Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH:2]1([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][C:17]=2[Cl:18])[CH:14]([C:19](Cl)=[O:20])[CH2:13][CH2:12]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C1C=CC=CC=1>[CH:2]1([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][C:17]=2[Cl:18])[CH:14]([C:19]([NH2:1])=[O:20])[CH2:13][CH2:12]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C1CCc2cc(C3CCCCCC3)c(Cl)cc21
Reactant: N
Solvent: c1ccccc1
Product: NC(=O)C1CCc2cc(C3CCCCCC3)c(Cl)cc21

Procedure:
A vigorous stream of ammonia gas is passed into a solution of 9 g of 5-cycloheptyl-6-chloro-1-indanecarboxylic acid chloride in 150 ml of absolute benzene at 20° C, for 30 minutes, whilst cooling and stirring. The crude amide which precipitates is filtered off, thoroughly washed with water and dried. Two crystallisations from ethanol yield pure 5-cycloheptyl-6-chloro-1-indanecarboxylic acid amide; melting point 170°-171° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[N:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1>C(O)C.[Pt].O>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][CH:4]([NH:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=NNC(=O)OC(C)(C)C)CC(C)(C)C1
Agent: [Pt]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(NNC(=O)OC(C)(C)C)CC(C)(C)C1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
t-Butyl N′-(3,3,5,5-Tetramethylcyclohexylidene)hydrazine carboxylate (10.0 g, 0.0373 moles) was dissolved in ethanol (600 ml) and 5% Platinum on carbon (0.4 g) was added in water (2 mL). Stirred overnight under a hydrogen atmosphere (balloon). Filtered through HyFlo to remove the catalyst and evaporated the solvents to give a grey solid. Triturated with water and filtered off the grey solid. Dried in a desiccator to give the product as a grey solid (8.4 g, 83%). 1H NMR (300 MHz DMSO-d6) 8.1 (brm, 1H), 4.1 (brm, 1H), 2.95 (m, 1H), 1.45 (m, 2H), 1.35 (s, 9H), 1.15 (m, 1H), 0.95 (m, 1H), 0.95 (s, 6H), 0.9 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][C:3]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[ClH:20].CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:39][NH:40][CH2:41][C:42]1[S:46][C:45]2[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=2[C:43]=1[CH3:51].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:20].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:40]([CH3:39])[CH2:41][C:42]2[S:46][C:45]3[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=3[C:43]=2[CH3:51])=[O:12])=[CH:4][C:3]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CNCc1sc2ccccc2c1C
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCOCC3)c2)sc2ccccc12
Yield: 67 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (111 mg, 67%) was prepared as a pale, yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.60 (br s, 1H), 8.40 (s, 1H), 7.87 (d, J=7.4 Hz, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.51 (d, J=15.3 Hz, 1H), 7.42-7.15 (m, 3H), 5.12-4.88 (m, 2H), 3.91-3.35 (m, 12H), 3.15 (s, 3H), 2.93 (s, 1H), 2.41 (s, 3H); MS (ESI) m/e 437 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:8]=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][C:12]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[CH:8]=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)=[O:43]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:42]([OH:43])[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:46][CH2:45]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (115 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added i-PrMgCl/LiCl (0.3 mL, 0.39 mmol). The mixture was stirred 0° C. for 3 hours and tert-butyl 4-formylpiperidine-1-carboxylate (70.7 mg, 0.33 mmol) in THF (0.1 mL) was added. The mixture was stirred at 0° C. to room temperature for 3 hours and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-50% ethyl acetate in hexanes) to afford the title compound (62.2 mg, 44%). 1H NMR (400 MHz, CDCl3) δ ppm 1.12-1.19 (m, 1H) 1.20-1.32 (m, 1H) 1.43 (s, 9H) 1.69-1.78 (m, 1H) 1.89 (dd, J=13.07, 1.87 Hz, 1H) 2.46-2.67 (m, 2H) 3.99-4.15 (m, 2H) 4.18 (s, 3H) 4.66-4.73 (m, 2H) 4.68-4.83 (m, 4H) 4.87 (d, J=15.77 Hz, 1H) 7.33 (s, 1H) 7.55 (s, 2H) 7.64 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 696.2, Found: 697.6 (M+1)
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH3:31])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:25]([CH3:31])[CH:26]=1
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(F)cc3C)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(F)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
90.8 mg (1.40 mmol) of potassium cyanide were added to 294 mg (0.70 mmol) of the compound from Example 62A in 15 ml of DMF. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 188 mg (77% of theory) of the title compound.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[Cl:35][C:36]1[N:37]=[C:38]([CH2:52][O:53][Si](C(C)(C)C)(C)C)[N:39](COCC[Si](C)(C)C)[C:40]=1[C:41](O)=[O:42].C(=O)(O)[O-].[Na+].FC(F)(F)C(O)=O>CN(C=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:41]([C:40]2[NH:39][C:38]([CH2:52][OH:53])=[N:37][C:36]=2[Cl:35])=[O:42])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]c(CO)nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
EDC (0.025 g, 0.131 mmol) and HOBT (0.018 g, 0.131 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.042 g, 0.119 mmol) and 4-chloro-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.119 mmol) in DMF (2 mL). The mixture was stirred at RT for 4 hrs, saturated sodium bicarbonate was added and the solution was extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.3 mL, 3.89 mmol) was added. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.030 g, 47%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 8.32-8.41 (m, 1H), 7.79-7.84 (m, 1H), 7.57-7.65 (m, 1H), 7.47-7.52 (m, 1H), 7.44 (t, 1H), 7.31 (t, 1H), 5.54 (br. s., 1H), 4.45-4.53 (m, 2H), 4.37-4.44 (m, 2H). ES MS: m/z 512, 514.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:14][CH:13]([NH:15][C:16]([O:18][CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=3)=[O:17])[CH2:12]2)[CH2:10][NH:9]1.Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([F:41])[CH:37]=2)[N:32]=1.C(N(CC)C(C)C)(C)C>ClCCl.CO>[F:41][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]=[C:31]([N:9]1[CH2:10][C:11]3([CH2:12][CH:13]([NH:15][C:16]([O:18][CH2:19][C:20]4[O:24][N:23]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=4)=[O:17])[CH2:14]3)[CH2:8]1)[CH:40]=[CH:39]2
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CNC3)C2)on1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(C2)CN(c2ccc4cc(F)ccc4n2)C3)on1

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.6.). Starting with 0.43 g (1.03 mmol) of ethyl 5-(2-azaspiro[3.3]hept-6-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate, obtained in step 11.8., 0.187 g (1.03 mmol) of 2-chloro-6-fluoroquinoline and 0.399 g (3.09 mmol) of N,N-diisopropylethylamine, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.15 g of pure product in the form of a beige-coloured solid is thus obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:15]=[C:14](Cl)[C:13]([F:17])=[CH:12][C:9]=1[C:10]#[N:11].[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:7][C:8]1[N:15]=[C:14]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:13]([F:17])=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c(C#N)cc1F
Temperature: 60 °C
Reaction time: 10 h
Yield: 59.8 %

Procedure:
Potassium carbonate (3.62 g) and 2,6-dichloro-5-fluoronicotinonitrile (5.00 g) were added to a THF (50 ml) solution containing tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (5.61 g), followed by reflux at 60° C. for 8 hours. Then, the solvent was distilled away at 70° C. 1,4-dioxane (100 ml) was added to the resulting solution, followed by stirring at 100° C. for 10 hours. The reaction solution was adjusted to room temperature. Ethyl acetate and 2M hydrochloric acid were added to the reaction solution. The organic layers were collected. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 2:1). Diisopropyl ether was added to the obtained oily matter and a solid precipitate was collected by filtration. A white solid of tert-butyl ((1S,2R)-2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)cyclohexyl)carbamate (5.77 g) was thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12](OCC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C.O>C(OCC)C.C1(C)C=CC=CC=1>[C:25]([O:24][C:22]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][CH:12]=[O:13])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al]CC(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)[C@H](CCC=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of the material from Step 2 (9.73 g, 24.12 mmol) in diethyl ether (240 mL) at −70° C. was slowly added 1.0 M Dibal-H (40.2 mL, 40.2 mmol) in toluene. The reaction mixture was stirred at −70° C. for 45 minutes. Water (10 mL) was slowly added, and the reaction mixture was allowed to warm up to room temperature and aged for 30 minutes. Additional water (80 mL) was added, and aged for 1 hour. It was filtered on a short pad of celite, rinsed with tert-butyl methyl ether (3×). The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 8.67 g of the title compound that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7](N)=[CH:6][C:5]=1[O:12][CH3:13].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:24].[K+].II>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([I:24])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Reactant: [I-]
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(Cl)c(I)cc1OC
Temperature: -1 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
4-Amino-5-chloro-2-methoxy benzoic acid methyl ester of Step A (5.00 g, 23.2 mmol) was suspended in water (52 mL) and concentrated sulfuric acid (13 mL) was added. The resulting suspension was cooled to −1° C. and a solution of sodium nitrite (1.76 g, 25.5 mmol) in water (10 mL) was added at a rate which maintained the temperature below 0° C., resulting in the formation of a clear yellow solution. A mixture of potassium iodide (4.23 g, 25.5 mmol) and iodine (3.24 g, 12.8 mmol) in water (50 mL) was then added dropwise and the reaction stirred at 0° C. for 1.5 hours. The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed sequentially with 1 M aqueous sodium thiosulfate, 1 N sodium hydroxide and brine, and dried over anhydrous magnesium sulfate, filtered and concentrated, whereupon the product crystallized. The resulting orange crystals were suspended in petroleum ether, filtered and dried in vacuo to provide the title compound (6.38 g), m.p. 72-73° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[CH2:16]([C:23]1[O:24][CH:25]=[C:26]([CH2:28]Cl)[N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:24][CH:25]=[C:26]([CH2:28][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(Cc2ccccc2)n1
Product: c1ccc(Cc2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 23 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-benzyl-4-chloromethyloxazole to give 2-benzyl-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 23%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 61-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]([CH2:21][CH3:22])[CH:18]([OH:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=O>>[CH2:21]([CH:17]1[C:5]2[C:6](=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]([C:27]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=2)[O:20][CH:18]1[CH3:19])[CH3:22]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCC(c1ccc(OCc2ccccc2)c(OC)c1)C(C)O
Product: CCC1c2cc(OC)c(OCc3ccccc3)cc2C(c2ccc(OC)c(OC)c2)OC1C

Procedure:
Reaction of 3-(3-methoxy-4-benzyloxyphenyl)pentan-2-ol with 3,4-dimethoxybenzaldehyde to yield 4-(4-ethyl-6-methoxy-7-benzyloxy-3-methyliso-chromanyl)-1,2-dimethoxybenzene.
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])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4n3)c2cc1OC
Temperature: 115 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (147 mg, 0.67 mmol) in toluene (3 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by 2-(chloromethyl)quinoline hydrochloride (158 mg, 0.74 mmol) and the mixture was stirred at 115° C. for 25 min under microwave irradiation. Another portion of a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) was then added at RT followed by 2-(chloromethyl)quinoline hydrochloride (70 mg, 0.33 mmol) and the mixture was stirred at 115° C. for 10 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (5 mL) and neutralised with a 10% aqueous citric acid solution before extraction with CH2Cl2 (50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 100:7) gave 49 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol as a yellow solid. The free base (45 mg) was dissolved in MeOH (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (5.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-2-ylmethyl)isoquinolin-3-ol hydrochloride 23 as a yellow solid (54 mg, 19% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[CH:31][CH:30]=1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (2.17 g) in toluene (40 mL) was added p-anisidine (900 mg) and molecular sieves 4A (6.0 g). The mixture was refluxed overnight, then filtered and the filtrate was evaporated. The residual oil was dissolved in ethanol (40 mL) and sodium borohydride (276 mg) was added. The mixture was stirred at room temperature for 2 hours before concentration in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to silica gel column chromatography using chloroform-methanol (50:1) to give the title compound as yellow amorphous.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:25]=[O:26])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]([F:19])([F:17])[F:18]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc2cc[nH]c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Phosphorus oxychloride (1.83 ml) was added dropwise to dimethylformamide (16 ml) under ice-cooling, and the mixture was stirred at 0° C. for 20 min. 6-Chloro-5-(trifluoromethyl)-1H-indole (3.24 g) dissolved in dimethylformamide (10 ml) was added to the reaction mixture, and the mixture was stirred at 0° C. for 3 hr. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr, and the mixture was alkalified with a 1N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water and dried to give 6-chloro-5-(trifluoromethyl)indole-3-carbaldehyde (3.25 g, yield 89%).
Reaction SMILES: [Al](Br)(Br)Br.[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2.Br.Cl>>[C:5]1([CH:14]2[CH2:13][C:12](=[O:11])[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: Oc1cccc2cccnc12
Agent: Br
Agent: Br[Al](Br)Br
Agent: Cl
Product: O=C1CC(c2ccccc2)Cc2cccnc21
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a stirred suspension of AlBr3 (4.80 g, 18 mmol) in benzene (4.8 mL, 55 mmol) was added 8-hydroxyquinoline (0.50 g, 3.4 mmol). The resulting mixture was saturated with HBr (g) and then stirred at 40° C. for 48 h. The reaction mixture was cooled to ambient temperature and poured onto ice (50 g). The resulting mixture was adjusted to pH=1-2 by addition of concentrated HCl and then was extracted with EtOAc (3×20 mL), discarding the organic extracts. The aqueous layer was adjusted to pH 12 by addition of NaOH (s), keeping the temperature below 10° C., and was then extracted with EtOAc (3×20 mL). These combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=223.8 (M+1).