Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)CCO
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCC(c1ccncc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 2-dimethylaminoethanol (54 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 2-dimethylaminoethanol (54 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (49 mg, 55%) as a white solid. The resulting solid was washed with hexane-ether and then, collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:16]([NH:15][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[C:9]2[NH:12][N:13]=[CH:14][C:8]=12)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNc1c(C(=O)OCC)cnc2[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCNc1c(C(=O)O)cnc2[nH]ncc12

Procedure:
4-Butylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is treated with sodium hydroxide in ethanol for 20 hours at room temperature. The solvent is removed in vacuo and the residue is dissolved in water. On acidification with acetic acid, 4-butylamino-1H-pyrazolo[3,4-b]pyridine-5-caboxylic acid solidifies and is filtered off. The product is purified by recrystallization from acetic acid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[O:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:49]4[CH:48]=[C:47]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:46]=[C:45]([N:42]5[CH2:41][CH2:40][O:39][CH2:44][CH2:43]5)[CH:50]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc(N3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(N5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 43.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (45 mg, 0.08 mmol) was treated with N-(3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (44 mg, 0.12 mmol), sodium carbonate (22 mg, 0.21 mmols) and bis(triphenylphosphine)palladium(II) dichloride (21 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 27 mg (32% yield) of the title compound. Purity 70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][C:33]1([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C:33]4([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: NC1(C(=O)O)CC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)C1(NCc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 1-aminocyclopropanecarboxylic acid (98.1 mg; 0.97 mmol) to give Example 162 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.95-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.56-7.47 (4H, m), 3.95 (2H, s), 1.18-1.14 (2H, m), 0.96-0.92 (2H, m). LC/MS (Method C): 498 (M+H)+. HPLC (Method F) Rt 2.70 min (Purity: 98.6%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:31][C:32](Cl)=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:32](=[O:33])([O:31][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.24 g. of chloroformic acid n-nonyl ester as in Example 1. The 2.026 g. of yellowish, turbid oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.646 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-nonyl carbonate obtained melts at 53.0°-53.1° and has a clearing point of 70.0°. The compound is smectic up to 68.1°. UV (EtOH): ε 271 = 26600.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH-].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:12]2[N:8]([CH3:7])[CH:9]=[N:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: Cn1ccnc1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cncn2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
4-(3-Methyl-3H-imidazol-4-yl)-benzoic acid methyl ester was prepared using the procedure similar to that outlined by Pivsa-Art, S.,; Satoh, T., Kawamura, Y., Miura, M., Nomura, M. Bull. Chem. Soc. Jpn. 71, 1998, 467. In a flask was dried Cs2CO3 (3.29 g, 12 mmol) in vacuo at 150° C. for 1.5 hr. After cooling to ambient temperature, N-methylimidazole (0.5 mL, 6 mmol), methyl-4-iodo-benzoate (3.29 g, 12 mmmol), Pd(OAc)2 (0.14 g, 0.6 mmol), PPh3 (4.09 g, 12 mmol), and 20 mL dimethylformamide. The mixture was stirred under nitrogen at 140° C. for 24 hrs and an additional 16 hrs at ambient temperature. The mixture was poured onto 10% aqueous NaOH and extracted with CH2Cl2, dried over Na2SO4. Purification by chromatography (5% MeOH/CHCl3) gave 0.50 g (37%) of 4-(3-methyl-3H-imidazol-4-yl)-benzoic acid methyl ester. A solution of 4-(3-methyl-3H-imidazol-4-yl)-benzoic acid methyl ester (216 mg, 1 mmol), lithium hydroxide (44.0 mg, 1 mmol), tetrahydrofuran (0.6 mL), water (0.6 mL), and methanol (0.6 mL) was stirred at ambient temperature under nitrogen for 24 hrs. The mixture was concentrated in vacuo and then lyophilized to give 242 g of crude material which was taken on without further purification for preparation of compound 42 of Table 1.
Reaction SMILES: O.[NH2:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CN(C)C=O>[N:2]1([CH2:3][CH:4]2[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=43)[C:7](=[O:17])[NH:6][CH2:5]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CNC(=O)c2cccc3[nH]cc1c23
Reactant: BrCCCCCBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCC(CN2CCCCC2)c2c[nH]c3cccc1c23
Temperature: 25 °C

Procedure:
4 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-Cd]indole hydrate (for preparation see Example 1C) were dissolved in 40 ml of dimethylformamide. 2.6 ml of triethylamine were added to the solution and subsequently, while stirring at room temperature, 2 4 ml of 1,5-dibromopentane were added. The reaction mixture was heated at 50° C. for 3.5 hours. The reaction mixture was worked up by evaporating it under reduced pressure (water pump vacuum) and taking up the residue in a 9:1 dichloromethane/methanol mixture. Then saturated aqueous sodium carbonate solution was added until pH 11 was reached. The organic phase was separated and the aqueous phase was washed twice more with 50 ml portions of the dichloromethane/methanol mixture. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in ethanol, and diethyl ether was added to the solution until a slight turbidity appeared. The resulting crystals were filtered out and dried. 3.5 g of crystalline 3-(1-piperidinylmethyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole were obtained with a melting point of 119° to 122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].[CH3:21][OH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:22][CH3:21])=[O:10]
Reactant: CO
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
1 g (0.00326 mol) (±)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 20 mL methanol and refluxed at 85° C. During the reflux 10 mL polyphosphoric acid was added dropwise over a period of 1 hr and refluxing was continued for 6 hour. The excess of solvent was removed under reduced pressure. To the residue, 50 mL ethyl acetate was added at 0° C. and the reaction mixture was made basic with aq. NaHCO3, up to pH 9. Out of the two phases separated, the organic layer was isolated, dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by column chromatography using hexane:ethyl acetate (9:1) as eluent. The product obtained was stored under nitrogen atmosphere and kept in refrigerator before converting into salt. The yield of titled product was 310 mg (30%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-Nitrophenylhydrazine (32.0 g, 0.21 mole) was slurried in acetonitrile (500 ml) and the mixture was cooled to 0° C. A solution of 4-chlorobenzoyl chloride (17.5 g, 0.10 mole) in acetonitrile (25 ml) was added dropwise to the cooled slurry. The reaction mixture was allowed to stand overnight. The mixture was filtered and the solid was washed with acetonitrile, then thoroughly with water. The product was recrystallized from acetonitrile and decolorized with charcoal to give a pale yellow solid. Yield 24.8 g (85%), m.p. 245.5°-248.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:20][CH2:19]2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}(methyl)carbamate (68 mg, 0.135 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.203 mmol) to afford the crude product (90 mg) as a brown oil: ESI MS m/z 580 [C32H38ClN3O5+H]+.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([CH3:15])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[N:14]=[CH:13][N:12]([C:18](=[O:19])[N:17]([CH3:21])[CH3:16])[N:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)c2nc[nH]n2)cc1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)c2ncn(C(=O)N(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A suspension of 3-(4-toluenesulfonyl)-1H-1,2,4-triazole (100 mg), dimethylcarbamoyl chloride (62 μl) and potassium carbonate (124 mg) in N,N-dimethylformamide was stirred at room temperature for 70 minutes. To the reaction mixture were added ethyl acetate and water, and extraction was carried out with ethyl acetate. The obtained organic layer was washed three times with water, and then dried over magnesium sulfate. The residue was purified by a short-column chromatography (eluent: n-hexane/ethyl acetate=3/1) to yield a clear oil (77 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].O.O.Cl[Sn]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9])[NH2:10]
Reactant: CCc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CCc1ccc(N)cc1Cl
Yield: 97.9 %

Procedure:
A solution of 8.9 g (48 mmol) of 31 and 54.6 g (241 mmol) of SnCl2.2H2O in 100 mL of absolute alcohol was refluxed for 1 h. It was evaporated to remove most of the solvent and the residue was treated with 2N NaOH to pH=9. The mixture was filtered and the solid was washed with methanol (10 mL) and ethyl acetate (200 mL). The filtrate was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic solution was dried (MgSO4) and evaporated to leave 7.31 g (98%) of liquid. 1H NMR (CDCl3), 1.178 (t, 3, J=7.5), 2.639 (q, 2, J=7.4), 6.532 (dd, 1, J=2.2, 8.1), 6.700 (d, 1, J=2.2), 6.996 (d, 1, J=8.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:27][N:28]=[C:29]=[O:30].N1C=CC=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:28][C:29]([N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[N:17]1)=[O:30]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Agent: c1cn[nH]c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 60 °C
Yield: 13.7 %

Procedure:
The 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide (prepared in example 2, 115 mg, 0.29 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and warmed to 60° C. in a sealed vial. Methyl-isocyanate (165 mg, 2.90 mmol) was transferred via syringe to the pyrazole solution. The mixture was heated at 60° C. for 2 h while stirring in the sealed vial. The mixture was diluted with ethyl acetate (25 mL), washed with water (2×15 mL), saturated aqueous brine solution (15 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid methylamide (18 mg, 14%) as a white powder: ESI-LRMS m/e calcd for C20H25ClN4O4S [M+] 452.1, found 453.2 [M+H+], 395.9 [M−CONCH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.23 (m, 2H, CH2), 1.43-1.97 (m, 8H, 4×CH2), 2.11-2.34 (m, 1H, CH), 2.95 (d, J=4.6 Hz, 3H, NCH3), 3.27 (s, 3H, SO2CH3), 3.65 (t, J=7.5 Hz, 1H, CH), 6.81 (q, J=4.6 Hz, 1H, NH), 6.84 (d, J=2.7 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz, 1 H, Ar), 8.07 (d, J=2.7 Hz, 1H, Ar), 8.32 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[S:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:44]=[C:43]1[S:51](Cl)(=[O:53])=[O:52]>C(#N)C>[S:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:44]=[C:43]1[S:51]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:53])=[O:52]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc4ccccc4s3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 1-benzothiophene-2-sulfonylchloride (0.0357 g, 0.195 mmol) to obtain 4-(benzothiophene-2-sulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0120 g, yield 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=1)([O-])=O>O1CCCC1.[Pd]>[C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[O:24])=[CH:13][CH:14]=1)(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(=O)Nc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc(C(=O)Nc2ccccc2N)cc1

Procedure:
13.1 g (40 mMole) N-(2'-nitrophenyl)-4-isobutyrylaminobenzamide are hydrogenated under standard conditions in 400 mL tetrahydrofuran in the presence of 10% palladium charcoal. After concentrating the solvent to 120 mL, the precipitated crystals are filtered off with suction. Yield 10.2 g (86% of theory); m.p. 247.6° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][CH2:9][NH:10][CH:11]([CH2:14][N:15]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:16]([C:18](OC)=[O:19])[CH3:17])[C:12]#[N:13])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.O>[CH2:25]([O:24][C:22]([N:15]1[CH2:14][CH:11]([C:12]#[N:13])[N:10]([CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:32])[C:18](=[O:19])[C@@H:16]1[CH3:17])=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](C)N(CC(C#N)NCCCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(CCCC(=O)OC(C)(C)C)C(C#N)CN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 78 %

Procedure:
To 1.0 g (2 mmol) of 4-[({[benzyloxycarbonyl-((S)-1-methoxycarbonyl-ethyl)-amino]-methyl}-cyano-methyl)-amino]-butyric acid tert-butyl ester in 2 ml of THF was added 0.1 g (2 mmol) of lithium hydroxide monohydrate in 0.5 ml of water. The reaction was stirred for 16 h after which time it was evaporated to dryness. The residue was redissolved in 2 ml of DMF and 0.5 g (2 mmol) of EDCI and 0.3 g (2 mmol) of HOBT was added and the mixture stirred for 2 h. The reaction was then evaporated, the residue redissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to give after flash silica gel column (n-heptane/EtOAc 4:6 to 1:1) the title compound in 78% yield as a colorless gum. MS: 416.3 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][N:5]=[C:6]=[S:7].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][NH:5][C:6](=[S:7])[NH:11][NH2:12]
Reactant: NN
Reactant: COC(CN=C=S)OC
Solvent: O
Solvent: CCO
Product: COC(CNC(=S)NN)OC
Reaction time: 12 h
Yield: 70.4 %

Procedure:
2,2-Dimethoxyethyl isothiocyanate (37.7 g) is added in the course of 1 hour to a solution of hydrazine hydrate (14.35 g) in ethanol (40 cc), whilst stirring at a temperature of between 5 and 9° C. After 12 hours at 4° C., the mixture is concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The yellow syrup obtained crystallises after seeding. The solid is dissolved in hot methanol (50 cc) and the solution is filtered and diluted with diethyl ether (200 cc). After about ten hours at 4° C., the mixture is filtered and 4-(2,2-dimethoxyethyl)-thiosemicarbazide (32.3 g) is obtained in the form of a white solid.