Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Yield: 75 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-morpholin-4-yl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (7 mL), water (7 mL) and 1 M HCl (0.6 mL) and chromatographed on a 5 g C18 cartridge {gradient 10 to 50% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (23 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (bs, 3H), 7.67 (dd, J=7.5 and 2.1 Hz, 1H), 7.45-7.29 (m, 9H), 7.25 (d, J=8.3 Hz, 2H), 3.74 (t, J=4.1 Hz, 4H), 3.13 (t, J=3.6 Hz, 4H), 2.58-2.44 (m, 4H), 2.19-2.06 (m, 1H), 1.82-1.70 (m, 1H). LCMS (Method E): RT=3.44 min, [M+H]+=453.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].Cl.[Cl:20]C1C=CC=C(C(OO)=O)C=1.O>CC(N(C)C)=O>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Cl:20])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(Cl)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3'-Azido-2',3'-dideoxyuridine (0.25 g; 1 mMol) was dissolved in 2 mL dry dimethylacetamide (DMAC), cooled to 0° C. and 2 mL of 0.5M HCl in DMAC was added. m-Chloroperbenzoic acid (0.277 g; 1.6 mMol) was added in two portions over ten minutes and the mixture was allowed to come to ambient temperature. After two hours, 4 mL H2O was added and the solution filtered. The aqueous DMAC solution was extracted with Et2O (3×3 mL) and the Et2O was evaporated in vacuo to an oil which was applied to a silica gel column. Elution with CHCl3MeOH (15:1 v/v), combination of the appropriate fractions and evaporation in vacuo yielded an oil which was crystallized from Et2O to give 58.5 mg (0.2 mMol, 20%): mp=169°-170° C.
Reaction SMILES: [ClH:1].[CH2:2]=O.[C:4]1([CH3:11])[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1>>[CH3:11][C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][C:9]=1[CH2:2][Cl:1]
Reactant: Cc1cccc(C)c1
Reactant: Cl
Reactant: C=O
Product: Cc1ccc(CCl)c(C)c1

Procedure:
Hydrogen chloride was introduced at 70° C. for 5 hours into a mixture of 106 g of m-xylene, 531 g of 16N hydrochloric acid and 39 g of paraformaldehyde. Subsequently, the organic phase was separated off and distilled. In the boiling range of from 96° C. to 100° C. at a pressure of 16 mb, 105 g (0.68 moles) of 2,4-dimethylbenzyl chloride, corresponding to 65% of the theoretical yield, were obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:18][CH2:19]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
The crude 2-[3-(4-benzhydryl-piperazin-1-yl)-propyl]-isoindole-1,3-dione (930 mg) was dissolved in ethanol (2 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was stirred at room temperature overnight. The white solid was precipitated. The white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×15 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product 3-(4-benzhydryl-piperazin-1-yl)-propylamine was obtained (276 mg, 42.7% yield).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]=[CH:33][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:35][CH:36]=1)[CH3:30]
Reactant: CCc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: CCc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a yellow solid. UPLC-MS (condition 1) tR=1.90 min, m/z=487.0 [M+H]+, m/z=485.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.58 Hz, 3H) 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.28 (m, 1H) 2.82 (q, J=7.58 Hz, 2H) 2.99 (dd, J=11.00, 6.60 Hz, 1H) 3.08-3.20 (m, 2H) 3.21-3.30 (m, 2H) 3.29-3.38 (m, 1H) 4.60 (br. s, 1H) 7.34 (d, J=8.80 Hz, 2H) 7.38 (d, J=8.07 Hz, 1H) 7.75 (dd, J=7.82, 1.96 Hz, 1H) 7.86 (d, J=9.05 Hz, 2H) 8.02 (d, J=2.20 Hz, 1H) 8.55 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH:12]3[CH:21]4[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)=[N:5][C:4]=2[CH:3]=1.[NH2:29][C:30]1[CH:34]=C(Br)S[C:31]=1[C:36]([NH2:38])=O.C(OC(N1CC2CC1(C(O)=O)C2)=O)(C)(C)C.C([Cl:62])(=O)OCC(C)C.[OH-].[Na+]>CO.O1CCCC1.C(N(CC)CC)C>[ClH:62].[CH:12]1([C:6]2[NH:7][C:8](=[O:11])[C:9]3[S:10][C:2]([C:31]4[CH:36]=[N:38][NH:29][C:30]=4[CH3:34])=[CH:3][C:4]=3[N:5]=2)[CH:21]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14][NH:13]1
Reactant: CC(C)COC(=O)Cl
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC2CCCCC2C1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: CC(C)(C)OC(=O)N1CC2CC1(C(=O)O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1[nH]ncc1-c1cc2nc(C3NCCC4CCCCC43)[nH]c(=O)c2s1
Product: Cl

Procedure:
In the same manner as in Example 71, step A, tert-butyl 1-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)octahydroisoquinoline-2(1H)-carboxylate (180 mg) as a colorless solid from 3-amino-5-bromothiophene-2-carboxamide (0.22 g) produced in Example 1, step D, 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (0.57 g), 2-methylpropyl chlorocarbonate (0.27 g), triethylamine (0.20 g) and tetrahydrofuran (10 mL), and 2M aqueous sodium hydroxide solution (1 mL) and methanol (5 mL). In the same manner as in Example 83, step C, 2-(decahydroisoquinolin-1-yl)-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride was obtained from the compound obtained above, tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (270 mg), cesium carbonate (290 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1)(18 mg), 1,2-dimethoxyethane (10 mL), water (1 mL), and 4M hydrochloric acid/ethyl acetate solution (2 mL) and methanol (10 mL). This was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (36 mg) as a colorless solid.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:30])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:5]([O:23][CH:24]([CH3:25])[CH3:20])([CH3:7])[CH3:6].[CH2:26]([C:21]1[C:20]([CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:30])=[CH:13][N:14]=2)=[C:24]([CH3:25])[O:23][N:22]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)OC(C)C
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Trimethylaluminium (3 mL of a 2 M solution in toluene, 6 mmol) was added dropwise to a stirred solution of isopropylamine (355 mg, 6.0 mmol) in dioxane (4 mL) at room temperature and under argon. After 1 h, a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (537 mg, 1.5 mmol) in dioxane (4 mL) was added and the reaction mixture warmed to 90° C. After 2 h the reaction mixture was cooled and poured onto ice/water. The resultant mixture was extracted with ethyl acetate then the combined extracts were washed with Seignette salt solution. The organic phase was dried, filtered and evaporated then purified by chromatography (silica, 0 to 60% ethyl acetate in heptane) then trituration with diisopropyl ether to give the title compound (76 mg, 15%) as a white solid. MS: m/e=332.4 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:7](C(=O)C)[C:6](=[O:11])[N:5](C(=O)C)[C:4]=1[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[CH3:25][OH:26].Br>O1CCCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:4]2[NH:5][C:6](=[O:11])[NH:7][C:3]=2[CH2:2][O:26][CH3:25])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)c2c(CBr)n(C(C)=O)c(=O)n2C(C)=O)cc1
Reactant: CO
Agent: Br
Solvent: C1CCOC1
Product: COCc1[nH]c(=O)[nH]c1C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.0 g of 5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one in 50 ml of dry tetrahydrofuran is cooled to -78° C. under argon, 1.0 ml of dry methanol is added by syringe, and the solution is allowed to warm to 25° C. over 1.5 hours. Concentrated hydrobromic acid (1 ml) is then added and the mixture is stirred at 25° C. overnight. The solvent is then evaporated and the residual solid is recrystallized twice from a mixture of methanol and water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-(methoxymethyl)-2H-imidazol-2-one melting at about 211°-212° C. with decomposition. This compound has the following structural formula: ##STR6##
Reaction SMILES: Br[C:2]1[N:3]([CH3:27])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]1)[N:7]=[CH:6][N:5]=2.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C(N(C(C)C)CC)(C)C.[H-].[Na+]>C(O)C>[N:28]1([C:2]2[N:3]([CH3:27])[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[NH:19][C:18]4=[O:26])[CH2:15][CH2:16]2)[N:7]=[CH:6][N:5]=3)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1c(-n2ccnc2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-[1-(8-Bromo-9-methyl-9H-purin-6-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (50 mg, 0.12 mmol) was dissolved in ethanol (1 mL). To this solution was added imidazole (24 mg, 0.35 mmol) and diisopropylethylamine (39 μL, 0.23 mmol). This mixture was irradiated in the microwave at 180° C. for 6 hours. The ethanol was removed in vacuo and replaced by DMA (1 mL). To this solution was added 1 equiv. of sodium hydride. After heating to 100° C. for 1 hour, the mixture was filtered and purified by prep HPLC to obtain 24 mg of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.39-8.28 (m, 1H), 8.27-8.16 (m, 1H), 7.78 (m, 1H), 7.18 (m, 1H), 7.14 (m, 1H), 6.99-6.82 (m, 3H), 5.47 (s, 1H), 4.63-4.40 (m, 1H), 3.67 (s, 3H), 3.22 (m, 3H), 2.42-2.20 (m, 2H), 1.80 (m, 2H). EI (MS) for C21H21N9O, found 416 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:18](O)[CH2:19]O>O1CCCC1>[CH2:16]([O:15][C:13]([C:8]1[S:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[C:9]=1[O:12][CH2:19][CH2:18][O:11]2)=[O:14])[CH3:17]
Reactant: OCCO
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
ADC01 (2.9 g, 16.9 mmol) was slowly added to a solution of 3,4-dihydroxythiophene-2,5-dicarboxylic acid diethyl ester (2.0 g, 7.7 mmol), ethylene glycol (0.5 g, 8.5 mmol), and PHOL (3.4 g, 16.9 mmol) in dry tetrahydrofuran (150 ml) at 25° C. The reaction mixture was stirred for 3 h and then refluxed for 9 h. The reaction mixture was allowed to cool to 25° C. and concentrated by rotary evaporator to remove the THF. The residue was diluted with diethyl ether and allowed to stand overnight to enable the tributylphosphine oxide to precipitate out. The tributylphosphine oxide was then removed by filtration and the residue purified by chromatography on silica gel (eluant: ethyl acetate/ hexane=2/1) to give 2.1 g of 2,3-dihydro-thieno[3,4-b][1,4]dioxine-5,7-dicarboxylic acid diethyl ester as white crystals (95% yield) as fully characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OCC)(=O)C>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Yield: 91.3 %

Procedure:
To a solution of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine (1.28 g) in ethanol (50 ml)/ethyl acetate (50 ml) in a parr bottle was added Palladium hydroxide (500 mg). The parr bottle was charged to 40 psi on a shaker for 6 h. The reaction mixture was filtered and concentrated. MPLC biotage chromatography eluting with methanol (1-7%)/chloroform provided the title compound (860 mg, 91%). 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 8.39 (d, J=5.8 Hz, 2H), 7.15 (m, 4H), 6.72 (d, J=8.7 Hz, 1H), 3.84 (s, 3H); MS: (M+H m/z=252.2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+].CCO>CCOC(C)=O.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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[CH:3]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: Nc1ccc(Br)cc1I
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A flask is charged with 4-bromo-2-iodo-phenylamine (1.10 g, 3.70 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (0.630 g, 4.07 mmol), Pd(PPh3)4 (0.24 g, 5 mol %), 2 M Na2CO3 (16 mL), EtOH (16 mL) and toluene (32 mL) and heated at 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. The crude product was purified by flash silica gel chromatography eluting with 10% EtOAc/hexanes to give 0.680 g (66%) of the title compound as a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C14H18BrN, 280.1 (M+H). found 280.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][C:13]([CH3:18])=[C:12]([C:19]([NH2:21])=[O:20])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[C:26]12([CH2:36]Br)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>CN(C=O)C>[C:26]12([CH2:36][NH:21][C:19]([C:12]3[C:11]4[CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:17][C:16]=4[CH:15]=[N:14][C:13]=3[CH3:18])=[O:20])[CH2:27][CH:28]3[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]3)[CH2:35]1)[CH2:33]2
Reactant: BrCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ncc2c(c1C(N)=O)CCN(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc2c(c1C(=O)NCC13CC4CC(CC(C4)C1)C3)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-benzyl-5,6,7,8-tetrahydro-3-methyl-2,7-naphthyridine-4-carboxamide (40 mg, 0.142 mmol) was taken up in anhydrous DMF (0.5 ml) under an inert atmosphere. NaH (60% in mineral oil) (6.8 mg, 0.17 mmol) was added to the reaction vessel and the mixture stirred for 30 minutes until the evolution of hydrogen gas ceased. To this mixture was added 1-adamantylmethylbromide in DMF (0.5 ml) and reaction was stirred at room temperature for 4 hr. The reaction was monitored by TLC and LCMS. Excess NaH and 1-adamantylmethylbromide and heated from 40 to 75° C. for 3 days. The mixture was cooled to room temperature, and added to ice water. The aqueous layer was extracted with EtOAc, washed with water, brine, dried over sodium sulfate, and reduced in vacuo. The crude was purified by flash chromatography followed by prep. TLC using MeOH:DCM (5-10%) to afford the title compound. (5 mg, 8%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[CH:4][C:3]=1[C:10]1[C:14]([Cl:15])=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]([CH3:20])[N:11]=1.C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][C:4]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([C:16]([F:17])([F:18])[F:19])[N:12]([CH3:20])[N:11]=2)=[C:2]([F:1])[CH:8]=[C:7]([Cl:9])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(F)cc(Cl)c(N)c2Br)c(Cl)c1C(F)(F)F
Reaction time: 8 h

Procedure:
28 g (0.086 mol) of 4-fluoro-6-chloro-3-(4-chloro-5-trifluoromethyl-1-methyl-1H-pyrazol-3-yl)aniline (described in EP-A 0791571) were dissolved in 200 ml of acetic acid and admixed with 35 g (0.42 mol) of sodium acetate. 13.7 g (0.086 mol) of bromine were added dropwise to this mixture. The mixture was stirred overnight, the volatile components were removed under reduced pressure and the residue was taken up in 200 ml of dichloromethane. This solution was washed with 2 N aqueous NaOH and dried over MgSO4, and the residue obtained after concentration of the solution was chromatographed on silica gel using cyclohexane/ethyl acetate (4/1 v/v). This gave 20 g of the title compound IVc.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)=O>[Ir].CO>[CH2:1]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Ir]
Solvent: CO
Solvent: O=CO
Product: c1ccc(CNCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
Under an argon-gas atmosphere, 5 mL of dehydrated methanol, 505 μL (5.0 mmol) of benzaldehyde (MW: 106.12), 545 μL (5.0 mmol) of benzylamine (MW: 107.15), 566 μL (15.0 mmol) of formic acid (MW: 46.43), and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and the mixture was stirred while heating at 60° C. for 1.5 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product dibenzylamine. Its conversion rate was 100% based on NMR measurement, with 95% of dibenzylamine, 3% of tribenzylamine, and 2% of benzyl alcohol.
Reaction SMILES: [Na].[CH:2]([C:13](OCC)=O)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:18](Br)[C:19]#C.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:13]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:18]#[CH:19]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: C#CCBr
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCC(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 180.3 %

Procedure:
To a mixed solution of triethyl methanetricarboxylate sodium salt (25.0 g) in toluene/DMF (120 mL/120 mL) was added propargyl bromide (25.0 g), and the mixture was stirred at 80° C. for 1.5 hr. After allowing to cool, dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was dissolved in THF (30 mL), sodium ethoxide (7.60 g) was added, and the mixture was stirred at room temperature for 1 hr. 1 mol/L Hydrochloric acid (150 mL) was added, and the mixed solution was extracted with chloroform (100 mL). The organic layer was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (35.0 g) as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([CH:20]3[CH2:28][CH2:27][C:23]4[N:24]=[CH:25][NH:26][C:22]=4[CH2:21]3)=[O:19])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([CH:20]3[CH2:28][CH2:27][C:23]4[N:24]=[CH:25][NH:26][C:22]=4[CH2:21]3)=[O:19])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CN(C(=O)C3CCc4nc[nH]c4C3)c3ccccc32)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(C1CCc2nc[nH]c2C1)N1CC(c2cccc(O)c2)c2ccccc21
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
In 9 ml of chloroform, 300 mg of the optically active 5-[3-(3-methoxyphenyl]indolin-1-ylcarbonyl!-4,5,6,7-tetrahydrobenzimidazole obtained in Example 24 was solved. This solution and 3.1 ml of a 1.0M dichloromethane solution of boron tribromide added thereto in a stream of argon at -78° C. were together stirred at -78° C. for three hours and further at normal room temperature for three hours. The resultant reaction solution was poured into ice water, neutralized with an aqueous sodium hydrogen carbonate solution, and then extracted with a mixed solution of chloroform and ethanol. The organic layer was dried over magnesium sulfate and then distilled. The residue of the distillation was refined by silica gel column chromatography to obtain 220 mg of optically active 5-[3-(3-hydroxyphenyl)indolin-1-ylcarbonyl]-4,5,6,7-tetrahydrobenzimidazole (76.1%).