Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:22][S:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:19]([OH:21])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:22][S:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)=[O:5])[C:19]([OH:21])=[O:20])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Sodium perborate tetrahydrate (151 mg, 0.95 mmol) was added as a solid to a stirred solution of (2R)-tert-Butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionic acid (380 mg, 0.76 mmol) in acetic acid (10 mL) at 40° C. This solution was stirred at 40° C. for 2 hours (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a 2:1 mix of diastereoisomers as an off-white solid (372 mg, 95%): mp. 169-170° C. Rf 0.65 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 7.88 (2H, d, J=8 Hz, Ar—H), 7.62-7.78 (7H, m, Ar—H), 7.44 (2H, d, J=8 Hz, Ar—H), 7.36 (1H, d, J=8 Hz, NH), 7.11-7.22 (2H, m, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 4.06-4.26 (3H, m, CHN+PhCH2), 2.96-3.04 (2H, m, CH2CHN), 1.39 (3H, s, CMe3, minor isomer), 1.36 (6H, s, CMe3, major isomer), ESI-LCMS e/z calcd for C29H30N2O5S: 518.631, found 519 (M+H)+, 541 (M+Na)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:19][CH2:18][CH2:17]1)#[N:2]
Reactant: BrCCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCC2)c1
Yield: 42.3 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.8 g, 10 mmol), sodium hydride (60% in oil, 1.2 g, 30 mmol), 1,3-dibromopropane (3.0 g, 15 mmol) and dimethyl sulfoxide (30 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (0.91 g, 42%) was obtained as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][OH:26])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=[O:26])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A solution of oxalyl chloride (2.4 mL, 27.5 mmol) in 125 mL DCM as cooled to −78 C and DMSO (3.3 mL, 47.1 mmol) was added slowly. After 10 in a solution of 2-(N-tert-butoxycarbonyl-4-piperidyl)ethanol (4.5 grams, 19.6 mol) in 10 mL DCM was added. The mixture was stirred for 20 min then triethylamine (13.6 mL, 98.1 mmol) was added and the mixture was warmed to room temperature. After 30 min the mixture was diluted with ethyl acetate and washed with water (3×). The organic portion was dried over sodium sulfate and concentrated. Flash chromatography (3/1 hexane/EtOAc) afforded 3.7 grams (83%) of the desired aldehyde. 1H NMR (400 MHz, CDCl3). δ1.13-1.43 (m, 2H), 1.48 (s, 9H), 1.68-1.77 (m, 2H), 2.04-2.11 (m, 1H), 2.38-2.41 (d, 2H), 2.71-2.8 (m, 2H), 4.04-4.14 (m, 2H), 9.8 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[N:3]1
Reactant: C1COCCN1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Yield: 41.5 %

Procedure:
A mixture of 1-methyl-5-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 223 μmol), morpholine (156 μl, 1.79 mmol), propylphosphonic anhydride (50% in ethyl acetate, 329 μl, 558 μmol) and N,N-diisopropylethylamine (114 μl, 669 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The mixture is dissolved in ethyl acetate and washed with sodium bicarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by chromatography on a 20 g silica column using ethyl acetate/methanol 10% as eluent affording 1-methyl-4-(morpholine-4-carbonyl)-N-(2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (40 mg, 41.5%) as a white solid. mp.: 218-220° C. MS: m/z=433.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11]>>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1cncc(Cl)n1
Product: CS(=O)(=O)c1ccc(-c2cncc(N)n2)cc1

Procedure:
6-(4-Methanesulfonyl-phenyl)-pyrazin-2-ylamine was prepared from 6-chloro-pyrazin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford an off-white solid (99%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.39 (s, 1H), 8.25 (d, 7.6 Hz, 2H) 8.02 (d, 7.6 Hz, 2H), 7.95 (s, 1H), 6.70 (bs, 2H), 3.26 (s, 3H).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)n2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(Cl)n2)CC1

Procedure:
A solution of tert-butyl 4-cyano-4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0.82 mmol) in methanol (20 mL) with triethylamine (1 mL) was reacted with Raney nickel (0.5 mL of 50% slurry in water) under 40 psi hydrogen for 5 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of the solvent afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCOc1cccnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1cccnc1
Temperature: 90 °C
Yield: 21.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 3-(2-chloroethoxy)pyridine hydrochloride (234 mg, 1.2 mmol) and potassium carbonate (456 mg, 3.3 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)quinazoline (95 mg, 20%). m.p. 188-190° C. 1H NMR Spectrum: (DMSOd6) 3.90(s, 3H); 4.45(m, 4H); 7.24(s, 1H); 7.18(dd, 1H); 7.2-7.60(m, 3H); 7.80(s, 1H); 8.20(d, 1H); 8.35(s, 2H); 9.50(s, 1H) MS-ESI: 441 [MH]+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([CH:16]=[O:17])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.ClCCl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])[C:38]([C:2]4[CH:3]=[CH:4][C:5]5[O:19][CH2:18][N:8]6[C:9]7[CH:10]=[CH:11][CH:12]=[C:13]([CH:16]=[O:17])[C:14]=7[CH:15]=[C:7]6[C:6]=5[N:20]=4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1
Reactant: O=Cc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(C=O)cccc5n3CO4)cc12
Temperature: 100 °C
Yield: 80 %

Procedure:
To a solution of 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carbaldehyde (31 mg, 0.11 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.10 mmol) and K3PO4.3H2O (53 mg, 0.19 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was added X-Phos (5 mg) and Pd2(dba)3 (5 mg) under nitrogen. The mixture was heated at 100° C. for 16 hours, and then filtered through the celite pad. The filtrate was extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to provide the 2-(4-fluorophenyl)-5-(11-formyl-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, yield: 80%) by the prep-TLC (dichloromethane:MeOH=30:1). MS (M+H)+: 625.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.O1CCOCC1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][N:17]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH:22][C:20]1[C:19]([C:30]([NH2:32])=[O:31])=[CH:18][N:17]=[C:16]([NH:15][CH2:14][CH2:13][NH:12][C:2]([NH2:3])=[O:1])[N:21]=1
Reactant: N#C[O-]
Reactant: Cc1cccc(Nc2nc(NCCN)ncc2C(N)=O)c1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nc(NCCNC(N)=O)ncc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 147 mg portion of potassium cyanate and 450 μl of 4 M hydrochloric acid-dioxane solution were added to a mixture of 312 mg of 2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide and 3 ml of water and 3 ml of 1,4-dioxane, followed by stirring at room temperature for 1 day. The reaction mixture was alkalified by adding 1 M sodium hydroxide aqueous solution, and the thus formed precipitate was collected by filtration. The filtered material was washed by stirring it in methanol while heating and then collected by filtration to obtain 212 mg of 4-(3-methylanilino)-2-[(2-ureidoethyl)amino]pyrimidine-5-carboxamide (colorless solid).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([NH2:10])=[O:9].[C:11]1([CH3:21])[CH:16]=CC(S(O)(=O)=O)=[CH:13][CH:12]=1.CN(C=O)C.C(=O)CC(C)C>C1(C)C=CC=CC=1>[CH2:12]([C:13]1[NH:10][C:8](=[O:9])[C:3]2[C:4]([CH3:7])=[N:5][S:6][C:2]=2[N:1]=1)[CH:11]([CH3:21])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nsc(N)c1C(N)=O
Agent: CC(C)CC=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nsc2nc(CC(C)C)[nH]c(=O)c12
Temperature: 130 °C
Reaction time: 7 h
Yield: 89 %

Procedure:
To a 2 L flask equipped with Dean Stark was charged 5-amino-3-methylisothiazole-4-carboxamide (method 63) (1 equiv), p-toluene sulphonic acid (0.049 equiv), DMF (9.75 volumes). The reaction was stirred until a solution was obtained and isovaleraldehyde (1.10 equiv) and toluene (4.9 volumes) were added. The resulting mixture was heated to 130° C. and held at reflux for 1 hour removing water via a Dean Stark apparatus. Once the reaction was complete toluene was removed under vacuum distillation. Sodium bisullfite (2.50 equiv) was charged and the mixture was held at 115° C. for 7 hours, then cooled to room temperature overnight. The solid was removed by filtration through harborlite and washed with DMF (1 volume). Analysis showed conversion to product and the reaction was heated to 50° C., water (15 volumes) was added and the resulting precipitate was cooled to room temperature and held for 1 h. The product was isolated by filtration and washed with water (2×0.5 volumes), dried to give a pale brown solid (typical yield 89%).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:13]1([CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>CO>[C:2]1([C:1]2[CH:9]=[C:10]([NH2:11])[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH3:21])[N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccccc1-n1nc(-c2ccccc2)cc1N
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Benzoylacetonitrile (500 mg, 3.44 mmol) and o-tolylhydrazine hydrochloride (574 mg, 3.61 mmol) were placed in a microwave vial and dissolved in methanol (1.7 mL). The reaction vessel was sealed, placed in a microwave oven and heated at 120° C. for 1 hour. After this period, the reaction mixture was concentrated onto silica gel and purified by flash chromatography (0-50% ethyl acetate/hexanes gradient) to afford the desired intermediate, 5-phenyl-2-o-tolyl-2H-pyrazol-3-ylamine (392 mg). LC/MS: Calc. C16H15N3 249.13 amu; Obs. [M+H]+=250.2 amu.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
The same operation as in Example (40a) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained by the method described in Example (112d) (0.5 g, 2.05 mmol) and benzyl chloroformate (0.5 mL, 3.50 mmol), to obtain 0.73 g of the title compound as a colorless oily substance (93%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:9][C@@H:10]([C:21]([O:23]CC1C=CC=CC=1)=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]>CN(C=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]([CH:8]([C:31]([OH:33])=[O:32])[CH2:9][C@@H:10]([C:21]([OH:23])=[O:22])[NH:11][C:12](=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(Nc1ccccc1)N[C@@H](CC(C(=O)OCc1ccccc1)N(CCCl)CCCl)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)N[C@@H](CC(C(=O)O)N(CCCl)CCCl)C(=O)O

Procedure:
A solution of the intermediate dibenzyl 4-[N,N-bis(2-chloro-ethyl)amino]-phenylcarbamoyl-L-glutamate (1.138 g) in DMF (15 ml) was hydrogenated over 10% Pd/C for 16 hours. After filtration and evaporation in vacuo, the residue was dissolved in CHCl3 (20 ml). After 18 hours the crystalline precipitate was filtered off and dried in vacuo to obtain 4-[N,N-bis-(2-chloroethyl)amino]phenylcarbamoyl-L-glutamic acid. Yield, 730 mg (93%). After recrystallisation from acetone/CHCl3 microscopic rods formed m.p. 116-118° C. NMR (CD3COCD3): δ 8.0(s)1H; 7.2(d)2H; 6.6(d)2H; 6.2(d)2H NH; 4.4(m)1H; 3.6(m)8H; 2.5-1.9(m)4H.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:27][C@H:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].CN(C)C=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:27][C@@H:26]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][C@H:17]1[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: [S-]c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)NC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Sc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
0.45 g (3.41 mmol) of sodium thiophenolate was added to a solution of 1.23 g (3.08 mmol) of (4R)-1-t-butoxycarbonyl-4-(p-toluenesulfonyloxy)-N-t-butyl-L-prolinamide [prepared as described in Preparation 6(a)] in 10 ml of a 2:1 by volume mixture of dimethylformamide and ethyl acetate, and the mixture was stirred for 3 hours. At the end of this time, the reaction mixture was poured into a 10% w/v aqueous solution of sodium hydrogen-carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent, to give 1.0 g of the title compound as a colorless powder, melting at 119°-121° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[BrH:11]>>[BrH:11].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Br:11])[CH:2]=1
Reactant: OCCCc1cccnc1
Agent: Br
Product: BrCCCc1cccnc1

Procedure:
A solution of 32.53 g (0.24 mole) of 3-(3-pyridyl)-propan-1-ol in 176 mL of 48% hydrobromic acid is refluxed for 24 hours. The reaction mixture is evaporated and the residue is taken up in 500 mL isopropanol and subjected to evaporation again. The evaporation procedure is repeated one more time. The resulting product is then taken up in hot isopropanol and treated with charcoal and filtered. The filtrate is cooled slowly to give 3-(3-pyridyl)propyl bromide hydrobromide, m.p. 103-105°.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][CH:5]=1.[Cl-].[Ca+2].[Cl-]>O.C(O)(C)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)C(CSc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(O)C(CSc1ccc(Cl)cc1)n1cncn1
Reaction time: 18 h
Yield: 87.8 %

Procedure:
1.39 g (0.0367 mol) of sodium borohydride in 30 ml of water were slowly added dropwise to a mixture of 16.2 g (0.05 mol) of 1-(4-chlorophenylthio)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-one (prepared as described in Example 1) and 3.86 g (0.035 mol) of calcium chloride in 250 ml of isopropanol at -15° C. After 18 hours, the reaction mixture was concentrated in vacuo, the residue was taken up in methylene chloride, and the solution was washed with water, dried over sodium sulphate, filtered, and concentrated again. The oily residue crystallized after being triturated with diisopropyl ether. 14.3 g (87% of theory) of 1-(4-chlorophenylthio)-4,4-dimethyl-2-(1,2,4-triazol-1-yl) -pentan-3-ol of melting point 84° C. were obtained.
Reaction SMILES: [SH:1][CH2:2][C@H:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:17]([O-])([O-])=[O:18].[K+].[K+].C1N=CN(C(N2C=NC=C2)=O)C=1.C(OC(C)C)(=O)C>C(#N)C.O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]2[C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][S:1][C:17]2=[O:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(CN[C@@H](CS)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)O)cc1
Temperature: 40 °C
Yield: 69.9 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with the title compound from Example 2 (400.0 g, 1.66 mol), K2CO3 (480.0 g, 3.47 mol) and water (2.8 L). The mixture was heated at 40° C. while stirring until it became homogeneous and was then cooled to room temperature. A solution of N,N-carbonyldiimidazole (400.0 g, 222.47 mol) in acetonitrile (2.8 L) was added dropwise at a rate that maintained an internal reaction temperature less than 30° C. The reaction was monitored by HPLC and was complete upon the disappearance of the starting material (about 15 minutes). The acetonitrile was removed by heating at 40° C. and 80-100 torr. Isopropyl acetate (200 mL) was added and the pH of the mixture was adjusted to 2 with 3 M H2SO4. The biphasic mixture was filtered, and the organic phase was isolated. Additional isopropyl acetate was added and the solution was dried by azeotropic distillation. The reaction volume was reduced further until a precipitate began to form. The yellow precipitate was isolated by filtration and dried at 50° C. overnight to afford the title compound (310 g, 70%).
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12])(=[O:7])=[O:6]>CO>[NH:1]([C:11]([C:10]1[CH:9]=[C:8]([S:5]([NH:4][CH3:3])(=[O:7])=[O:6])[CH:17]=[CH:16][CH:15]=1)=[O:12])[NH2:2]
Reactant: NN
Reactant: CNS(=O)(=O)c1cccc(C(=O)OC)c1
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 65 °C
Yield: 74.3 %

Procedure:
Hydrazine (43.3 mg, 1.352 mmol) was added to the methyl 3-(N-methylsulfamoyl)benzoate (155 mg, 0.676 mmol) in methanol and refluxed for 12 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield 3-(hydrazinecarbonyl)-N-methylbenzenesulfonamide (120 mg, 0.502 mmol, 74.3% yield). 1H NMR (CDCl3, 400 MHz): δ 8.25 (m, 1H), 8.01 (m, 2H), 7.64 (m, 2H), 4.63 (m, 1H), 4.17 (m, 2H), 2.69 (d, 3H, J=5.2 Hz). ESI-MS: 230.0 [M+H]+