 ml ofdimethylformamide, 40 g of butyraldehyde and 1.60 g of molecular sieves [Na12 (AlSiO4)12. 27 H2O], 36 g of sodium cyanoborohydride are added while stirring under nitrogen and keeping the temperature between about 20 and 30° for one hour. After stirring the mixture for 68 hours at room temperature, 6 lt of water are added, followed by 110 ml of concentrated hydrochloric acid and stirring is continued for one hour. The precipitate formed is filtered off, washed with water, dissolved in 1.2 lt of 2N aqueous sodium hydroxide and the solution refluxed for 2 hours under nitrogen. After cooling to room temperature it is filtered and the filtrate combined with 250 ml of glacial acetic acid. The precipitate formed is collected, 333 g thereof are dissolved in 2.8 lt of hot, 80% aqueous acetonitrile, the solution filtered, the filter washed with 500 ml more of said acetonitrile and the filtrate diluted with 3.3 lt of hot water. The precipitate formed at 14° is filtered off, taken up in 2.15 lt of hot, 90% aqueous ethanol and the solution diluted with 2.5 lt of hot water. The solids separated after cooling are collected and washed with water, to yield the 4-(4-aminophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid melting at 232°-234°it is identical with that obtained according to Example 3.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:16][OH:17].C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:16][OH:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 24, 2-oxo-4-phenylbutyric acid and L-serinyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-serinyl-L-proline.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][C:24]=4[F:36])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl.O1CCOCC1>CO>[F:36][C:24]1[CH:25]=[C:26]([C:29]2[N:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:27]=[CH:28][C:23]=1[C:20]1([C:17]2[N:13]3[CH2:14][CH2:15][S:16][C@:10]([CH2:9][OH:8])([CH3:37])[CH2:11][C:12]3=[N:19][N:18]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
The compound (366 mg, 0.68 mmol) obtained in Example 89-2) was dissolved in methanol (4 mL). 4 N hydrochloric acid-dioxane (1.69 mL) was added to the solution, and the mixture was stirred at room temperature for 2 h. The solvent was distilled off under reduced pressure, and the residue was separated into organic and aqueous layers with methylene chloride (150 mL) and saturated aqueous sodium hydrogencarbonate (50 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100 to 20:80) to obtain the title compound (210 mg, 73%) as a white solid.
Reaction SMILES: [C:1]([CH2:5][NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])(=O)[CH:2]=C.Cl[C:13](OCC)=O>>[CH3:13][C:7]1([CH3:8])[N:6]=[C:5]([CH:1]=[CH2:2])[O:10][C:9]1=[O:11]
Reactant: CCOC(=O)Cl
Reactant: C=CC(=O)CN[C@@H](C)C(=O)O
Product: C=CC1=NC(C)(C)C(=O)O1
Temperature: -78 °C

Procedure:
2-Vinyl-4,4-Dimethylazlactone (VDM) was prepared from N-acryloylmethylalanine (S. M. Heilmann and H. K. Smith II, J. Appl. Polym. Sci., 24, 1551 (1979)) by the Taylor and Platt procedure (L. D. Taylor and T. E. Platt, J. Polym. Sci. Polym. Lett. Ed., 7, 597 (1969)) with ethyl chloroformate as the dehydrating agent. A modified workup procedure was used in which, instead of cooling the filtrate to crystallize the product, the filtrate was concentrated on a rotary evaporator, and the crude product was distilled just above room temperature at 0.5 Torr. Receiving flasks were cooled to −78° C. to collect the product. Typical distilled yields were approximately 80%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][O:12]S(=O)[O:10]2)=[N:7][CH:8]=1)[CH3:2].O[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:10])[CH2:13][O:12][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C2COS(=O)O2)nc1
Solvent: CN(C)C=O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
0.5 g (0.0023 mol) 5-ethyl-2-(2-oxo-[1,3,2]-dioxathiolan-4-yl)-pyridine was added into solution of 0.343 g (0.0027 mol) p-hydroxy benzaldehyde dissolved in 5 mL DMF. Reaction mixture was heated at 80° C. for 14 hr. Subsequent work up furnished 0.3 g (47%) the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].C([O-])([O-])=O.[K+].[K+]>O=S(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([O:19][CH3:18])[CH:21]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: COc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (500 mg, 2.10 mmol, 1.0 eq) in SOCl2 (5 mL) was heated at 65° C. under N2 for 1 h. The solution was then evaporated in vacuo and the remaining residue dissolved in CH2Cl2 and added dropwise to a mixture of 3-methoxyaniline (220 mg. 1.9 mmol, 0.9 eq) and K2CO3 (1.4 g, 10.1 mmol, 5.0 eq) in THF (10 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the solution extracted with EtOAc. The combined organic extracts were washed with aqueous Na2CO3 and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a colourless oil (580 mg, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:9]([C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:17])[CH3:1]
Reactant: CN(C)c1cccc(C(=O)c2nnnn2C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a stirred solution of [3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (3.84 g, 17 mmol) in dry pyridine (30 mL) was added hydroxylamine hydrochloride (2.89 g, 42 mmol). The reaction mixture was stirred at 70° C. for 6 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded 3-[(hydroxyimino)(1-methyl-1H-tetrazol-5-yl)methyl]-N,N-dimethylaniline as a yellow solid [4.48 g, yield 99.6%; HPLC/MS:m/z=247 (M+H); log P(HCOOH)=1.17].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2cc[nH]c2c1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Br)ccc23)CC1
Yield: 46.9 %

Procedure:
A stirred solution of 6-bromoindole (390 mg, 2.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (438 mg, 2.2 mmol), and pyrrolidine (0.42 mL, 5.0 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (354 mg, 47%).