Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]#[N:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:6]=[C:5]([C:18]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:19]=2)[N:4]=1)#[N:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1cc(C#N)nc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1cc(C#N)nc(-c2nc(=O)c3ccccc3s2)c1
Yield: 36.5 %

Procedure:
tert-Butyl 3-(2,6-dicyano-4-pyridyl)propanoate (1.4 g, 5.5 mmol) and methyl thiosalicylate (1.7 g, 10.1 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The mixture was refluxed for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:3, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.79 g, 36%) as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([N:9]([O:25][SiH:26]([CH3:28])[CH3:27])[C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]#[N:36]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([N:9]([O:25][SiH:26]([CH3:27])[CH3:28])[C:10]2[CH:15]=[C:14]([N:16]([CH2:34][C:35]#[N:36])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Nc2cc(N(O[SiH](C)C)c3ccc(C(C)(C)C)cc3)ncn2)c(Br)c1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(N(CC#N)c2cc(N(O[SiH](C)C)c3ccc(C(C)(C)C)cc3)ncn2)c(Br)c1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of 4-(4-tertbutyldimethylsilyloxyanilino)-6-(2-bromo-4-methylanilino)pyrimidine (Reference Example 3, 396 mg) in tetrahydrofuiran (1 ml) under nitrogen atmosphere was added portion wise sodium hydride (60% dispersion in mineral oil, 58 mg). The solution was stirred for 30 minutes. Bromoacetonitrile (131 mg) was added and the reaction stirred for a further 1 hour. The solvent was evaporated and the residue purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 97.8:2:0.2 to give the title compound (158 mg, 37%) as a solid. M/z 524 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=1.Cl>O1CCOCC1>[OH:29][CH2:28][CH2:27][N:25]1[CH:26]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:12]([CH:15]=3)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=2)[CH:23]=[N:24]1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)cnc1N1CCCC1
Reactant: Nc1cnn(CCO)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(-c2ccnc(Nc3cnn(CCO)c3)n2)cnc1N1CCCC1
Temperature: 140 °C

Procedure:
5-(2-Chloro-pyrimidin-4-yl)-2-pyrrolidin-1-yl-nicotinonitrile (9) (31 mg, 0.108 mmol) and 2-(4-amino-pyrazol-1-yl)-ethanol (32 mg, 0.252 mmol) were dissolved in 1,4-dioxane (1 mL). 4N HCl in 1,4-dioxane (30 μL, 0.120 mmol) was added and the mixture was heated at 140° C. in the microwave (250 W, stirring) for 90 minutes. The solvent was evaporated in vacuo and the residue dissolved in DMSO (1 mL). The crude product was purified twice by reversed phase preparative LC-MS. Fractions containing desired product were combined and the solvents evaporated in vacuo. The title compound was obtained as a yellow solid (3.7 mg, 9%); LCMS, Rt=7.43 min (Method C), m/z 377 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[OH-].[Na+]>FC(F)(F)C(O)=O.O.O=[Pt]=O>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reaction time: 96 h
Yield: 56.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with PtO2 (1.0 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The yellow oil was dissolved in 200 mL of H2O then made basic (pH˜11) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5×75 mL) and the combined organic layers were dried over Na2SO4 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:15]=[O:16])[CH2:7][CH2:6]2.[OH-:17].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CCC(C=O)=C2
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)CCC(C(=O)O)=C2
Yield: 76.8 %

Procedure:
A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbaldehyde (2.2 g, 10 mmol) in EtOH (30 mL) was treated with a solution of silver nitrate (5.0 g, 30 mmol) in water (16 mL). A solution of NaOH (6.0 g, 150 mmol) in water (50 mL) was then added with continuous stirring and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then extracted with DCM and combined organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column using petroleum ether/ethyl acetate (from 6:1 to 3:1, v:v) as the eluent to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (1.8 g, 77%). LC-MS (ES-API); rt 8.23 min; m/z calculated for C13H14O4 [M+H]+ 235.1, found 235.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:19])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:19])[C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)c1ccccc1NC(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [2-(Methoxy-methyl-carbamoyl)-phenyl]-carbamic acid tert-butyl ester (15.0 g, 1.54 mmol) dissolved in THF (200 mL) is added p-chlorophenylmagnesium bromide (1.0M, 150 mL) at −30° C. The mixture is then stirred at RT overnight. The mixture is quenched with NH4Cl, extracted with ethyl acetate, dried over NaSO4 and concentrated then purified by silica gel. This provides the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:61]=[CH:60][C:5]([CH2:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:25][CH2:26]C)([O:22][CH2:23]C)[O:19][CH2:20]C)[CH:10]=[CH:9][C:8]=2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][Si:42]([O:49][CH2:50]C)([O:46][CH2:47]C)[O:43][CH2:44]C)=[CH:33][C:32]=2[CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)(=[O:30])=[O:29])=[CH:4][CH:3]=1>CO>[CH3:1][C:2]1[CH:61]=[CH:60][C:5]([CH2:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][Si:18]([O:22][CH3:23])([O:25][CH3:26])[O:19][CH3:20])[CH:10]=[CH:9][C:8]=2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][Si:42]([O:46][CH3:47])([O:49][CH3:50])[O:43][CH3:44])=[CH:33][C:32]=2[CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)(=[O:29])=[O:30])=[CH:4][CH:3]=1
Reactant: CCO[Si](CCCCOc1ccc(S(=O)(=O)c2ccc(OCCCC[Si](OCC)(OCC)OCC)cc2Cc2ccc(C)cc2)c(Cc2ccc(C)cc2)c1)(OCC)OCC
Solvent: CO
Product: CO[Si](CCCCOc1ccc(S(=O)(=O)c2ccc(OCCCC[Si](OC)(OC)OC)cc2Cc2ccc(C)cc2)c(Cc2ccc(C)cc2)c1)(OC)OC

Procedure:
The compound produced in Example 2 was refluxed with a chloroplatinic catalyst in methanol for 3 hours, and was then concentrated to give the desired product as a maize oily material.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.076 mmol), 4-aminobutyric acid (624 mg, 6.05 mmol), and NaOMe solution (9 mL, 4.54 mmol) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 17 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].I[CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:12]([O:10][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])[CH3:13]
Reactant: CCI
Reactant: O=Cc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1c(F)cccc1C=O
Temperature: 80 °C

Procedure:
A mixture of commercially available 3-fluoro-2-hydroxybenzaldehyde (5.000 g; 35.70 mmol), iodoethane (11.131 g; 71.40 mmol), and K2CO3 (5.918 g; 42.80 mmol) in anh. DMF (100 ml) was heated to 80° C., under nitrogen, for 3 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-3-fluorobenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.74 min.; no ionisation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([N:13](C)[C:14](=O)C(F)(F)F)=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[O-]CC.[Na+].O>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(-n2ccc(N(C)C(=O)C(F)(F)F)n2)ccc1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNc1ccn(-c2ccc(Br)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To an ice cold solution of N-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide (300 mg, 0.793 mmol) in EtOH (5 mL) was added a solution of 21% sodium ethoxide in EtOH (0.4 mL, 0.793 mmol). The mixture was stirred at room temperature overnight, then was poured into water. The mixture was extracted with EtOAc. The combined organic layers were washed with aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-bromo-3-methoxyphenyl)-N-methyl-1H-pyrazol-3-amine (200 mg, MS: 284.3 [M+H+]).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:15]([C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:31]([NH2:32])=[O:33])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 92, 2.6 grams, 5.2 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at rt for 1 h and then was concentrated to give a white solid (1.6 grams, 84%). MS(ESI), (M+H)+402.15; 1H NMR (DMSO-d6, 500 MHz), δ7.87 (d, 2H, J=8.5), 7.66 (d, 2H, J=8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H, J=7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H), 2.65-2.80 (m, 2H), 1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m, 1H), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H), 0.75-0.90 (m, 1H), 0.82 (d, 3H, J=7.3), 0.80 (d, 3H, J=7.0).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[N:15]([CH3:20])[C:16](=[O:19])[CH:17]=[CH:18][C:13]=2[CH:12]=[N:11]1>C(O)(=O)C.O>[Br:1][C:17]1[C:16](=[O:19])[N:15]([CH3:20])[C:14]2[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:11]=[CH:12][C:13]=2[CH:18]=1
Reactant: Cn1c(=O)ccc2cnn(-c3ccccc3Cl)c21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c(Br)cc2cnn(-c3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
At RT, bromine (206 mg, 1.29 mmol) was added to a solution of 1(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (319 mg, 1.23 mmol) in 1.5 mL of glacial acetic acid. After stirring at RT for 30 min, it was diluted with water and stirred for 5 min. The precipitated white solid was filtered off and rinsed with water, collected and dried to afford 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (323 mg). The filtrate was extracted three times with EtOAc. The combined EtOAc layers were washed with 2 N NaOH followed by brine, dried and concentrated to afford additional 5-bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (82 mg). The crude material was used without further purification. MS (ESI, pos.ion) m/z: 338.0/340.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH:31]=O>>[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH2:31][N:18]1[CH2:17][CH2:16][CH:15]([N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][CH:12]=2)[CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][CH2:19]1
Reactant: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCNCC1
Reactant: CC(C)(C)CC=O
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(CCC(C)(C)C)CC1

Procedure:
The preparation of Example 43: [1-(3,3-Dimethyl-butyl)-piperidin-4-yl]-[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine was prepared in accordance with the methods of Step 7 in Example 40, except that [4-(4-Fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-piperidin-4-yl-amine (43c) was used instead of (4-Cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-piperidin-4-yl-amine (40f) and 3,3-dimethylbutyraldehyde was used instead of isovaleraldehyde.
Reaction SMILES: CS([O:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH:27]([CH3:34])[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:24][CH:23]=1.Cl>C(C(C)=O)C>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[O:5][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH:27]([CH3:34])[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:24][CH:23]=1
Reactant: CCCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: CS(=O)(=O)OC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOC(=O)C(C)Oc1ccc(OC2Cc3ccccc3C2)cc1
Reaction time: 8 h
Yield: 12.2 %

Procedure:
2-Methylsulphonyloxyindane (15.9 g) in methyl ethyl ketone (80 ml) was treated with potassium carbonate (15.53 g). The mixture was stirred and then n-propyl 2-(4-hydroxyphenoxy)propionate (16.8 g) in methyl ethyl ketone (20 ml) was added dropwise. The mixture was stirred at 90°-100° for 2.5 hours and was then poured into dilute hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed thoroughly with water, dried and concentrated to an oil which semi-solidified on standing overnight. The oil was triturated with diethyl ether and petroleum ether. The mixture was filtered, and the filtrate concentrated to give an oil which was subjected to preparative thin layer chromatography on silica gel, eluting with chloroform/acetone/acetic acid (90:10:5), to give, as an oil, n-propyl 2-[4-(indan-2-yl-oxy)phenoxy]propionate (3.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH3:16]N(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[CH:13][N:14]([CH3:16])[N:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2cn(C)nc2c1Cl

Procedure:
Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (4.5 g, 0.02 mole) and dimethyl formamide demethylacetal2 (10 ml, 0.04 mole) in dry toluene (200 ml) were heated together under reflux for 1 h. The solvent and excess of reagent were distilled off under reduced pressure to give a brown oil containing two isomers. The 1-methyl3 and 2-methyl isomers were separated by column chromatography on silica gel with ethyl acetate as eluant to give the title compound as a white crystalline solid m.p. 118°-120° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:18][C:19]1[C:20]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1>>[O:17]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=3)[CH2:28][CH2:29]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)nc1C
Yield: 75.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (64 mg) described in Preparation Example 18 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (51 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 87, the title compound (83 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:8](OC)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:8][OH:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
According to example 184, 5.00 g of methyl 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzoate was reduced using 31.8 mL of 1M diisobutylaluminum hydride/toluene and 50 mL of anhydrous toluene. Analysis of the reaction mixture by tlc after 30 min indicated some remaining starting material. To ensure complete reduction, an additional 5 mL of 1M diisobutylaluminum hydride/toluene was added and the reaction was allowed to proceed for an additional 5 min. Work-up in the usual manner afforded 4.11 g (90%) of 3-tert-butyl-4-((tert-butyldimethylsilyl)oxy)benzyl alcohol as a cloudy oil. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=O)[N:12]([CH3:17])[C:13]3=[O:16])=[N:8]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:11]1[N:12]([CH3:17])[C:13](=[O:16])[C:14]2[C:9](=[N:8][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][CH:4]=3)[CH:15]=2)[N:10]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(Br)cc3)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Temperature: 0 °C
Yield: 94 %

Procedure:
2-(4-Bromobenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (159 g, 475 mmol) is suspended in POCl3 (300 mL), and then slowly heated to reflux. After the mixture is refluxed for 60 h, POCl3 is removed under reduced pressure. The obtained residue is dissolved in methylene chloride (5 L), cooled to 0° C., and then adjusted to pH 8-9 with saturated sodium bicarbonate. After filtration, the obtained solids are washed with water twice, and then dried under vacuum to give 157 g of product (yield: 94%). MS (ESI) m/z 353.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:20][CH:21]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A mixture of tert-butyl 4-(1-phenylvinyl)benzoate (0.59 g, 2.1 mmol) and palladium on carbon (10%, 100 mg) in methanol (20 mL) was stirred at 20° C. under hydrogen atmosphere (4 atm) for 24 hours. Once the start material has been consumed, the resultant mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give tert-butyl 4-(1-phenylethyl)benzoate (500 mg, 84%). 1H NMR (300 MHz, CD3OD): δ 7.85 (d, J=4.8 Hz, 2H), 7.30-7.15 (m, 7H), 4.19-4.16 (m, 1H), 1.61 (d, J=7.2 Hz, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 2-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M Na((TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.