Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.O1C=CCC[CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[CH:19][CH:20]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: C1=COCCC1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Yield: 93 %

Procedure:
According to the method described for the synthesis of 207d, 206e (18.2 g, 63.8 mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH2Cl2 (300 mL) to give 207e (22.0 g, 93%) as an oil, which was used without further purification. 1H NMR (CDCl3): δ 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H), 3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H), 1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m, 1H). 13C NMR (CDCl3): δ 142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MO: 369.1429, found: 369.1451.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[CH3:24])=O)(=O)OC.O.[NH2:30][NH2:31]>>[C:25]([N:22]1[C:23]([CH3:24])=[C:19]([C:17]2[N:31]=[N:30][C:4]3[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=3[CH:16]=2)[CH:20]=[N:21]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(C)CC(=O)C(=O)C1
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C)OC
Reactant: NN
Solvent: O
Product: Cc1c(-c2cc3c(nn2)CC(C)(C)C3)cnn1C(C)(C)C

Procedure:
yellow crystalline solid. MS (ESI): 285.1 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[P:17]([OH:20])([OH:19])[OH:18]>N1C=CC=CC=1>[CH2:1]([NH:16][CH:9]([P:17](=[O:18])([OH:20])[OH:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: OP(O)O
Reactant: O=Cc1ccccc1
Solvent: c1ccncc1
Product: O=P(O)(O)C(NCc1ccccc1)c1ccccc1

Procedure:
The imine from benzaldehyde and benzylamine (19.5 g; 0.1 mole) was dissolved in pyridine (9 g) and phosphorous acid (8.2 g; 0.1 mole) was added. The mixture was heated at reflux for 3 hours, cooled, basified and extracted with benzene. The residue was acidified to yield a white solid. Crystallization gave N-benzyl α-amino benzylphosphonic acid mp 233°-4°. Phosphorus nmr of a basified aqueous solution gave a peak at -15.9 ppm (relative to 85% H3PO4) consistent with the assigned structure given in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH2:25])[CH3:24]>CO.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([C:1]([OH:5])([CH3:3])[CH3:2])[C:20]([NH:25][CH2:23][CH3:24])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Reactant: CCN
Solvent: CO
Solvent: CCOCC
Product: CCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Reaction time: 8 h

Procedure:
A solution of 400 mg (1.08 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 20 ml of methanol was saturated with ethylamine. After it had been allowed to stand at room temperature overnight, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue obtained, as an oily substance was dissolved in warm diethyl ether. The solution was then allowed to stand, and the needle-like crystals which deposited were collected by filtration, to give 317 mg of the title compound, melting at 155°-157° C.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[C:5]([CH:21]=CC)=[C:6]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=[CH:7]2.N1C(C)=CC=CC=1C.[O:33]1CCOCC1>O.C(Cl)Cl.O=[Os](=O)(=O)=O>[F:24][CH:2]([F:1])[O:3][C:4]1[C:5]([CH:21]=[O:33])=[C:6]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH:8]=[CH:7]2
Reactant: CC=Cc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OC(F)F)c(C=O)c2ccn(C(=O)OC(C)(C)C)c12
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 5-(difluoromethoxy)-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate (1.83 g, 5.42 mmol) in dioxane (40 mL) and water (13.56 mL) at 0° C., 2,6-lutidine (1.26 mL, 10.85 mmol), OsO4 (1.36 mL, 0.108 mmol) (2.5% in t-BuOH) and NaIO4 (4.64 g, 21.70 mmol) were added and the reaction was stirred at room temperature. After 1 hour the reaction was diluted with DCM and the layers separated. The organics were washed with sat. NH4Cl and water, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H) 7.93 (d, J=3.54 Hz, 1H) 7.37 (d, J=3.54 Hz, 1H) 7.34 (t, J=73.6 Hz, 1H) 7.16 (s, 1H) 2.63 (s, 3H) 1.61 (s, 9H). MS (ESI+) m/z 326.2 (M+H).
Reaction SMILES: Br[C:2]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:9]2[C:4](=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=2)[C:3]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:3]1[C:4]2=[N:5][C:6]([O:18][CH3:19])=[CH:7][CH:8]=[C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:2]=1[CH:26]=[CH2:27])[CH3:25]
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccc(OC)nc12
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(CC(=O)OCC)c2nc(OC)ccc2n1C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 66.6 %

Procedure:
Under a nitrogen atmosphere, tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (207 mg, 0.5 mmol), tributylvinyl tin (175 μL, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) were combined in 10 mL of DMF, and the mixture was heated to 85° C. overnight. The reaction was allowed to cool to ambient temperature and was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl and brine. The organic layer was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by RP HPLC eluting with acetonitrile and water to afford 120 mg of tert-butyl 3-(2-ethoxy-2-oxoethyl)-5-methoxy-2-vinyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. MS (m/z): 361.2 [M+H]+; HPLC retention time 4.69 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.OS(O)(=O)=O.O=S(=O)=O.[CH3:22]O.[CH:24]([OH:26])=[O:25]>>[CH3:22][O:25][C:24]([C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2)=[O:26]
Reactant: CO
Reactant: O=CO
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 5-hydroxy-2-adamantanone (2.0 g, 12.0 mmol) in 99% formic acid (12 mL) was added dropwise with vigorous gas evolution over 40 minutes to a rapidly stirred 30% oleum solution (48 mL) heated to 60° C. (W. J. le Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 1983, 48, 1099-1101.). Upon completion of addition, more 99% formic acid (12 mL) was slowly added over the next 40 minutes. The mixture was stirred another 60 minutes at 60° C. and then slowly poured into vigorously stirred methanol (100 mL) cooled to 0° C. The mixture was allowed to slowly warm to 23° C. while stirring for 2 hours and then concentrated in vacuo. The residue was poured onto ice (30 g), and methylene chloride (100 mL) was added. The layers were separated, and the aqueous phase was extracted twice more with methylene chloride (100 mL aliquots). The combined methylene chloride solutions were concentrated in vacuo to 50 mL, washed with brine, dried over N2SO4, filtered, and concentrated in vacuo to provide the title compound as a pale yellow solid (2.5 g, 99% crude).
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][NH2:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[C:14](O)(=O)[CH3:15].[OH2:18]>C(O)C>[F:1][C:2]1[C:11]([N:12]2[N+:6]([O-:18])=[C:5]3[CH2:4][CH2:3][CH2:2][CH2:14][C:15]3=[N:13]2)=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: NNc1cc2[nH]c(=O)sc2cc1F
Reactant: O
Reactant: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2cc(-n3nc4c([n+]3[O-])CCCC4)c(F)cc2s1

Procedure:
6-Fluoro-2(3H)-benzothiazolon-5-ylhydrazine (6.60 g) and 4-(2-hydroxyimino-1(6)-cyclohexen-1-yl)morpholine (6.50 g) were dissolved in ethanol (120 ml), a catalytic amount of acetic acid was added thereto, and the resulting mixture was heated under reflux for 5 hours. Water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was concentrated, a mixture of cupric sulfate pentahydrate (16.0 g), water (64 g), 15% aqueous pyridine (160 g) and tetrahydrofuran (128 ml) was added thereto, and the resulting mixture was refluxed for 5 hours. After cooling, water and ethyl acetate were added thereto. The organic layer was separated from the aqueous layer, washed with dilute hydrochloric acid, dried and concentrated. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (1:9) as an eluent to give 2-[6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (0.62 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[CH:19]([N:22]1[CH2:27][CH2:26][N:25]([C:14]([C:11]2[CH:10]=[N:9][C:8]([CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:13][N:12]=2)=[O:16])[CH2:24][CH2:23]1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cnc(CN2CCCCC2)cn1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2cnc(CN3CCCCC3)cn2)CC1
Reaction time: 1 h
Yield: 28.5 %

Procedure:
A mixture of 5-piperidin-1-ylmethyl-pyrazine-2-carboxylic acid (0.125 g, 0.53 mmol),1-isopropyl-piperazine dihydrochloride (0.117 g, 0.58 mmol), HOBt (0.086 g, 0.64 mmol) and N-methylmorpholine (0.323 g, 3.19 mmol) in DCM (7 mL) was stirred for 1 h. The mixture was then treated with EDC (0.122 g, 0.64 mmol) and stirring was continued for 18 h. The reaction was quenched by the addition of 1 N NaOH (10 mL), and was stirred for 30 min. The mixture was diluted with H2O (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to yield the crude product (0.145 g). The crude was purified on SiO2 using 0-5% 2 M NH3 in MeOH/DCM to provide the title compound (0.05 g, 26%). MS (ESI): exact mass calcd. for C18H29N5O, 331.46; m/z found 332.5 [M+H]+. 1HNMR (500 MHz, CDCl3): 8.85 (d, J=1.4,1H), 8.64 (d, J=1.4, 1H), 3.82 (t, J=4.9, 2H), 3.68 (s, 2H), 3.63 (t, J=4.9, 2H), 2.77-2.70 (m, 1H), 2.62 (t, J=4.9, 2H), 2.53 (t, J=4.9, 2H), 2.48-2.42 (m, 4H), 1.63-1.57 (m, 4H), 1.49-1.42 (m, 2H), 1.05 (d, J=6.6, 6H).
Reaction SMILES: [C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31]Cl)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[I-].[Na+].C(#N)C.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O>[C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]([C:20]1[N:21]([CH2:29][CH2:30][CH2:31][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: C1CCNCC1
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCN1CCCCC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To 1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)cyclohexyl]-amide (200 mg, 0.44 mmol) was added sodium iodide (66 mg, 0.44 mmol), acetonitrile (2 mL), and piperidine (0.1 mL, 1.3 mmol). The reaction mixture was heated to 50° C. and stirred for 24 hrs. Water (15 mL) was added to the reaction and extracted with three 20 mL portions of ethyl acetate. The combined organics were washed with saturated NaHCO3 (20 mL), dried on sodium sulfate, and concentrated. Purification by column chromatography (5:95 methanol:chloroform) gave 1-(3-piperidin-1-yl-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide as a white solid (150 mg, 68%). MS: 506 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])=[O:7].[C:18]([N:26]=[C:27]=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:18]([NH:26][C:27]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]1=[O:17])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1Nc2ccccc2C1C(=O)c1ccco1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccccc21)c1ccccc1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A mixture of 909 mg (4.0 mmole) of 3-(2-furoyl)-2-oxindole and 706 mg (4.8 mmole) of benzoyl isocyanate in 25 ml of toluene was heated to reflux and then it was heated at reflux temperature for 7 hours. The mixture was allowed to stand at room temperature overnight and then the precipitate which had formed was removed by filtration, giving 1.3 g of crude product. The crude product was recrystallized from ca 30 ml of acetic acid, giving 920 mg of the title compound, mp 184° C. (dec).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:10]#[N:11])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:19]([O:1]/[N:2]=[C:3](\[C:10]#[N:11])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#C/C(=N\O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O/N=C(\C#N)c2ccccc2)cc1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of (Z)—N-hydroxybenzimidoyl cyanide (8 g, 55.1 mmol) and 4-methylbenzene-1-sulfonyl chloride (10.51 g, 55.1 mmol) in toluene (70 mL) was heated at reflux. After 2 h, the reaction was allowed to cool, diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield (Z)—N-(tosyloxy)benzimidoyl cyanide (10 g, 33.3 mmol, 60.4% yield) as a light yellow solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[NH:39][CH:43]=[CH:42][CH:41]=1)(=[O:14])=[O:13])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Yield: 29.9 %

Procedure:
2-Methylsulfonyl-N-[3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 365 mg of 1-(tert-butyloxycarbonyl)pyrrole-2-boronic acid, 20 ml of dimethylformamide, 1.87 ml of saturated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 108 mg of 2-methylsulfonyl-N-[3-(1H-pyrrol-2-yl)-1H-indazol-5-yl]benzenesulfonamide are thus obtained in the form of a pale green solid melting at 255° C. (analysis C18H16N4O4S2 % calculated: C, 51.91; H, 3.87; N, 13.45; O, 15.37; S, 15.40. % found C, 51.63; H, 3.87; N, 13.27; S, 15.21).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(S(=O)(=O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
tert-Butyl 4-(4-nitrophenylsulfonyl)piperidine-1-carboxylate (2.214 mmol, 820 mg) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and purified by SCX chromatography to give the intermediate 4-(4-nitrophenylsulfonyl)piperidine (640 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH2:22]([N:24](CC)CC)C.Cl.CN>>[CH3:22][NH:24][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: CN
Agent: Cl
Product: CCC(=O)[O-]
Product: CNS(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 21.2 %

Procedure:
This compound is prepared according to synthesis 25, from 115 mg (0.35 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2), 147 μL (1.05 mmol) of triethylamine and 28 mg (0.42 mmol) of methylamine hydrochloride. After purification by chromatography on silica (eluent dichloromethane/methanol 9/1), 13 mg (11%) of 8-methylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH2:22])=[O:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH2:22])=[O:21])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1cccc(C(N)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of 3-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (61.2 mg) in acetonitrile (10 mL) were added sodium iodide (54.5 mg) and chloro(trimethyl)silane (0.184 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with ethyl acetate to give the title compound (50.6 mg).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:7]=1.[Cl:23]C1C(NC(=O)C)=C(C)C=CC=1.NC1C=CC(C)=C(NC(=O)C)C=1>>[Cl:23][C:7]1[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[C:5]([CH3:22])[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1c(C)cccc1Cl
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: CC(=O)Nc1cc(N)ccc1C
Product: Cc1cccc(Cl)c1Nc1ncc(-c2ccc(C#N)cc2)o1
Yield: 89 %

Procedure:
The same procedure outlined above in the preparation 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(6-chloro-2-methyl-phenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=89%.
Reaction SMILES: [C:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O>[CH2:24]([NH:17][S:14]([C:5]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:1](=[O:3])[CH3:2])(=[O:15])=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(=O)(=O)NCc1ccccc1
Temperature: 75 °C
Yield: 44 %

Procedure:
A mixture of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (500 mg, 1.69 mmol), potassium carbonate (469 mg, 3.39 mmnol) and benzyl bromide (0.24 mL, 2.0 mmol) in 20 mL of N,N-dimethylformamide was heated to 75° C for 24 hours. The mixture was acidified with 1 N aq. HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), gave the desired product (274 mg, 42%). EI-MS (m/z) 383.3, 385.3 (M−).
Reaction SMILES: C(OC(CC[N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=O)C.OO.C(OCC)(=[O:20])C>O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([OH:20])[CH2:9][CH2:10]1)=[O:15]
Reactant: CCOC(=O)CCN1CCN(C=O)CC1
Reactant: CCOC(C)=O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=CN1CCN(O)CC1
Reaction time: 1 h

Procedure:
The crude 4-ethoxycarbonylethyl-1-formylpiperazine (114 g) prepared as described above is dissolved in water (500 ml) and sodium tungstate dihydrate (7.25 g) is added to the solution. At a temperature of 30°-35° C., 31% hydrogen peroxide (82 ml) is added dropwise to the solution and the mixture is stirred for one hour. The reaction mixture is stirred for 3 hours at room temperature and for another 5 hours at a temperature of 50°-55° C. The resulting reaction mixture is then shaken with ethyl acetate (300 ml). The aqueous layer is evaporated under reduced pressure to remove water to yield a dark brown oil. The oil is applied to a silica gel column chromatography for the purification (2 kg of silica gel, eluent; chloroform:methanol=10:1) and then is recrystallized from ethyl acetate to give 1-formyl-4-hydroxypiperazine (38.2 g), m.p. 118°-124° C.