Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])=[CH:7][CH:6]=1.[OH-].[Li+]>CO>[C:16]([O:15][C:13]([N:11]([CH3:12])[C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:20])=[O:2])=[CH:10][CH:9]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)cc1
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of [4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-acetic acid methyl ester (prepared according to the procedure of Hay et al. as described in J. Chem. Soc. Perkin Trans I. 1999, 19, 2759) (2.68 mmol) in methanol (10 mL) was added 1.0M aqueous lithium hydroxide solution (13.7 mL) and the mixture heated to 50° C. for 35 mins. The reaction mixture was cooled in an ice bath then washed with ether (25 mL), acidified with 3.0M aqueous hydrochloric acid to pH=4 while stirring and cooling in an ice bath. The precipitate was isolated by filtration, washed with water and dried in vacuo to give [4-(tert-butoxycarbonyl-methyl-amino)-phenyl]-acetic acid as a colorless solid (70%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a suspension of 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (290 mg, 0.895 mmol) in THF (5 ml) was added NaH (60%, 43 mg, 1.08 mmol) in one portion at 0° C. The resulting mixture was stirred for 20 minutes before a solution of para-toluenesulfonyl chloride (188 mg, 0.98 mmol) in THF (2 mL) was added. The reaction mixture was then stirred at room temperature for 3 hours. Solvents were removed and the resulting dark brown residue washed with aqueous KOH, water and dried to afford the title compound (423 mg, 99% yield) as a light brown solid. 1H-NMR (500 MHz, d6-DMSO) δ 8.60 (d, 11.5 Hz, 1H), 7.99 (d, 11.5 Hz, 2H), 7.44 (d, 7.5 Hz, 2H), 2.34 (s, 3H). MS: m/z 477.8/479.8 [MH+].
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:9][CH:8]=1)=[O:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:11][CH:12]=1)=[O:6]
Reactant: COc1ccccc1C(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(Nc2ccccc2[N+](=O)[O-])cc1)c1ccccc1O

Procedure:
To a cooled (−78° C.) solution of 2-Methoxy-4′-(2-nitrophenylamino)-benzophenone (Compound 215, 0.35 g, 1 mmol) in methylene chloride (10 ml), under argon, was added boron tribromide (0.1 ml, 1 mmol) under stirring. The reaction mixture was allowed to come to room temperature. After stirring for 3 h , the reaction mixture was poured into saturated sodium bicarbonate (50 ml) before being extracted with ethyl acetate (2×50 ml). The organic phase was dried (MgSO4), filtered and evaporated to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH2:23])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][NH:23][CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNCC(O)c2ccc(C)cc2)cc1OC
Temperature: 100 °C

Procedure:
Similarly a mixture of 10.6 g. (0.0789 mol) of p-methylstyrene oxide and 14.3 g. (0.0789 mol) of 3,4-dimethoxyphenylethylamine is stirred under argon and heated at 100° C. for 18 hours to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-methylphenyl)ethylamine, m.p. 99°-100° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:19][CH:20]=2)[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:12]1([C:15]2[CH:20]=[N+:19]([O-:9])[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(C2CC2)cn1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C2CC2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
m-Chloroperbenzoic acid (55 g) was added to a solution of ethyl 5-cyclopropylpyridine-2-carboxylate (15.5 g) in chloroform (300 mL) under ice-cooling, and the mixture was stirred at room temperature for four hours. The reaction solution was poured into a mixed solvent of saturated aqueous sodium bicarbonate and a saturated sodium thiosulfate solution, and the mixture was stirred at room temperature for 30 minutes. After extraction with chloroform, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give ethyl 5-cyclopropylpyridine-2-carboxylate 1-oxide (15.4 g) as a pale yellow oil.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:65]([CH2:66][O:67]C(=O)C)[O:64][C@@H:28]([O:29][N:30]2[CH:34]=[C:33]([CH2:35][O:36][C@H:37]3[CH2:61][CH2:60][C@@:59]4([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]5[C@@H:58]4[CH2:57][CH2:56][C@@:55]4([CH3:63])[C@H:43]5[CH2:44][CH2:45][C@@H:46]4[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]3)[N:32]=[N:31]2)[C@H:27]([O:71]C(=O)C)[C@H:26]1[O:75]C(=O)C)(=O)C.C[O-].[Na+]>C1COCC1.CO.CO>[C@H:6]1([O:24][C@@H:25]2[C@@H:65]([CH2:66][OH:67])[O:64][C@@H:28]([O:29][N:30]3[CH:34]=[C:33]([CH2:35][O:36][C@H:37]4[CH2:61][CH2:60][C@@:59]5([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]6[C@@H:58]5[CH2:57][CH2:56][C@@:55]5([CH3:63])[C@H:43]6[CH2:44][CH2:45][C@@H:46]5[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]4)[N:32]=[N:31]3)[C@H:27]([OH:71])[C@H:26]2[OH:75])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](On3cc(CO[C@H]4CC[C@@]5(C)C(CC[C@H]6[C@@H]7CC[C@H]([C@H](C)CCCC(C)C)[C@@]7(C)CC[C@@H]65)C4)nn3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(O[C@@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Peracetate 95 (190 mg) was dissolved in THF/MeOH (1:1). NaOMe in MeOH (11M, 20 μL) was added and the solution was stirred at room temperature for 3 hours. The solution was neutralised with H+ resin, filtered and the solvent evaporated to give 125 mg (90%) of the off-white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=1)[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1)[CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)CCc2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CCc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate was dissolved in a solution of methanol (20 ml) and tetrahydrofuran (20 ml). To this solution was added aqueous 2N sodium hydroxide (10.5 ml) and the mixture heated at reflux for 24 hours; cooled and the volume reduced by evaporation to half the original volume. Water (20 ml) was added and the mixture acidified with acetic acid. The resulting solid was filtered and dried under vacuum at 60° C. to give the title product (950mg) m.p. 175° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH:19]([CH2:23][NH:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])[C:20]([OH:22])=O)=[O:17])(=[O:13])=[O:12].[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH3:39][CH:40]1[CH2:45][CH2:44][N:43]([C:20]([CH:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])[CH2:23][NH:24][C:25]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH2:31][CH2:32]2)=[O:26])=[O:22])[CH2:42][CH2:41]1
Reactant: CC1CCNCC1
Reactant: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)O
Product: CC1CCN(C(=O)C(CNC(=O)C2CCN(c3ccncc3)CC2)NC(=O)CNS(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 22 %

Procedure:
Using an analogous procedure to that described in Example 20, 2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionic acid was reacted with 4-methylpiperidine to give N-{1-(4-methylpiperidin-1-ylcarbonyl)-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}-2-(2-naphthalenesulphonamido)acetamide in 22% yield.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14](=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C:20]([CH3:29])([CH3:28])[NH:19]2)[C:15](N)=[O:16])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C([OH:32])C.Cl>O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]=[N:13][C:14](=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C:20]([CH3:28])([CH3:29])[NH:19]2)[C:15]([OH:32])=[O:16])=[CH:10][CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N=NC(C(=O)O)=C2NC(C)(C)Cc3ccccc32)cc1
Temperature: 25 °C

Procedure:
Potassium hydroxide and 2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene)-acetamide (Asinex Corp., Russia) are added to ethanol, and the mixture is refluxed under heating. The refluxed product is cooled to room temperature and, then, added with distilled water, and further added with hydrochloric acid to make the pH neutral, followed by extracting the reaction product with diethylether. The reaction product is dried by using anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:9]1[C:14]([S:15][CH3:16])=[C:13]([O:17]C)[N:12]=[C:11]([O:19]C)[N:10]=1)C(OC)=O.Cl>CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:9]1[C:14]([S:15][CH3:16])=[C:13]([OH:17])[N:12]=[C:11]([OH:19])[N:10]=1
Reactant: COC(=O)C(C(=O)OC)c1nc(OC)nc(OC)c1SC
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1nc(O)nc(O)c1SC
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(2,6-dimethoxy-5-methylsulfanyl-pyrimidin-4-yl)-malonic acid dimethyl ester (2.85 g, 9.0 mmol.) was added dropwise to slurry of HCl (37% w/w) (1.0 ml) in MeOH (50 ml). The reaction mixture was stirred at 100° C. for 24 hr and dried, and the solvent was evaporated in vacuo to give a crude as a pale yellow solid of 1.85 g (89.2%). 1H NMR (500 MHz, DMSO-d6): δ11.35 (s, 1H), 11.23 (s, 1H), 3.81 (s, 2H), 3.66 (s, 3H), 2.11 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]=[C:24]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:9]=2[CH3:31])=[CH:4][CH:3]=1.I[CH3:33].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]=[C:24]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:23]([CH3:33])[N:22]=3)[C:9]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2n[nH]c(C3CCCC3)n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2nc(C3CCCC3)n(C)n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A solution of 3-(5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-5-cyclopentyl-1H-1,2,4-triazole (400 mg, 0.82 mmol), iodomethane (0.19 ml, 2.5 mmol) and potassium hydroxide (138 mg, 2.5 mmol) dissolved in methanol (3 ml) was placed in a round bottom flask, stirred at room temperature for 1 day. After evaporation of the volatile solvent, the crude residue was purified by column chromatography to obtain the title compound (330 mg, 80%) as white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C1(C)C=CC(S(O[CH2:25][C@H:26]2[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:31][C:28]1([CH3:32])[O:27][C@@H:26]([CH2:25][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:30][O:29]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Temperature: 25 °C

Procedure:
A solution of 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (9.24 g, 47.6 mmol), (R)-(−)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (15.00 g, 52.38 mmol) and CsHCO3 (23.3 g, 71.4 mmol) in anhydrous DMF (236 mL) was heated to 100° C. for 16 h. The reaction mixture was cooled to rt and partitioned between EtOAc and H2O. The aqueous layer was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (2×) and brine (2×), dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as an orange oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 130 °C
Yield: 91 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (0.6 g, 2.3 mmol) was dissolved in anhydrous dioxane (2 mL) and 4-(trifluoromethyl)aniline was added (0.43 mL, 3.45 mmol), followed by HI/H2O (0.2 ml, 47%). The mixture was heated at 130° C. in a sealed tube for 10 min in a microwave (Smith creator model, Personal Chemistry). The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the desired compound as a yellow solid (800 mg, 91%) which was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]([CH3:28])=[CH:13][CH:14]([CH3:27])[CH:15]([O:25]C)[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]([CH3:28])=[CH:13][CH:14]([C:15](=[O:25])[C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH3:27]
Reactant: COC(c1ccc(N(C)C)cc1)C(C)C=C(C)C=CC(=O)Nc1ccccc1N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C=CC(=O)Nc1ccccc1N)=CC(C)C(=O)c1ccc(N(C)C)cc1
Reaction time: 0.25 h
Yield: 7.4 %

Procedure:
To a stirred solution of compound 34 (85 mg, 0.216 mmol) in wet benzene (2 mL, benzene: H2O=9:1) at room temperature was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 98 mg, 0.432 mmol). After being stirred vigorously for 15 min., the mixture was diluted with ethyl acetate (30 mL), washed with water (2×5 mL), dried (anhydr.MgSO4), and concentrated. Purification by flash silica gel chromatography (50% ethyl acetate in hexanes, and then ethyl acetate only) afforded the title compound 35 (6 mg, 7% yield): 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=9.0, 2H), 7.87 (br. s, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.27 (d, 7.8 Hz, 1H), 7.00 (m, 1H), 6.72 (m, 2H), 6.62 (d, J=9.0 Hz, 2H), 5.97 (d, J=15.6 Hz, 1H), 5.97 (d, J=9.3 Hz, 1H), 4.34 (dq, J=9.3, 6.9 Hz, 1H), 3.03 (s, 3H), 1.87 (br. s, 3H), 1.29 (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 12.6, 17.6, 39.9, 40.8, 110.7, 118.0, 119.0, 119.3, 123.8, 124.4, 125.1, 126.9, 130.6, 132.5, 140.8, 146.2, 153.4, 164.8, 198.6.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH2:25])=[CH:20][CH:19]=2.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH3:15])=[CH:24]3)=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc2cc(NC(=O)c3ccc(F)c(C(F)(F)F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Synthesis: 4-Fluoro-3-trifluoromethyl benzoyl chloride (0.42 mL, 2.77 mmol) was added to a solution of 2-methyl-1H-indol-5-ylamine (472 mg, 3.23 mmol) and triethylamine (0.42 mL, 3.01 mmol) in anhydrous dichloromethane at room temperature. The reaction mixture was stirred at room temperature for two hours then diluted with a 1:1 mixture of ethyl acetate and water (80 mL). The organic layer was washed sequentially with 0.5N HCl, saturated NaHCO3, water, saturated NaCl and dried over anhydrous sodium sulfate. The desired 4-fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide was obtained as a purple solid in nearly quantitative yield. This material was taken onto the next step without further purification. 4-Fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide (1.02 g, 3.03 mmol) and piperazine (1.83 g, 21.21 mmol) was dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was heated in a sealed glass tube at 125° C. for two and a half hours. The crude mixture was then cooled to room temperature, concentrated and the residue chromatographed with 10% MeOH/CH2Cl2+2% triethylamine to afford N-(2-Methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide, the title compound (86% yield). 1H NMR (400 MHz , CD3OD) δ 8.26 (d, J=2.3 Hz, 1H), 8.18 (dd, J=8.6, 2.3 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H, 7.55 (d, J=8.6 Hz, 1H), 7.28-7.17 (m, 2H), 2.99 (s, 8H), 2.41 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[NH2:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:7][C:6]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Yield: 74 %

Procedure:
The reaction of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine and (S)-tert-butyl 2-(aminomethyl)pyrrol-idine-1-carboxylate under the amine displacement conditions described in example 5.6.5 afforded 74% product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[Cl:51][C:52]1([C:67]([O:69][CH3:70])=[O:68])[CH2:57][CH2:56][C:55](B2OC(C)(C)C(C)(C)O2)=[CH:54][CH2:53]1>>[Cl:51][C:52]1([C:67]([O:69][CH3:70])=[O:68])[CH2:57][CH2:56][C:55]([C:7]2[C:8]([CH3:48])([CH3:47])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:46])([C@@:13]4([CH3:45])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH2:37][CH2:36]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:54][CH2:53]1
Reactant: COC(=O)C1(Cl)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(Cl)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described in general procedure Step 5, using (1R,3 aS,5aR,5bR,7aR,11aR,11bR,13 aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diastereomers, which was used in next step without purification. MS: m/e 771.5 (M+H)+, 3.06 min (method 4).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].Br[C:14]1=[C:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:16][CH:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])[CH2:18]/[C:19]/1=[N:20]\OS(C)(=O)=O>CCOCC>[NH2:20][C:19]1[CH:18]=[C:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[F:33])[N:16]=[C:15]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:14]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)C1=C(Br)/C(=N/OS(C)(=O)=O)CC(c2ccc(Cl)cc2F)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2F)cc(N)c1OCC(F)(F)F
Reaction time: 0.5 h

Procedure:
To a mixture of 2,2,2-trifluoroethanol (3.9 mL) and K2CO3 (54 mg, 3.9 mmol) was added (E)-ethyl 3-bromo-6-(4-chloro-2-fluorophenyl)-4-(((methylsulfonyl)oxy)imino)-1,4,5,6-tetrahydropicolinate (prepared as in Renga, J. M. et al. U.S. Patent Appl. Publ. 2010/0311594 A1, Dec. 9, 2010; 450 mg, 1 mmol). The mixture was stirred for 30 min, then diluted with Et2O and washed with 1 M HCl. The organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 0-50% EtOAc/hexanes affording an off-white solid: (190 mg, 74%): mp 123-135° C.; 1H NMR (300 MHz, CDCl3) δ 8.00 (t, J=8.5 Hz, 1H), 7.23 (m, 3H), 7.15 (dd, J=11.1, 2.0 Hz, 1H), 4.59 (s, 2H), 4.46 (m, 4H), 1.44 (t, J=7.1 Hz, 3H); ESIMS m/z 393 ([M+H]+), 391 ([M−H]−).