Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([F:17])=[CH:12][C:11]=2[Cl:18])[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2[CH2:25][CH2:26][CH2:27][CH2:28][C:20]1=2>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([N:16]3[C:22](=[O:23])[CH:21]4[C:20](=[CH:28][CH2:27][CH2:26][CH2:25]4)[C:19]3=[O:24])[C:13]([F:17])=[CH:12][C:11]=2[Cl:18])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CCC1
Solvent: CC(=O)O
Product: COC(=O)C1(Sc2cc(N3C(=O)C4=CCCCC4C3=O)c(F)cc2Cl)CCC1
Temperature: 0 °C
Yield: 62.1 %

Procedure:
A mixture of 4.4 g of 1-(5-amino-2-chloro-4-fluorophenylthio)-cyclobutanecarboxylic acid methyl ester and 2.4 g of 3,4,5,6-tetrahydrophthalic anhydride in 60 ml of glacial acetic acid is heated under reflux for 5 hours while stirring. The reaction mixture is then introduced into ice-water and the resulting glutinous product is extracted with ethyl acetate. After drying the organic phase over sodium sulfate and concentrating by evaporation in vacuo, petroleum ether is added to the resulting residue and the substance solidifies. Filtering yields 4 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclobutanecarboxylic acid methyl ester having a melting point of +98° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2C=[CH:16][C:15](O[Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(O[S:52](C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[S:52][C:15]([CH3:16])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 170.0 mg (0.366 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 202.0 mg (1.48 mmol) of zinc chloride, 24 mg (0.022 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF, and 5-methyl-2-lithiothiophene (prepared by adding 58.6 mg (0.36 ml, 0.915 mmol) of n-butyllithium (2.5 M solution in hexanes) to a cold solution (−78° C.) of 89.8 mg (0.915 mmol) of 2-methylthiophene in 2.0 ml of THF). 1H NMR (CDCl3): δ 8.00 (2H, d, J=8.3 Hz), 7.59 (1H, d, J=1.7 Hz), 7.55 (2H, d, J=8.2 Hz), 7.43 (1H, dd, J=1.7, 8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 6.87 (1H, d, J=3.5 Hz), 6.74 (1H, d, J=2.8 Hz), 6.15 (1H, t, J=4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 2.52 (3H, s), 2.32 (2H, d, J=4.8 Hz). 1.40 (3H, t, 7.1 Hz), 1.32 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:17])=[O:5].C([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH:8]1[C:28]2[CH2:19][C:18]3[CH:3]=[CH:2][CH:21]=[CH:20][C:31]=3[CH2:30][N:26]([C:11]([C:10]3[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=4[Cl:1])=[C:8]([CH3:17])[CH:9]=3)=[O:13])[C:27]=2[CH:29]=[CH:15][CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.8 %

Procedure:
A mixture of 1.69 g of 4-[(2,4-dichlorobenzoyl)amino]-3,5-dimethylbenzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under argon for i hour. The volatiles are evaporated and the residue evaporated in vacuo from toluene to give a residue. A solution of the residue in 25 ml of methylene chloride is treated with 0.75 g of N,N-di-isopropylethylamine and 0.98 g of 10,11-dihydro-5H-dibenz[b,e]azepine is stirred at room temperature for 18 hours. The reaction mixture is washed with saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a glass which is dissolved in methylene chloride dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated to give 1.89 g of the desired product as an amorphorous solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([C:26](=[O:40])[NH:27][CH2:28][C:29]4[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=4[CH:35]([CH3:37])[CH3:36])[C:23]([CH3:41])=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]([N:42]([CH2:49][CH3:50])[CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[C:23]([CH3:41])=[C:24]([CH:25]=3)[C:26]([NH:27][CH2:28][C:29]3[C:30](=[O:39])[NH:31][C:32]([CH3:38])=[CH:33][C:34]=3[CH:35]([CH3:37])[CH3:36])=[O:40])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CCN(c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
tert-butyl(1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)pyridin-2-yl)piperidin-4-yl)carbamate (0.31 g, 0.44 mmol) was taken in DCM (5 mL) and TFA (1 mL) was added to it and stirred at rt for 2 h. After completion of reaction, solvent was removed under reduced pressure and saturated NaHCO3 solution was added to it. Extraction was carried out using 10% MeOH/DCM; the combined organic layers were washed with water and brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to give the title compound (0.26 g, 98.11%)
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:28])[NH:19][C:20]3[S:21][C:22]([C:25]([OH:27])=O)=[CH:23][N:24]=3)=[CH:12][C:11]=12.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([NH:19][C:20]3[S:21][C:22]([C:25]([NH:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])=[O:27])=[CH:23][N:24]=3)=[O:28])=[CH:12][C:11]=12
Reactant: CC(C)CCN
Reactant: O=C(NCc1ccn2ccnc2c1)Nc1ncc(C(=O)O)s1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CCNC(=O)c1cnc(NC(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting 3-methylbutan-1-amine for 3-methylbutan-1-amine and 2-(3-(imidazo[1,2-a]pyridin-7-ylmethyl)ureido)thiazole-5-carboxylic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) ppm 8.49 (d, J=7.8 Hz, 1H), 8.21 (t, J=5.9 Hz, 1H), 7.88-7.89 (m, J=1.4 Hz, 1H), 7.87 (s, 1H), 7.52 (d, J=1.4 Hz, 1H), 7.39 (s, 1H), 7.18 (t, J=5.8 Hz, 1H), 6.83 (dd, J=6.8, 1.7 Hz, 1H), 4.38 (d, J=6.1 Hz, 2H), 3.16-3.25 (m, 2H), 1.52-1.67 (m, 1H), 1.38 (q, J=6.9 Hz, 2H), 0.83-0.91 (m, 7H); MS (ESI(+)) m/e 387 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: COc1ccccc1CN
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 115.2 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), o-methoxybenzylamine (21.8 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 46 mg (81%) of the title compound as a TFA salt (1.5 H2O, 1.5 TFA, effective MW=673.59). 1H NMR (DMSO-d6): δ 9.83 (1H, s), 9.03 (1H, t, J=3.4), 8.70 (1H, d, J=3.7), 8.08 (4H, m), 7.82 (1H, d, J=7.4), 7.49 (4H, m), 7.21 (3H, m), 6.96 (4H, m), 4.48 (2H, d, J=6.3). ESIMS (M+H+): 476.1.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CON(C)[C:36]([C:38]1([CH3:44])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:37]>>[CH3:44][C:38]1([C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=4)[N:9]=3)[NH:4][CH:3]=2)=[O:37])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: CON(C)C(=O)C1(C)CCOCC1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCOCC4)c3n2)cc(OC)c1OC

Procedure:
(4-Methyl-tetrahydro-pyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 4-methyl-tetrahydro-pyran-4-carboxylic acid methoxy-methyl-amide following general procedures as described in these Examples. 66, to afford a pale yellow solid. M+H=412.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CCOCC>[CH3:24][S:25]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC[C@@H](CCCO)OC1CCCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCC[C@@H](CCCOS(C)(=O)=O)OC1CCCCO1
Reaction time: 4 h

Procedure:
A mixture of (4S)-4-(2-tetrahydropyranyloxy)-1-nonanol (29.2 g., 0.12 mole) and pyridine (20 ml.) is cooled to 5° by means of an ice bath. Methanesulfonyl chloride (17.2 g., 0.15 mole) is added dropwise during 20 minutes and the mixture is stirred 4 hours with ice bath cooling. The mixture is then taken up in ether, washed with 4 portions of water and with brine and dried over sodium sulfate. The ether is distilled on the rotary evaporator to leave as a residual oil crude (4S)-1-methylsulfonyloxy-4-(2-tetrahydropyranyloxy)-nonane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[C:13](=O)([O:39]C1C=CC=CC=1)[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:26]=3[N:25]=[C:24]2[CH2:37][CH3:38])=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:36][C:29]1[C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:26]2[N:25]=[C:24]([CH2:37][CH3:38])[N:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:13](=[O:39])[NH:10][S:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)(=[O:9])=[O:8])=[CH:22][CH:21]=3)[C:27]=2[CH:28]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
To a stirred solution of 3-pyridinesulfonamide (Rafik, Karaman; et al., J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, 0.76 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 27 mg, 0.68 mmol) at room temperature. After 10 min., phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 313 mg, 0.64 mmol) was added, and the mixture was stirred for 9 h at 80° C. The mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by TLC developing with dichloromethane/methanol (6:1) and TLC developing with dichloromethane/methanol (10:1) gave 67 mg (19%) of the title compound as colorless solid.
Reaction SMILES: O.S.[Na].[N:4]([CH2:7][C:8]1[N:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=[C:15]([SH:16])[N:10]2[N:9]=1)=[N+]=[N-].[C:19]1([C:25]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[O:29][C:28]3[CH:30]=[CH:31][C:32]([C:34](ON4C5C=CC=CC=5N=N4)=[O:35])=[CH:33][C:27]=3[O:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[SH:16][C:15]1[N:10]2[N:9]=[C:8]([CH2:7][NH:4][C:34]([C:32]3[CH:31]=[CH:30][C:28]4[O:29][C:25]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[O:26][C:27]=4[CH:33]=3)=[O:35])[N:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=1
Reactant: Cc1cc(S)n2nc(CN=[N+]=[N-])nc2n1
Reactant: O=C(On1nnc2ccccc21)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S)n2nc(CNC(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Yield: 86.2 %

Procedure:
A dried solution of 2.0 g of sodium hydrogen sulphide monohydrate (drying agent molecular sieve 4 Å) in 100 ml of dimethylformamide is treated with 2.2 g of 2-azidomethyl-5-methyl[1.2.4]triazolo[1,5-a]pyrimidine-7-thiol and stirred until the evolution of gas has finished (about 15 minutes). Thereupon, 4.35 g of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxol-5-carboxylate are added and the reaction mixture is stirred at room temperature for 20 hours and at 45° C. for 24 hours. The solvent is evaporated in a high vacuum, the residue is taken up in 200 ml of ethyl acetate and 200 ml of water and stirred in an ice bath for 30 minutes. The resulting precipitate is filtered off under suction, washed with water and ethyl acetate and dried in a vacuum at 40° C. The yellow product is dissolved in 100 ml of methanol, a small amount of insoluble material is removed by filtration and the filtrate is concentrated to dryness. The residue in 100 ml of acetonitrile is heated at reflux on a steam bath for 1 hour. After cooling in an ice bath the product is filtered off under suction and dried. There are obtained 4.25 g of N-[(7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)methyl]-2,2-diphenyl-1,3-benzodioxol-5-carboxamide as a yellow solid of melting point 267°-271° C. (dec.).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:11]1[CH:12]=[N:13][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[N:9][CH:10]=1)=[O:16])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: O=C(O)c1cnc(-c2cccnc2)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 2-(3-pyridyl)-pyrimidine-5-carboxylic acid hydrochloride (237 mg 1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (15 mL) is treated with diisopropylethylamine (0.36 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc. The resulting solid is filtered, washed with ether to afford 2-(3-pyridyl)-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (185 mg, 48%). MS: 384 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (d, 3H), 4.65 (d, 2H), 7.45-7.55 (q, 1H), 7.60-7.75 (m, 3H), 7.80 (s, 1H), 8.72-8.80 (m, 2H), 9.35 (s, 2H), 9.55 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:61]C1C=C(N=C=S)C=CC=1>>[Cl:61][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O

Procedure:
The compound of example 63 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 3-chlorophenyl isothiocyanate. The compound of example 63 was used directly without isolation for the preparation of compound of example 64.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[C:19]2=[O:26].FC1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]1[C:20](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:19]2=[O:26]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: COc1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Yield: 24 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-methoxyisatin for 5-fluoroisatin gave the title compound in 24% yield: mp 267.6°-269° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, 1H) 8.25 (d, 1H) 7.93 (d, 2H) 7.68-7.78 (m, 1H) 7.37-7.46 (m, 2H) 3.88 (s, 3H); MS (M+H)+ 279.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[F:39][C:40]([F:48])([F:47])[CH:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1>>[CH3:30][C:29]1[CH:28]=[CH:27][O:26][C:25]=1[C:23]([NH:22][C:18]1[CH:17]=[C:16]([C:15]#[C:14][C:12]2[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=2)[C:7]([N:6]=[S:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:4][CH2:3][CH2:2][N:43]2[CH2:44][CH2:45][CH2:46][CH:41]([C:40]([F:48])([F:47])[F:39])[CH2:42]2)=[O:31])[CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: FC(F)(F)C1CCCNC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN3CCCC(C(F)(F)F)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-(trifluoromethyl)piperidine were converted to the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([F:23])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C@H:10]1[C@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CCNC[C@H]1F)c1ccccc1
Yield: 95.5 %

Procedure:
Using a similar procedure to that described in Example 1, step 4, trans-1-tert-butoxycarbonyl-3-fluoro-4-[(1R)-1-phenylethylamino]piperidine (0.1147 g, 0.356 mmol) was reacted with trifluoroacetic acid (0.5 mL) in dichloromethane (1.0 mL) to give 75.6 mg (96%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.19 (1H, m), 1.35 (3H, d, J=6.6 Hz), 1.68 (1H, m), 2.40-2.73 (3H, m), 2.85 (1H, m), 3.26 (1H, m), 3.99 (1H, q, J=6.6 Hz), 4.28 (1H, two m, J=49.8 Hz), 7.20-7.35 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([OH:11])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH3:1])=[N:3][NH:4]2)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1n[nH]c2cccc(O)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2cccc(O[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a solution of 3-methyl-1H-indazol-4-ol (0.13 g, 0.90 mmol) in N,N-dimethylformamide (10 ml) was added imidazole (0.31 g, 4.52 mmol) and tert-butyldimethylchlorosilane (0.16 g, 1.04 mmol) at 0° C. Following stirring at room temperature for 12 hours and the addition of distilled water (10 ml), the reaction mixture was extracted three times with ethyl acetate, washed with distilled water and brine, dried over magnesium sulfate, filtered, and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give 0.21 g of 4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-1H-indazole (Yield 89%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(=O)NCCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (15.5 mmol) 2,6-dichloro-3-nitropyridine in 50 mL of THF at −78° C. under Ar atmosphere was added 2.7 mL (15.5 mmol) of N,N-diisopropylethylamine followed by 1.6 mL (15.5 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for 72 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with MeOH/dichloromethane gradient (1→10%) to provide N-(2-(6-chloro-3-nitropyridin-2-ylamino)ethyl)acetamide as pale yellow solid.