Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:38](O)=[O:39])[CH2:26][C:27]3[CH:36]=[C:35]([CH3:37])[C:30]4[NH:31][C:32](=[O:34])[O:33][C:29]=4[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[NH:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:26][C:27]3[CH:36]=[C:35]([CH3:37])[C:30]4[NH:31][C:32](=[O:34])[O:33][C:29]=4[CH:28]=3)[C:38](=[O:39])[N:1]3[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]3)=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[NH:10]1
Reactant: O=C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
200 mg (1.30 mmol) piperidin-4-one (used as the hydrate of the hydrochloride salt) were added to a solution of 500 mg (0.98 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 350 mg (1.09 mmol) TBTU, 300 μL (2.15 mmol) triethylamine in 10 mL DMF and the reaction mixture was stirred for 4 h at RT. The reaction solution was evaporated down i. vac., the residue was taken up in DCM, the organic phase was washed with saturated NaHCO3 solution and dried on Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient DCM/MeOH 20:1 to DCM/MeOH 10:1). The fractions containing the product were concentrated by evaporation, the residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8](=[O:12])[CH:9]([CH3:11])[CH3:10].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[OH:12][C@H:8]([C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH:1]=[O:7])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C=O
Reactant: CCCCCC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCC[C@H](C=O)[C@@H](O)C(C)C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of freshly distilled hexanal (120 μL, 1.0 mmol) in 500 μL dimethylformamide was added slowly over the course of 24 h to a stirring suspension of isobutyraldehyde (272 μL, 3.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at room temperature. After 24 h, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (7:3 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 80% yield (127 mg, 0.80 mmol), 98% ee and 96:4 anti:syn. IR (film) 3458, 2960, 2934, 2874, 2725, 1720, 1467, 1328, 1220, 1146, 1024, 991.2, 959.9, 901.1, 775.6 cm−1; 1H NMR (300 MHz, CDCl3) δ9.75 (d, 1H, J=3.3 Hz, CHO); 3.56 (dd (apparent q), 1H, J=6.0, 5.7 Hz, CHOH); 2.46 (dddd, 1H, J=8.4, 5.7, 5.7, 3.3 Hz, CHCH2); 1.99 (d, 1H, J=6.0 Hz, OH); 1.82 (m, 1H, CH(CH3)2); 1.70 (m, 1H, CHCH2); 1.58 (m, 1H, CHCH2); 1.30 (m, 4H, CH2CH2CH3); 0.97 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.93 (d, 3H, J=6.6 Hz, CH(CH3)2); 0.90 (dd (apparent t), 3H, J=6.6, 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ206.1, 76.7, 54.9, 31.3, 29.5, 26.7, 23.2, 20.0, 17.1, 14.2; HRMS (CI) exact mass calcd for [M+H]+ (C10H21O2) requires m/z 173.1541, found m/z 173.1540; [α]D=−15.4 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto, supra) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=97.8 min, (2R, 3R) anti isomer tr=102.7 min, (2R, 3S) and (2S, 3R) syn isomers tr=94.4, 96.5 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:22]([NH:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: CCCCCCNC(=O)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 28.5 %

Procedure:
4-{[4-(2-aminoethyl)phenyl]sulfonyl}-N-hexyl-1-piperidinecarboxamide (0.53 g, 1.34 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.461 g, 1.14 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.260 g, 0.325 mmol).
Reaction SMILES: Br[C:2]1[C:3](=[O:8])[O:4][CH2:5][CH2:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:9]1([C:2]2[C:3](=[O:8])[O:4][CH2:5][CH2:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1OCCC=C1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1OCCC=C1c1ccccc1

Procedure:
A solution of 3-bromo-5,6-dihydropyran-2-one (Org. Syn., 1996, 73, 231) (74.9 g), phenylboronic acid (51.8 g), potassium carbonate (294 g) and tetrakis(triphenylphosphine) palladium(0) (3.4 g) in toluene was heated (100° C.) under an atmosphere of nitrogen for 24 hours. The cooled solution was diluted by addition of ethyl acetate (1000 ml) and water (1000 ml) and the mixture filtered through Hiflo™. The organic phase was dried (MgSO4), evaporated in vacuo and the residue crystallised from methanol and then toluene to give the title compound, 43 g. mp. 100-101° C.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:20][S:21]([CH:24]2[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH2:4]1)[CH3:2].[OH-].[K+].[I:29]I.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[C:19]([I:29])=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:20][S:21]([CH:24]2[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Reactant: II
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1c1nnc2cnc3[nH]cc(I)c3n12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.396 g, 1.06 mmol, prepared as detailed in WO2009152133) in DMF (20 mL) was added KOH (0.190 g, 3.38 mmol). The mixture was stirred at rt for 5 min. Iodine (0.268 g, 1.058 mmol) was added in small portions and the reaction mixture was stirred at rt for 30 min. The mixture was added dropwise into a saturated aqueous ammonium chloride (200 mL). The precipitate was collected by filtration, washed with water, and dried to give N-((1S,3R,4S)-3-ethyl-4-(8-iodo-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.494 g, 93%) as an off-white solid: LC/MS (Table 1, Method a) Rt=1.83 min; MS m/z 501 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9]O)[CH2:5][CH2:4]1.C(N(S(F)(F)[F:33])CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9][F:33])[CH2:5][CH2:4]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(CF)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one dimethyl ketal (0.37 g, 1.02 mmol) in methylene chloride (5 mL) was added dropwise to a solution of diethylaminosulfur trifluoride (0.14 mL, 1.02 mmol) at -78° C. under an argon atmosphere. The mixture was allowed to warm to room temperature and after 0.75 h, 5% aqueous sodium carbonate was added. The mixture was extracted with chloroform, the organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo to provide a yellow oil (0.3 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[CH:13]=1.C(OC([N:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH:23]=[C:22]1[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37])=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:22]4[NH:21][C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[CH:23]=4)[C:32](=[O:37])[CH2:33]3)=[O:12])[S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Product: O=C1CN(C(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2cnccc2[nH]1
Reaction time: 8 h

Procedure:
The title compound is prepared as described in EXAMPLE 123 using 6-chloro-benzo[b]thiophene-2-carboxylic acid, EXAMPLE 1 and 2-(2-oxopiperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester EXAMPLE 69. The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH2Cl2 and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a solid. The crude material can be used in the subsequent step without further purification.
Reaction SMILES: C(OC([N:11]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.C(N(CC)CC)C>[F:51][C:47]1[CH:46]=[C:45]2[C:13]3([CH2:14][CH2:15][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:20])[CH2:17][CH2:18]3)[CH2:12][NH:11][C:50]2=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccc(F)cc12
Reactant: [H][H]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Yield: 100.7 %

Procedure:
To a solution of 0.330 g of the intermediate obtained from Step A in 5 mL of ethanol at was added 1 drop of triethylamine and hydrogenated with hydrogen balloon for 3 h. The catalyst was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give 0.269 g of the product as a colorless foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:23][C:24](=[O:47])[CH:25]([CH2:44][CH2:45]O)[N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:21]=[CH2:22].C(Br)(Br)(Br)[Br:49].O>O1CCCC1>[CH2:20]([O:23][C:24](=[O:47])[CH:25]([CH2:44][CH2:45][Br:49])[N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:21]=[CH2:22]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCOC(=O)C(CCO)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C(CCBr)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 86.1 %

Procedure:
After triphenylphosphine (4.72 g, 18.0 mmol) was added to a solution of (±)-2-(2-hydroxyethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine allyl ester (6.08 g, 15.0 mmol), the product of Example 41(2), in tetrahydrofuran (45 ml), a solution of carbon tetrabromide (5.97 g, 18.0 mmol) in tetrahydrofuran (20 ml) was added over 20 minutes to the solution with ice-cooling and with stirring. The mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/1 as the eluant to afford the desired compound (6.05 g, yield 86%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(O)C.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:9][NH:8][C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NNc1ccc(Cl)nn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(C=NNc2ccc(Cl)nn2)cc1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 14.5 g (0.1 moles) of 6-chloro-3-pyridazinylhydrazine, 145 ml of ethanol and 15.1 g (0.1 moles) of 4-nitrobenzaldehyde is refluxed with stirring for 2 hours, cooled and 75 ml of water are added. The precipitate is filtered, washed with water, triturated with hot ethanol, filtered again and dried to give 25.4 g (91.5%) of the named compound; m.p. 290° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12].[CH3:20][CH:21]([CH2:24]O)[CH2:22]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:20][CH:21]1[CH2:24][N:10]([C:3]2[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[S:11](=[O:13])(=[O:12])[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:22]1
Reactant: COC(=O)CNS(=O)(=O)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CC(CO)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)CN1CC(C)CN(c2c(Cl)cc(Cl)cc2Cl)S1(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To methyl 2-(N-(2,4,6-trichlorophenyl)sulfamoylamino)acetate (3.0 g, 8.3 mmol), 2-methylpropan-1,3-diol (1.18 mL, 8.3 mmol) and PPh3 (5.4 g, 20.7 mmol), was dropwisely added DIAD (4 mL, 20.7 mmol) with adjustment of external temperature to 0° C. The reaction mixture was agitated for 3 hr at room temperature, extracted with EtOAc, dried (Na2SO4), filtered and concentrated under reduced pressure, followed by column chromatography (MeOH/DCM 1%), finally giving the title compound (2.3 g, y=65%, solid). 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=2.4 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 4.44 (d, J=17 Hz, 1H), 4.37-3.86 (m, 5H), 3.59-3.41 (m, 1H), 3.38-3.13 (m, 1H), 2.75-2.53 (m, 1H), 1.32 (t, J=7.1 Hz, 3H), 0.94 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]([O:15]CC)=[O:14])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]([OH:15])=[O:14])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1nc2ccccn2c1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc2ccccn2c1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of compound 12-B (1.04 g, 4.52 mmol) in MeOH (6 mL) and H2O (3 mL) was added sodium hydroxide (0.241 g, 6.04 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2N HCl to pH 4-5 and concentrated in vacuo. The resulting residue was taken up in EtOAc, and the organic layer was washed with H2O and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to give Compound 12-C (0.841 g, 92%), which was used as such in the next reaction; MS m/z (M+H+) 203.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][CH:24]=2>CCO>[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH:31][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:25][CH:24]=2
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Solvent: CCO
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(C)c5c4)c3s2)C1
Yield: 96.1 %

Procedure:
A solution of (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone (139 mg, 0.47 mmol) and 2,3-dimethyl-1H-indol-5-ylamine (75 mg, 0.47 mmol) in EtOH (10 mL) was heated to reflux. After 12 h the reaction mixture was concentrated onto silica gel (5 mL) and purified on silica gel by flash column chromatography CH2Cl2/MeOH/NH4OH (98.5/1/0.5) to afford the title compound as a yellow solid, (190 mg). MS: 421.3 (MH+); HPLC Rf: 4.708 min.; HPLC purity: 99%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=C(S(N[C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[C:35]4[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:39][C:34]=4[N:33]=[C:32]3[CH2:45][CH3:46])=[CH:27][CH:26]=2)(=O)=O)C=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:21](=[O:47])[O:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[C:35]4[CH:36]=[C:37]([Cl:44])[C:38]([C:40]([F:41])([F:43])[F:42])=[CH:39][C:34]=4[N:33]=[C:32]3[CH2:45][CH3:46])=[CH:29][CH:30]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccncc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 4-pyridinesulfonamide (Comrie, A. M.; et al., J. Chem. Soc., 1958, 3514) and 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 243).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.C(Cl)(Cl)Cl.C[OH:64]>C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@@:3]12[O:64][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: CCC1=C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](OC(C)=O)[C@]3(O)C(=O)OC)C2)C1
Reactant: CO
Solvent: ClC(Cl)Cl
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
A solution of 50 mg of "anhydrovinblastine" III in 3 cm3 of chloroform at ambient temperature (20° C.) is stirred in the air in the presence of 50 mg of silica for 72 hours then diluted with 20 cm3 of chloroform/methanol 85/15 mixture, filtered and evaporated under reduced pressure. The mixture obtained is purified by chromatography on a thick layer of silica under the same conditions as in Example 1 and provides 13.8 mg of leurosine I and 20 mg of "anhydrovinblastine" III which may be recycled.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=O)#[N:12].N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:16]([C:15]3[CH:14]=[C:13]([CH:21]=[CH:20][CH:19]=3)[C:11]#[N:12])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: N
Product: N#Cc1cccc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3-cyanobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.86 (t, J=7.9 Hz, 1H), 8.09 (ddd, J=8.1, 1.4, 1.2 Hz, 1H), 8.40 (dd, J=5.4, 2.2 Hz, 1H), 8.55 (dt, J=7.9, 1.6 Hz, 1H), 8.64 (t, J=2.0 Hz, 1H), 9.46 (dd, J=5.4, 1.4 Hz, 1H), 9.88 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z=250 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28]C[CH2:26]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CN(CC1CCCCC1)C1C=CC=C(F)C=1F.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:31])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2cccc(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CN(CC1CCCCC1)c1cccc(F)c1F
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(F)c2F)s1

Procedure:
The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(2,3-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(2,3-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=1[F:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>Cl.CCO.[Pd]>[NH2:16][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([F:17])=[C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])[CH:14]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(C#N)ccc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)c1cc(CN)ccc1F
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A mixture of N-tert-butyl-5-cyano-2-fluoro-benzenesulfonamide (0.3 g) and Pd/C (50 mg) in 1N HCl/EtOH (1 ml 1N HCl in 10 ml EtOH) was stirred under H2 for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth, washed with MeOH and concentrated to about 3 ml. The residue was diluted with H2O and lyophilized to give 5-aminomethyl-N-tert-butyl-2-fluoro-benzenesulfonamide (0.27 g, 90% yield) as a white powder.