Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH3:54])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:53]([O:52][C:48]1[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:54]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOc1cccc(OB([O-])[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-ethoxyphenyl borate (115 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(3-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 117) (180 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.[O:46]1[CH:50]=[CH:49][C:48]([C:51](O)=[O:52])=[CH:47]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([C:48]4[CH:49]=[CH:50][O:46][CH:47]=4)=[O:52])=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNC(=O)c2ccoc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A solution of 44 mg (0.068 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 15 mg (0.14 mmol) of 3-furoic acid, and 36 μL (0.20 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous DMF was treated with 52 mg (0.14 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and the resulting solution was stirred at RT. After 18 hours the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 97:3 CH2Cl2/MeOH) to afford 38 mg (75%) of the desired compound as a white foam. 1H NMR (CDCl3): 7.88 (s, 1H), 7.38 (s, 1H), 7.29 (d, 1H), 7.10 (m, 3H), 6.84 (d, 1H), 6.76 (d, 2H), 6.56 (s, 1H), 6.34 (br s, 1H), 6.05 (s, 2H), 5.60 (d, 1H), 5.00 (m, 2H), 4.01 (t, 2H), 3.90 (dd, 1H), 3.80 (m, 3H), 3.64 (m, 2H), 3.55 (q, 2H), 3.17-2.63 (m, 8H), 2.03 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.49 (m, 1H), 0.89 (d, 3H), 0.83 (d, 3H). MS(ESI): 744(M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[H][H]>O1CCOCC1.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([Cl:11])[CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(Cl)cnc1Cl
Yield: 75.5 %

Procedure:
26.0 g of Raney nickel catalyst are washed with ethanol and then added to a solution of 129.2 g (0.69 mol) of 2,5-dichloro-3-nitropyridine in 1300 ml of dioxane. This mixture is hydrogenated with hydrogen under normal pressure and at a temperature in the range from 20° to 35° C. After reaction of 20% of the required amount of hydrogen, a further 30.0 g of Raney nickel catalyst are added to the reaction mixture. After a hydrogenation period of 22 hours, the catalyst is removed, the solvent is evaporated off and the residue is crystallised from ethyl acetate/hexane, affording 84.9 g (78% of theory) of 3-amino-2,5-dichloropyridine, m.p. 129°-132° C.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[C:2]#[CH:3].C(O[C:21](=[O:27])[C:22]([O:24]CC)=O)C>>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:21](=[O:27])[C:22]1=[O:24])[C:2]#[CH:3]
Reactant: C#CCNCCNc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)OCC
Product: C#CCN1CCN(c2cccc(C(F)(F)F)c2)C(=O)C1=O

Procedure:
Condensation of N-propargyl-N'-(3-trifluoromethyl-phenyl)-ethylenediamine, obtainable according to 3.2, with diethyloxalate gave 1-propargyl-4-(3-trifluoromethyl-phenyl)-piperazin-2,3-dione. This compound was reduced to the title compound with lithium aluminum hydride or borane and was processed according to Example 5. White crystals, melting point 218°-219° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCOCC1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCCCOc1ccc(N)cc1
Solvent: C1COCCO1
Product: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 1.26 (6.03 mmol) of 4-(4-Dimethylamino-butoxy)-phenylamine in 15 ml dioxane was treated with 1.13 ml (6.1 mmol) Hünigsbase and 1.86 g (7.59 mmol) 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction mixture was stirred over night at room temperature and extracted with aqueous saturated NaHCO3 solution/EtOAc (3×). The organic phase was dried over Na2SO4 and evaporated. The residue (partially disulfonamide) was dissolved in 20 ml dioxane, treated with 11.1 ml 1N NaOH and heated for 1 h at 100° C. The reaction mixture was neutralized (pH 7 with 1 N HCl) and extracted with EtOAc (2×). The organic phase was washed with aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to yield 2.1 g (84%) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide, MS: 417 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O.[CH3:21][N:22](C=O)[CH3:23]>>[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Thionyl chloride (0.01 mL, 0.11 mmol) was added slowly to a solution of 4-(2-Fluoro-4-nitrophenyl)butanoic acid (82) (18 mg, 0.08 mmol) in DMF (3 mL) cooled at −5° C. The mixture was stirred for an additional 1 h at −5° C. Excess dimethylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 h. Ethyl acetate (30 mL) was added to the mixture, which was washed with brine (2×30 mL). The organic layer was dried over MgSO4, and concentrated to yield 4-(2-Fluoro-4-nitrophenyl)-N,N-dimethylbutanamide (77) (18 mg, 87%): 1H NMR δ 7.98 (dd, 1H, J=8.3, 2.1 Hz), 7.89 (dd, 1H, J=9.5, 2.1 Hz), 7.42 (dd, 1H, J=8.3, 7.4 Hz), 2.98 (s, 3H), 2.95 (s, 3H), 2.81 (t, 2H, J=7.6 Hz) 2.36 (t, 2H, J=7.2 Hz) 1.96-2.04 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([NH:42][C:41]3[CH:43]=[CH:44][C:38]([F:37])=[CH:39][CH:40]=3)=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 87.6 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added 4-flouroaniline (0.025 mL, 0.25 mmol), triethylamine (0.05 mL, 0.36 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (26 mg, 88%). LC-MS m/z 594 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3H), 2.79 (s, 6H), 3.16 (m, 2H), 3.55 (m, 2H), 4.21 (s, 2H), 7.15 (m, 4H), 7.54 (m, 1H), 7.71 (m, 3H), 7.85 (m, 1H).
Reaction SMILES: S(=O)(=O)=O.[CH3:5][S:6]([CH3:8])=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[CH3:5][S:6]([CH3:8])=[N:15][C:14]1[CH:16]=[CH:17][C:11]([C:10]([F:9])([F:18])[F:19])=[CH:12][CH:13]=1
Reactant: CS(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)=O
Solvent: ClCCl
Product: CS(C)=Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
Sulfur trioxide (4.84 g, 60.5 mmol) in dichloromethane (10 mL) was added to dimethyl sulfoxide (4.84 g, 62.0 mmol) in dichloromethane (10 mL) at −5 to 0° C. When the addition was complete 4-(trifluoromethyl)aniline (5.00 g, 31.0 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature. After about 1 h the mixture was diluted with dichloromethane (80 mL) and washed with sodium hydroxide (1 N, 100 mL), dried and evaporated to give the title product as a solid (6.58 g, 96% yield).
Reaction SMILES: [C:1]12([S:11](Cl)(=[O:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)(=[O:13])=[O:12])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=S(=O)(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=S(=O)(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanesulfonamide.
Reaction SMILES: ONC(=O)C=CC1C=C[C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][I:30]>CN(C=O)C>[CH3:9][NH:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:16]1[CH:21]=[CH:20][C:29]([I:30])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=C(C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1)NO
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 196.6 %

Procedure:
To compound 28 (from Example 18) (500 mg, 1.39 mmol) in DMF (10 mL) were added at room temperature K2CO3 (962 mg, 6.96 mmol), followed by methyl iodide (395 mg, 2.78 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The solvent is then removed and water was added. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were dried and concentrated. Purification by flash chromatography using hexane:ethyl acetate (8:2) afforded 510 mg (98%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[Cl-].[CH3:29][O:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([OH:36])=[O:35]>O1CCCC1.N1C=CC=CC=1.C1(C)C=CC=CC=1.C(OC(=O)C)C>[CH3:26][O:25][C:24]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19](/[CH:18]=[CH:17]/[C:15]([CH2:14][C:12](/[CH:11]=[CH:10]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)=[O:13])=[O:16])[CH:27]=1.[CH3:29][O:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]([O:36][CH3:1])=[O:35]
Reactant: COC(=O)CCC(=O)O
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCC(=O)OC
Reaction time: 24 h

Procedure:
To a solution of 3.68 g curcumin (10 mmole) in 20 ml tetrahydrofuran and 3 ml pyridine was slowly added at 0° C. a solution of 2.83 ml succinic acid monomethylesterchloride (23 mmole) in 5 ml of toluene. After stirring for 24 h at ambient, the reaction mixture was diluted with 100 ml acetic acid ethylester and washed with water. The organic phase was evaporated and the residue crystallised from ethyl acetate to yield 4.4 g curcumin-bis-methylsuccinate, m.p. 145-147° C.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:3]2[N:2]=[N:1][C:5]([C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH:18]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)=[N:4]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3nn[nH]n3)cc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2nnc(-c3ccc4[nH]c5ccccc5c4c3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
3-(2H-Tetrazol-5-yl)-9H-carbazole (example 401, 17 g, 72.26 mmol) was dissolved in N,N-dimethylformamide (150 mL). Triphenylmethyl chloride (21.153 g, 75.88 mmol) and triethylamine (20.14 mL, 14.62 g, 144.50 mmol) were added consecutively. The reaction mixture was stirred for 18 hours at room temperature, poured into water (1.5 L) and stirred for an additional 1 hour. The crude product was filtered off and dissolved in dichloromethane (500 mL). The organic phase was washed with water (2×250 mL) and dried with magnesium sulfate (1 h). Filtration followed by concentration yielded a solid which was triturated in heptanes (200 mL). Filtration furnished 3-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (31.5 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:28])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CC(=O)c1cc(Cl)c2cn[nH]c2c1-c1cc(F)cc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cn[nH]c2c1-c1cc(F)cc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1H-indazol-6-yl]ethanone (0.20 g, 0.65 mmol) and ammonium acetate (0.50 g, 6.5 mmol) and sodium cyanoborohydride (0.082 g, 1.3 mmol) in methanol (2 mL) and acetonitrile (2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the crude amine which was used directly in the next step. LCMS calculated for C15H10ClF2N2 (M−NH2)+: m/z=291.0; Found: 291.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(C(F)(F)F)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-trifluoromethylacetophenone (M. Kihara, M. Kashimoto, and Y. Kobayashi, Tetrahedron, 1992, 48, 67-78). 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.03 (1H, br s), 7.89 (1H, br d, J=7.7 Hz), 7.74 (1H, br d, J=8.1 Hz), 7.59-7.54 (2H, m), 7.33 (1H, dd, J=1.8, 8.4 Hz), 5.93 (2H, br s), 3.80 (2H, q, J=7.0 Hz), 0.88 (3H, t, J=7.0 Hz)
Reaction SMILES: [C:1](O)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:4][CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:1](=[O:5])[CH2:2]1
Reactant: C/C=C/C(=O)O
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CC(=O)c2ccccc21

Procedure:
A solution of crotonic acid (20 g, 0.232 moles) in benzene (147 ml) was added AlCl3 (93 g, 0.748 moles) and the mixture was refluxed for 7 hours. Completion of the reaction was monitored by HPLC & GC. Excess benzene was distilled off and the reaction mixture was poured slowly into ice cold HCl. The organic compound was extracted with ethylacetate. The organic phase was washed thoroughly with water, dried, and evaporated under vacuum. The resultant oil was purified by high vacuum distillation (90-94° C. at ˜2 mm) giving 25 g (74%) of 99.2% pure 3-methyl-indan-1-one.
Reaction SMILES: C(OC([N:6]1[CH2:19][CH2:18][C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C.CO>C(Cl)(Cl)Cl>[CH2:12]1[C:11]2[C:10]3[CH2:18][CH2:19][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)CCC3
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1cc2c(c3c1CCC3)CCNCC2
Temperature: 60 °C
Yield: 63.6 %

Procedure:
Into a glass vial, the product from step (a) (0.126 mmol) in CHCl3 (3 ml) was placed. To this stirred solution, TMSI (172 μL, 1.26 mmol) was added. The reaction mixture was heated to 60° C. for 3 h. The reaction mixture was allowed to cool to room temperature and methanol (1 ml) was added to quench. The solvent was evaporated in vacuo to give the crude product as a yellow residue. The crude product was purified by semi-prep RP-HPLC to give the title compound as light yellow oil (15 mg). Recovered as acetate salt: 1H NMR (CDCl3) δ 7.18 (bs, 2H), 7.02 (d, J=7.2 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 3.15-3.05 (m, 8H), 2.94-2.84 (m, 4H), 2.12-2.02 (m, 2H) 1.98 (s, 3H); MS: ESI (positive): 188 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)n(C)n1
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(Cl)c1[N+](=O)[O-]

Procedure:
148.0 gms. of 5-chloro-1,3-dimethylpyrazole are added to 530 ml. of concentrated sulfuric acid at 0° and 370 ml. of fuming nitric acid are added dropwise with stirring. The reaction mixture is then stirred at 0° for 4 hours, poured over 250 gms. of ice and extracted with methylene chloride. 138 gms. of the product, 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole, are obtained from the dried organic phase as white crystals, m.p. 77°-78°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([CH2:23][CH2:24][CH3:25])=[N:16][N:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([CH2:23][CH2:24][CH3:25])=[N:16][N:17]([CH3:22])[C:18]=1[C:19]([NH2:21])=[O:20])=[O:7])[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane (50 ml) was added to a stirred solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine (0.02 g, 0.164 mmol) and triethylamine (3.34 g, 33.0 mmol) in dichloromethane (50 ml) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for a further 2 hours. The solvent was evaporated under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane and methanol (250 ml), and then the solution washed with 1N hydrochloric acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude material was chromatographed on silica gel (200 g), eluting with a 97:3 mixture of dichloromethane and methanol, to give a pink solid; crystallisation from ethyl acetate-hexane gave the pyrazole-3-carboxamide as a pale pink solid (2.2 g, 40%), m.p. 153-155° C. Found: C,61.66; H,6.77; N,16.95. C17H22N4O3 requires C,61.80; H,6.71; N,16.96%.