Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=3)[CH2:18][C:17]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[CH2:33]([O:32][C:30]([CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:17](=[O:35])[CH2:18]2)=[CH:23][CH:24]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)COc1ccc(N2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C2)cc1
Agent: Cl
Product: CCOC(=O)COc1ccc(N2CCN(CCC3CCNCC3)C(=O)C2)cc1

Procedure:
Prepared from 4-[2-(1-tert-butyloxycarbonylpiperidin-4-yl)ethyl]-1-(4-ethoxycarbonylmethyloxyphenyl)piperazin-3-one and ethereal hydrochloric acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:16][CH3:17])=[N:4][N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[C:5]([CH2:16][CH3:17])=[N:4][N:3]=[C:2]2[NH:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:23][CH2:24]1
Reactant: CCc1nnc(Cl)c2cc(OC)cc(OC)c12
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: CCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)cc(OC)c12

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-5,7-dimethoxy-4-ethylphthalazine with 4-amino-1-(naphthalen-2-yl-methyl)piperidine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:9])[CH2:5][CH2:6][C:7]=1[CH3:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:8][C:7]1[CH2:6][CH2:5][C:4](=[O:9])[C:3]=1[CH2:2][O:1][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: CC1=C(CO)C(=O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(COC2CCCCO2)C(=O)CC1
Reaction time: 2 h
Yield: 94 %

Procedure:
2-(hydroxymethyl)-3-methyl-2-cyclopentene-1-one (2.417 g, 19.16 mmol), prepared in example 14, was dissolved in methylene chloride (60 mL). Then, dihydropyran (4.02 g 47.9 mmol) and p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) were added at room temperature. This solution was stirred for 2 hours, and then diluted with ethyl acetate (150 mL). The solution was neutralized with a saturated sodium bicarbonate solution (150 mL), and methylene chloride (200 mL) was added for extraction. After taking the organic layer, moisture was removed with magnesium sulfate, and the solvent was removed in vacuo. Pure 3-methyl-2-[(tetrahydropyranyloxy)methyl]-2-cyclopenten-1-one was obtained by column chromatography (hexane:ethyl acetate=1:1) (yield: 94%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>[Pd].CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH:21]([CH3:23])[CH3:22])=[CH:2][N:10]=1
Reactant: CC(C)OCOCCCOn1cnc2c(Cl)nc(NC=O)nc21
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)OCOCCCOn1cnc2cnc(N)nc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 41.5 %

Procedure:
A mixture of 6-chloro-2-formamido-9-[3-(isopropoxymethoxy)propoxy]purine (1.86 g, 5.40 mmol), 10% palladium on charcoal (190 mg), triethylamine (3.8 ml, 27 mmol) and methanol (30 ml) was stirred under an atmosphere of hydrogen at 20° C. for 4 hr. The suspension was filtered, the catalyst washed with chloroform and the combined filtrates evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 ml), washed with saturated brine-water (2:1), dried (magnesium sulphate) and evaporated. The residue was dissolved in 0.5M sodium methoxide in methanol (21.6 ml) and heated at reflux for 1 hr. The solution was taken to neutrality using AMBERLITE IR 120(H) and evaporated. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (20:1) affording the title compound (630 mg, 41%) after recrystallisation from acetone-hexane; νmax (KBr) 3333, 3192, 1661, 1623, 1577, 1516, 1433 cm-1 ; δH [(CD3 )2SO] 1.09 (6H, d, J 6.05 Hz, 2×CH3), 1.95 (2H, quintet, J 6.6 and 6.3 Hz, CH2CH2CH2), 3.63 (2H, t, J=6.3 Hz, CH2OC), 3.77 (1H, septet, J=6.0 Hz, CH), 4.39 (2H, J=6.6 Hz, CH2ON), 4.64 (2H, s, OCH2O), 6.69 (2H, br.s, D2O exchangeable, NH2), 8.31 (1H, s, H-8), 8.59 (1H, s, H-6). Found: C, 51.21; H, 6.84; N, 24.82%; C12H19N5O3 requires: C, 51.22; H, 6.82; N, 24.89%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](OC)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N[C:15]1C=C(C)C=CC=1C(O)=O>>[NH2:1][C:2]1[CH:11]=[C:10]([CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: COC(=O)c1cc(OC)ccc1N
Product: COC(=O)c1ccc(C)cc1N

Procedure:
In a manner similar to that described above for methyl 2-amino-5-methoxybenzoate, 1.90 g of 2-amino-4-methylbenzoic acid was converted to i-g (94%): MS m/z═166 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17][CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:11]12[CH2:17][CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:12]2
Reactant: C1CC2CNCC12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CC3CCC3C2)nc1
Temperature: 65 °C
Yield: 87.6 %

Procedure:
A mixture of 0.1 g (0.63 mmol) of 2-chloro-5-nitropyridine, 0.1 g (0.75 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 0.26 mL (0.19 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.121 g of the expected product in the form of a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CCOCC.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCN(CCc1ccc(CO)cc1)C(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CCCCCCCN(CCc1ccc(C=O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To a stirred solution of heptyl-[2-(4-hydroxymethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.9 mmol, 1.7 g) in anhydrous ether (50 mL) was added activated manganese dioxide (Aldrich, 5 g). The resulting suspension was stirred at room temperature adding further 2 g portions of manganese dioxide every 2 hours until the starting material had been consumed as determined by TLC. The mixture was filtered through a Celite® plug and washed through exhaustively with dichloromethane. The yellow filtrate was concentrated to a yellow oil which was chromatographed on silica gel (20% ethyl acetate/hexanes) to give [2-(4-formyl-phenyl)-ethyl]-heptyl-carbamic acid tert-butyl ester as a clear oil (1.30 g, 76%).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42](C2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:41][CH:40]1[CH2:76][OH:77])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[C:28]([F:31])([F:29])[F:30])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:41][CH:40]1[CH2:76][OH:77])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(O)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1CO

Procedure:
(2R) 2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:21])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])[N:14]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (100 mg) and ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (94 mg) in THF (3.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (140 mg) and tributylphosphine (136 μL), and the mixture was stirred at room temperature for 14 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (140 mg) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)=[O:21])[CH2:16][CH2:15]3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.O.[C].[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][CH:28]=4)=[O:21])[CH2:18][CH2:19]3)=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(c2ncnc3cc([N+](=O)[O-])ccc23)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2c1
Yield: 45 %

Procedure:
To a solution of 455.6 mg (0.97 mmol) of 4-(7-nitro-4-quinazolinyl)-N-(4-phenoxyphenyl)-1-piperazinecarboxamide obtained in Example 322 in 10 ml of ethanol was added a suspension of 100 mg of 10% palladium-carbon in 5 ml of ethanol and 2 ml of water, followed by stirring in a stream of hydrogen at room temperature for 4 hours. After the catalyst was separated by filtration using Celite, the solvent was evaporated. The residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:32])[C:15]([CH3:31])=[C:16]([CH:30]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C)C=O>[Si:37]([O:32][C:14]1[C:15]([CH3:31])=[C:16]([CH:30]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:13]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39]
Reactant: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(O[Si](C)(C)C(C)(C)C)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a suspension of 1.0 g of p-nitrobenzyl 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-2-methylbenzoate in 30 ml of dimethylformamide were added 0.71 g of tert-butyldimethylchlorosilane and 0.48 g of triethylamine, and the mixture was stirred at 20° C. for 24 hours. The solvent was evaporated in vacuo, and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using methylene chloride as eluent to yield 0.90 g of p-nitrobenzyl 3-(tert-butyldimethylsilyloxy)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl )-2-methylbenzoate as white solid, m.p. 125°-127° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15](Cl)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>C(O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15]([NH:18][C@H:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][OH:21])=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: Clc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Solvent: CCO
Product: OC[C@@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Yield: 94.4 %

Procedure:
First, 2.81 g of 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 60 ml of ethanol, then 3.2 g of (R)-(+)-2-amino-3-phenyl-1-propanol was added with stirring. After 48 hours the solvent was removed under vacuum and the oil was flash chromatographed (2-5-7% MeOH/CHCl3) to yield 3.80 g of (R)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (95%).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[Na+].[Cl-].[CH3:13][OH:14]>>[CH3:13][O:14][C:5]1[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=1
Reactant: CO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: COc1cc(N)nc(N)n1
Reaction time: 44 h

Procedure:
To a solution of 9.2 g (0.40 mol) sodium in 320 ml methanol were added 28.9 g (0.20 mol) 2,4-diamino-6-chloropyrimidine. The mixture was heated under reflux with stirring for 44 h. After the reaction was ended the precipitated NaCl was separated off and the solution was concentrated to dryness. The residue in 300 ml ethanol was heated to boiling and filtered hot. The product precipitated out of the filtrate on standing overnight. Recrystallization of the mother liquor likewise afforded product. After drying, 6-methoxy-2,4-diaminopyrimidine was obtained as a white solid (58.8 g, 84%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[NH2:15][C:16]1[C:23]([CH3:24])=[CH:22][C:21](I)=[CH:20][C:17]=1[CH2:18][OH:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:15][C:16]1[C:23]([CH3:24])=[CH:22][C:21]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[N:9][CH:10]=2)=[CH:20][C:17]=1[CH2:18][OH:19]
Reactant: COc1ccc(Br)cn1
Reactant: Cc1cc(I)cc(CO)c1N
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C)c(N)c(CO)c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (33 cm3 of a 1.6M solution in n-hexane) was added to a stirred solution of 2-methoxy-5-bromopyridine (9.4g) in tetrahydrofuran (THF) (70 cm3) at -70° under nitrogen. After stirring for 1 hour at -70° the mixture treated with a solution of anhydrous zinc chloride (14.2 g) in THF (70 cm3) and the mixture was warmed to room temperature. 2-Amino-5-iodo-3-methylbenzyl alcohol (3.9 g--see preparation 8) and tetrakis(triphenylphosphine) palladium (0) (0.4 g) were added and the mixture heated under reflux for 3 hours. Saturated ammonium chloride solution (50 cm3) was added to the cooled solution and the mixture was partitioned between ethyl acetate (300 cm3) and a solution of ethylenediaminetetraacetic acid disodium salt (20 g) in water (300 cm3). The aqueous phase was further extracted with ethyl acetate (300 cm3) and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give a brown oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 49:1. Combination and evaporation of appropriate fractions afforded the title compound as a waxy solid, m.p. 80°-82° (3.6 g), which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in CH2Cl2 (4 mL), triethylamine(0.36 mmol) and acetyl chloride (0.36 mmol) is added at 0° C. The reaction mixture stirred at room temperature for 1 day. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to crude product. Purification of the residue by silica gel column chromatography affords title compound in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]2.[CH2:13](N(CC)CC)C.ClC(OC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.Cl.O>[CH3:13][NH:12][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1
Reactant: CCN(CC)CC
Reactant: NC1CCc2cccc(Cl)c2C1
Agent: COC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCc2cccc(Cl)c2C1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 8-chloro-2-amino-1,2,3,4-tetrahydronaphthalene (250 mg, 1.38 mMol) in tetrahydrofuran (25 mL) was added triethylamine (0.38 mL, 2.76 mMol) followed by the careful addition of methyl chloroformate (0.26 mL, 2.76 mMol). The reaction mixture was stirred at room temperature for one-half hour. The reaction mixture was then diluted with 10% hydrochloric acid and extracted well with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give a viscous oil. The oil in tetrahydrofuran (5 mL) was added dropwise to a suspension of lithium aluminum hydride (110 mg, 2.76 mMol) in tetrahydrofuran (20 mL). The reaction mixture was stirred for three hours at room temperature and then one hour at reflux. The reaction mixture was then cooled to 0° C., and to it were added sequentially water (0.1 mL), 15% aqueous sodium hydroxide (0.1 mL) and water (0.3 mL). The suspension was then stirred at room temperature for two hours and then was filtered through a bed of Celite. The filtrate was concentrated in vacuo to give the title compound as a yellow viscous oil (240 mg 89%). The hydrochloride salt was formed and recrystallized (ethanol/diethyl ether) to give colorless crystals (m.p.=214°-215° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.O1CCOCC1.C(OCC)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)—N—((R)-1(4-chloro-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (14.6 g, 44.5 mmol) in methanol (25 mL) was added a solution of hydrochloric acid in p-dioxane (4.0 M in p-dioxane, 22.3 mL, 89.1 mmol), and the reaction was stirred at room temperature for 30 min. Diethyl ether was then added (400 mL) and the slurry was stirred for 10 min. The solid was collected by filtration, and washed with diethyl ether (2×200 mL). The solid was then dissolved in 5 M aqueous sodium hydroxide solution, and extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was used without further purification (7.8 g, 34.9 mmol, 79%, >96% ee, determined by Mosher's method).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[C:27]2[CH:28]=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][C:26]=2[N:25]=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[NH:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:3]=[C:4]([N:8]4[C:16]5[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=5[C:10]5[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]4=5)[CH:5]=[CH:6][CH:7]=3)=[CH:31][C:26]=2[N:25]=[CH:24]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: CC1(C)OB(c2ccc3[nH]cnc3c2)OC1(C)C
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: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc4[nH]cnc4c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-benzimidazole-5-boronic acid pinacol ester (137 mg, 0.561 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(1H-benzo[d]imidazol-5-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 9.08 (s, 1H), 8.02 (s, 1H), 7.86 (m, 3H), 7.72 (m, 2H), 7.48 (d, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.4 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.02-3.2 (m, 5H), 2.41 (s, 3H).