Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.ClCCCl>[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([N:27]2[CH2:28][CH2:29][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25][CH2:26]2)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CC(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
3-(4-phenoxyphenyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (221 mg, 0.572 mmol), 1-isopropyl-4-piperidone(89 mg, 0.63 mmol), sodium triacetoxyborohydride (182 mg, 0.86 mmol) and glacial acetic acid(40 ul, 0.63 mmol) were mixed with 3 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until PH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified by flash column chromatography to give 132 mg of 1-[1-(1-isopropyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 0.99(d, J=6.54 Hz, 6H), 1.42(m, 2H), 1.72(d, J=11.41 Hz, 2H), 1.88(d, J=9.61 Hz, 2H), 2.14(s, 3H), 2.16(m, 6H), 2.66(m, 2H), 2.83(d,J=10.98 Hz, 2H), 2.98(d,J=8.25 Hz, 2H), 4.62(m, 1H), 7.16(m, 5H), 7.44(m, 2H), 7.67(d, J=8.69 Hz, 2H), 8.23(s, 1H); LC/MS (MH+=512)
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([O:34]C)=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.O[Li].O.Cl>CC(C)=O>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([C:29]6([C:32]([OH:34])=[O:33])[CH2:31][CH2:30]6)[CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)C1(c2cccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)ccc3C)c2)CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylate (−0.26 mmol) was dissolved in acetone (3 mL) and water (3 mL) in a reaction tube. LiOH.H2O (25 mg, 60 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was acidified with 1N HCl until pH 1-2. The volatiles were removed under reduced pressure. The residue was taken up in methylene chloride and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The solid was triturated with Et2O, then hexanes to 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropanecarboxylic acid. ESI-MS m/z 493.2 (M+1)+. Retention time 1.80 minutes.
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:14]3[C:9](=[C:10]([N:39]4[CH2:44][CH2:43][CH:42]([C:45]([O:47]CC)=[O:46])[CH2:41][CH2:40]4)[CH:11]=[C:12]([C:15]([N:17]4[CH2:22][CH2:21][C:20]5([CH2:31][C:30](=[O:32])[C:29]6[C:24](=[CH:25][CH:26]=[C:27]([C:33]7[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=7)[CH:28]=6)[O:23]5)[CH2:19][CH2:18]4)=[O:16])[CH:13]=3)[CH:8]=[CH:7]2)[CH2:5][CH2:4]1.CO.Cl>C1COCC1>[CH:3]1([N:6]2[C:14]3[C:9](=[C:10]([N:39]4[CH2:44][CH2:43][CH:42]([C:45]([OH:47])=[O:46])[CH2:41][CH2:40]4)[CH:11]=[C:12]([C:15]([N:17]4[CH2:18][CH2:19][C:20]5([CH2:31][C:30](=[O:32])[C:29]6[C:24](=[CH:25][CH:26]=[C:27]([C:33]7[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=7)[CH:28]=6)[O:23]5)[CH2:21][CH2:22]4)=[O:16])[CH:13]=3)[CH:8]=[CH:7]2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCN(c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)cc3c2ccn3C2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(N5CCC(C(=O)O)CC5)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
Aqueous 1N NaOH (0.409 ml, 0.409 mmol) was added to a stirred solution of ethyl 1-(1-cyclopropyl-6-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}-1H-indol-4-yl)piperidine-4-carboxylate in THF (1 ml)-MeOH (1 ml) and the mixture was stirred at room temperature overnight. Aqueous 1N HCl (0.409 ml) was added to the mixture and the solvent was evaporated under reduced pressure. The residue was suspended in CHCl3-MeOH (8:2) and the mixture stirred for 1 h. at room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The crude material was purified by preparative HPLC (ODS, 0.1% HCOOH in H2O/MeCN, gradient) to give intended compound (44.4 mg, 0.073 mmol, 35.7% yield) as a pale orange solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:18]([O:20]C)=[O:19])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:18]([OH:20])=[O:19])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)OC)ccc2C)c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)O)ccc2C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a suspension of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 3) (0.58 g, 1.40 mmol) in dioxane (2 mL) was added 2N NaOH (1.05 mL, 2.10 mmol). Stirred at ambient temperature for 2 h. Cooled reaction mixture (0° C.), added 5% citric acid to precipitate the product, filtered solid, washed with water, and dried in vacuo. Obtained the product as a pale yellow solid (0.53 g, 95%). Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:25])[CH2:14][N:15]3[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[N:16]3)[CH2:9][CH2:8]2)[S:5][CH:6]=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO>C1COCC1>[CH3:20][C:19]1[N:15]([CH2:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:4]3[S:5][CH:6]=[C:2]([NH:1][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[N:3]=3)[CH2:8][CH2:9]2)=[O:25])[N:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(NC(=O)Nc3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (100 mg, 0.27 mmol) in THF (5 mL) is added dropwise a solution of phenylisocyanate (30 μL, 0.28 mmol) in THF (1 mL) at 0° C. After stirring overnight at RT, methanol (1 mL) is added to the reaction mixture. After stirring 15 min. at RT, the solvents are evaporated and the residue was triturated with diethylether (5 mL) to induce precipitation. The resulting solid is filtered and dried under vacuum to give 1-(2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-3-phenyl-urea as beige solid (Compound No. I.g.024, 105 mg, 79%). M.p.=192.6° C. 1H-NMR (400 MHz, CDCl3): δ=1H-NMR (MeOD): d=1.65 (m, 1H), 1.80 (m, 1H), 2.40 (m, 2H), 2.30 (s, 3H), 2.98 (m, 1H), 3.30 (m, 1H), 3.39 (m, 1H), 4.10 (m, 1H), 4.52 (m, 1H), 5.22 (2d, 2H, diastereotopic), 6.42 (s, 1H), 7.05 (t, 1H), 7.09 (s, 1H), 7.26-7.45 (m, 6H). MS: m/z=494 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[Na+].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)[O-])cc1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Temperature: 15 °C
Reaction time: 3.5 h
Yield: 68.6 %

Procedure:
To a solution of 63.7 g (0.226 Mol) 2,6-dibromo-4-nitropyridine in dimethylformamide (600 ml) at -15° C. were slowly added 50.0 g (0.226 Mol) 4-acetamido-benzenesulfinic acid sodium salt. The mixture was stirred at 15° C. for 3.5 h. Then 2.0 l water were added. It was stirred for another hour, filtered and the residue on the filter was washed with water (150 ml). It was then dissolved in aceton (hot, 700 ml) and evaporated. The residue was suspended in toluene (700 ml) and evaporated, again suspended in toluene and filtered. The residue on the filter was washed with toluene (200 ml) and dried in a high vacuum. It was obtained 67.3 g (69%) N-[4-(2,6-dibromo-pyridine-4-sulfonyl)-phenyl]-acetamide as a bright beige powder; mp.: 211° C.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[CH3:10][C:9]1([CH3:11])[O:8][C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)=[CH:3][C:4]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(I)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 6-iodo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Yellowish solid: mp 244-245° C.; 1H-NMR (DMSO-d6) δ10.38 (s, 1H, D2O exchangeable), 8.47 (s, 1H), 8.14-8.20 (m, 2H), 7.70-7.76 (m, 3H), 7.01 (d, 1H, J=8.1 Hz), 1.68 (s, 6H); MS (EI) m/z 297 ([M−H]−, 100%). Anal. Calc. For C16H14N2O4: C, 64.42; H, 4.73; N, 9.39. Found: C, 63.93; H, 4.91; N, 8.71
Reaction SMILES: S[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[Cl:13][C:14]1[CH:45]=[CH:44][C:17]([C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Si:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=2[C:42]#[CH:43])=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:19])([C:4]2[N:3]([CH3:7])[CH:2]=[N:6][CH:5]=2)[C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:33]=[CH:42][CH:43]=[C:36]([C:35]#[C:34][Si:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=2)=[CH:44][CH:45]=1
Reactant: Cn1ccnc1S
Reactant: C#Cc1c(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)cccc1[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#C[Si](C)(C)C)c1)cc(=O)n2C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved in anhydrous THF (200 mL) under an atmosphere of dry N2. The solution was cooled to −78° C. and a solution of tert-butyl lithium (1.7 M in pentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0° C. After a yellow precipitate formed, the solution was cooled to −78° C. and a solution of 6-(4chloro-benzoyl)-1-methyl-4-(3-trimethylsilanyl ethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mMol) in anhydrous THF (25 mL) was added. After 30 minutes, the solution was warmed to 0° C. and stirred at this temperature for 1 hour. The reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction was quenched with 20 mL of saturated aqueous ammonium chloride (NH4Cl) and then partitioned between DCM and water. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as a solid.
Reaction SMILES: [CH2:1]([C:5]1([N:22]([CH3:24])[CH3:23])[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Si]([Cl:29])(C)(C)C>CC(CC)=O>[ClH:29].[CH2:1]([C:5]1([N:22]([CH3:24])[CH3:23])[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH3:20])=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2[nH]c3ccc(F)cc3c2C)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
1-Butyl-4-(5-fluoro-3-methyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamine (266 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (30 ml). Me3SiCl (20.5 μl, 1.6 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl methyl ketone (2×5 ml) and then dried. Example 79 (193 mg, m.p. 255-265° C., 61%) was a white solid
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(N)ncn2)CC1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.4 g, 3.09 mmol) and diisopropylethylamine (0.399 g, 3.09 mmol) were suspended in n-butanol. tert-Butyl 1,4-diazepane-1-carboxylate 15-1 (0.618 g, 3.09 mmol) was then added. The reaction was stirred at 150° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and then air dried. 1H-NMR (CD3OD): 7.95 ppm (s, 1H); 5.65 ppm (s, 1H); 3.73 ppm (m, 2H); 3.61 ppm (m, 3H); 3.55 ppm (t, 1H); 3.38 ppm (m, 1H); 3.34 ppm (m, 1H); 1.89 ppm (m, 1H); 1.84 ppm (m, 1H); 1.41 ppm (s, 4H); 1.36 ppm (s, 5H).
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:45][O:46][C:47](=[O:63])[C@@H:48]([NH2:62])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:63])[C@@H:48]([NH:62][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)=[CH:54][CH:55]=1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (61 m g, LC/MS: m/z 842) was prepared from Intermediate D (100 mg) and (S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester bis hydrochloride according to general procedure A.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[ClH:20]>C(O)C>[ClH:20].[CH:12](=[C:7]1[C:8](=[O:11])[C:9](=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCN1CCC(=O)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A stirred solution of 31 g of 1-butyl-4-piperidone and 64 g of benzaldehyde in 300 ml of ethanol is cooled to 15° C, treated dropwise with 66 ml of concentrated hydrochloric acid, refluxed for 5 hours, and maintained for about 16 hours at room temperature. The bulk of ethanol is evaporated and the syrupy residue is cooled, diluted to 600 ml with water, treated with 300 ml of ether, stirred, and rubbed; a solid gradually separates. After cooling for several hours, the solid is filtered, washed with ether, and air-dried; yielding 36.7 g of material, melting point 203°-205° C. Following crystallization from 100 ml of dimethylformamide, the material weighs 24.2 g; melting point 212°-214° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13]Cl)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][N:25]3[CH2:26][CH2:27][CH:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: ClCc1ccnc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: c1ccc(CC2CCN(Cc3ccnc(-c4ccccc4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 50 mg of 2-phenyl-4-chloromethylpyrimidine in 5 mL chloroform was added 80 mg 4-benzylpiperidine and 1 mL of N,N-diisopropylethylamine. The reaction mixture was heated at reflux temperature for 4 hr, cooled to room temperature, washed with 5 mL 1N sodium hydroxide solution and the solvent removed by evaporation under reduced pressure to yield 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine. This material was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 2-phenyl-4-[(4-benzyl-piperidin-1-yl)methyl]-pyrimidine dihydrochloride (Compound 11), mp 211-213° C.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[F:5][C:6]1([F:24])[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([C:18](Br)([CH3:20])[CH3:19])=[O:17])=[CH:15][C:9]=2[O:8][C:7]1([F:23])[F:22].CS(C)=O>O>[F:5][C:6]1([F:24])[O:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([C:18]3[CH:20]=[CH:15][C:9]4[O:8][C:7]([F:23])([F:22])[C:6]([F:5])([F:24])[O:11][C:10]=4[CH:19]=3)=[O:17])=[CH:15][C:9]=2[O:8][C:7]1([F:23])[F:22]
Reactant: CC(C)(Br)C(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc2c(c1)OC(F)(F)C(F)(F)O2)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Yield: 136.1 %

Procedure:
0.65 g of sodium azide was added to a mixture comprising 1.78 g of α-bromoisopropyl 2,2,3,3-tetrafluoro-1,4-benzodioxan-6-yl ketone and 10 ml of dimethyl sulfoxide, followed by a reaction for two hours at 50° C. The reaction mixture was put into water, and extracted with diethyl ether, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/19) to obtain 1.5 g of oily α-azideisopropyl 2,2,3,3-tetrafluoro-1,4-benzodioxan-6-yl ketone. The NMR spectrum data of this product is as follows.
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[C:10]([CH3:22])[C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1>O>[Br:6][CH2:29][C:25]1[CH:24]=[C:23]([C:9]2[C:8]([CH3:7])=[CH:13][C:12]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=2[CH3:22])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CBr)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Concentrated sulfuric acid (1.4 g) was added dropwise to 48% hydrobromic acid (15 ml) at room temperature and [2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl]methanol (25 g) synthesized in accordance with the method described in [WO 2008/001931 pamphlet] was divided into five portions and added to the mixture. The reaction mixture was stirred at 60° C. for 2.5 hours and 48% hydrobromic acid (3.3 ml) was added to the mixture. The mixture was further stirred for 1 hour at the same temperature. After the reaction mixture was allowed to cool, water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The obtained organic phase was washed with water, then washed with brine, and dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to give the title compound (27 g) as a pale yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([S:16][CH2:15][CH2:14][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCSc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCSc1ccccc1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
Potassium phthalimide (5.43 g, 25 mmol) was added to a DMF (50 ml) solution of [(2-bromoethyl)thio]benzene (5,43 g, 25 mmol) and this stirred mixture under N2 was heated at 90° C. for 2 h. After cooling to room temperature, the reaction was filtered. The solvent was stripped from the filtrate under reduced pressure. The residue, dissolved in CH2Cl2 (100 ml), was filtered, concentrated, and flash chromotographed on a 4 inch column eluting with 1 to 6% EtOAc/toluene to produce 4.9 g of the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]=[C:7]2[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)([O-])=O.CO.[H][H]>C1(C)C=CC=CC=1.[Pd]>[N:35]1[CH:36]=[CH:37][C:32]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=3)[N:9]([C:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:33][CH:34]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 105.8 %

Procedure:
To a 500 ml round bottom flask equipped with a magnetic stir bar was added 5-nitro-3-(pyridin-4-yl)-1-trityl-1H-indazole (1332 g, 27.6 mmol) and dissolved in a mixture of toluene:MeOH (120 ml: 40 ml). While stirring, Pd/C (1.5 g, 10% wet) was added. The mixture was then subjected to a hydrogen balloon and stirred overnight. Upon completion of the reaction, which was determined by LC/MS, the mixture was filtered through celite and concentrated under vacuum to give 3-(pyridin-4-yl)-1-trityl-1H-indazol-5-amine (13.21 g) as a yellow solid.