Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=CC(CO)=CC=2Cl)=CC=1C)C.[CH2:25]([O:27][C:28](=[O:49])[CH2:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([S:38][C:39]2[CH:44]=[CH:43][C:42]([CH:45]=[O:46])=[CH:41][C:40]=2[Cl:47])=[CH:33][C:32]=1[CH3:48])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:49])[CH2:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[C:34]([S:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][C:40]=2[Cl:47])=[CH:33][C:32]=1[CH3:48])[CH3:26]
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2Cl)cc1C
Agent: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)cc1C
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(CO)cc2Cl)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.5, using compound 24.1 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.36 (1H, d, J=1.6 Hz); 7.33 (1H, s); 7.01 (1H, dd, J=1.9, 8.1 Hz); 6.67 (1H, s); 6.50 (1H, d, J=8.2 Hz); 4.68 (2H, s); 4.60 (2H, s); 4.30 (2H, q, J=7.2 Hz); 2.31 (3H, s); 2.25 (3H, s); 1.67 (1H, brs); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH2:23][NH2:24])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[C:20]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:21]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(N2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(N4CCOCC4)c3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 3-morpholin-4-yl-benzylamine (123 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-morpholin-4-yl-benzylamino)-2H-phthalazin-1-one: 52 mg (24.2%): m/z (M+H)=371. 1H-NMR (DMSO-d6) δ: 12.33 (s, 1H), 7.91 (d, 1H), 7.60 (m, 1H), 7.16 (m, 2H), 6.98 (m, 1H), 6.82 (m, 3H), 4.35 (d, 2H), 3.72 (m, 4H), 3.08 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[CH2:15]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC1CCCCN(CC2(c3ccc(Cl)cc3)CCC2)C1
Yield: 36.2 %

Procedure:
To a stirring 0° C. solution of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxymethyl-azepan-1-yl)-methanone (0.075 g, 0.26 mmol) under N2 in toluene (2.6 mL, 0.1M) was added sodium bis(2-methoxyethoxy)aluminum hydride (65+weight % in toluene) (0.28 mL, 0.91 mmol) dropwise with stirring. When the reaction was complete by HPLC, the reaction was quenched with H2O. 10% NaOH and ethyl acetate were added, and the organic was removed, dried with Na2SO4, and concentrated. The crude reaction mixture was purified by silica gel:chromatography (90:8:2 Hexanes:methylene chloride: 2N NH3 in ethyl alcohol). A 39% yield (0.0290 g) of pure material was obtained as well as other impure fractions. 1H NMR (CDCl3, 300 MHz) 7.28-7.25 (2H, m), 7.15-7.09 (2H, m), 3.44 (1H, dd, J=10.5, 4.5 Hz), 3.27 (1H, dd, J=10.3, 5.5 Hz), 2.89 (1H, d, J=13.9 Hz), 2.83 (1H, d, J=13.9 Hz), 2.72-2.60 (1H, m), 2.50-1.10 (16H, m) ppm. 13C NMR (CDCl3, 75 MHz) 146.5, 131.22, 128.10, 127.93, 70.95, 67.49, 61.85, 59.10, 47.62, 40.59, 32.12, 31.90, 29.92, 25.41, 16.20 ppm. LRMS: 308.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][N:10]([CH:20]1[CH2:22][CH2:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19].S(=O)(=O)(O)O>>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([Cl:19])[CH:14]=1)[CH2:11][N:10]([CH:20]1[CH2:22][CH2:21]1)[CH2:9][CH:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccccc1C(O)CN(Cc1ccc(Cl)cc1Cl)C1CC1
Agent: O=S(=O)(O)O
Product: Nc1ccccc1C1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21

Procedure:
The three fractions can all, as described below for 1-(2-aminophenyl)-2-[cyclopropyl-(2,4-dichlorobenzyl)amino]ethanol under b), be cyclized with sulfuric acid to give 2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[C:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:24][C:25]2[C:30]([C:31]=1[C:32](O)=[O:33])=[CH:29][CH:28]=[CH:27][CH:26]=2.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)(O)[CH2:51][CH2:52][CH3:53].C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C(#N)C.N1C=CC=CC=1>[CH3:20][O:21][C:22]1[C:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:24][C:25]2[C:30]([C:31]=1[C:32]1[O:33][C:50]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([CH2:51][CH2:52][CH3:53])[CH2:49][N:48]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCC1(c2ccccc2)CN=C(c2c(OC)c(-c3ccccc3)nc3ccccc23)O1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
Triphenylphosphine (2.10 g, 8.0 mmol) is added to a mixture of (3-methoxy-2-phenylquinolin-4-yl)carboxylic acid (0.61 g, 2.2 mmol), pyridine (anhydrous, 5 mL), acetonitrile (anhydrous, 5 mL), triethylamine (1.4 mL, 10 mmol), 1-amino-2-phenyl-2-pentanol (0.40 g, 2.2 mmol), and carbon tetrachloride (1.5 mL, 16 mmol) stirred under nitrogen at ambient temperature. After stirring for 1 h without heating, the mixture is stirred at 40° C. for 2 h. The reaction mixture is dissolved in chloroform (100 mL). The solution is washed with 10% acetic acid (100 mL) followed by 5% sodium bicarbonate (100 mL) and dried over sodium carbonate. The solvent is evaporated under reduced pressure. The crude product is subjected to column chromatography on silica gel using chloroform-diethyl ether (49:1) and then to preparative TLC using hexanes-diethyl ether (3:1) as an eluent to give the titled compound (160 mg, 17%). 1H NMR (CDCl3) δ 0.93 (t, J=7.5 Hz, 3 H), 1.32 (m, 1 H), 1.48 (m, 1 H), 2.13 (m, 2 H) 3.60 (s, 3 H), 4.35 (d, J=14.6 Hz, 1 H), 4.40 (d, J=14.6 Hz, 1 H), 7.31 (tt, J=7.1 and 1.5 Hz, 1 H), 7.40 (t, J=7.4 Hz, 2 H), 7.43-7.56 (m, 6 H), 7.67 (ddd, J=8.2, 6.9 and 1.5 Hz, 1 H) 7.96 (dd, J=8.4 and 1.5 Hz, 1 H), 8.07 (m, 2 H), 8.17 (d, J=8.5 Hz, 1 H). LC-MS data (same condition as given in example 1): HPLC: 2.62 min. MS (ES+): m/e 407 [MH]+.
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-])=O.C(=O)([O-])O.[Na+]>CO>[NH2:5][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1CCCCCC1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Concentrated hydrochloric acid (1.27 ml, 15.2 mmol) and anhydrous tin dichloride (1.43 g, 7.54 mmol) were sequentially added at 0° C. to a methanol (5 ml) solution of hexahydro-1-[2-nitro-4-(trifluoromethyl)phenyl]-1H-azepine (675 mg, 2.34 mmol), obtained as described in Referential Example 4-1. The resulting mixture was stirred for two hours. A saturated solution of sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=20/1). Thus, 1-[2-amino-4-(trifluoromethyl)phenyl]-hexahydro-1H-azepine (522 mg, 86.3%) was yielded as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc(Cl)c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 528.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCCCCC(C)=O
Product: CCCCCCC(C)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from 2-octanone and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10]>CO.O>[F:12][C:7]1[CH:6]=[C:5]([O:13][CH3:14])[C:4]([CH2:3][CH:2]=[O:1])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1cc(F)c(C#N)cc1CC(O)CO
Solvent: CO
Solvent: O
Product: COc1cc(F)c(C#N)cc1CC=O

Procedure:
A solution of 5-(2,3-dihydroxypropyl)-2-fluoro-4-methoxybenzonitrile (2.0 mmol) in 10 mL of methanol/water=3:1 was cooled to 0° C. by ice bath, and then NaIO4 (3.0 mmol) was added. After stirred the reaction at 0° C. for 2 hrs, the mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified with fast column chromatography to give the product 2-fluoro-4-methoxy-5-(2-oxoethyl)benzonitrile.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[S:5][C:6]([SH:9])=[CH:7][CH:8]=1.[Cl:10][CH2:11][CH2:12]Br>C(OCC)(=O)C>[Cl:3][C:4]1[S:5][C:6]([S:9][CH2:12][CH2:11][Cl:10])=[CH:7][CH:8]=1
Reactant: ClCCBr
Reactant: Sc1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: ClCCSc1ccc(Cl)s1
Reaction time: 16 h

Procedure:
28 cm3 of a 5N aqueous sodium hydroxide solution were added, with stirring, to a solution, cooled to a temperature in the region of 5° C., of 17.9 g of 2-chloro-5-thiophenethiol in 30 cm3 of 1-chloro-2-bromoethane, and then the temperature was allowed to return to the region of 20° C., while stirring was continued for 16 hours. The reaction mixture was diluted with 300 cm3 of ethyl acetate and washed with 3 times 150 cm3 of water. The organic solution was dried over sodium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 45° C. 20.6 g of 2-chloro-5-(2-chloroethylthio)thiophene were obtained in the form of an oil with a brown color.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=O)[CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)Cl>>[CH:14]1([C:12]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:9][CH2:10][N:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(CCNC(=O)C2CCCCC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2C1CCCCC1
Temperature: 0 °C
Yield: 29.2 %

Procedure:
A solution of cyclohexanecarboxylic acid [2-(3-methoxyphenyl)ethyl]amide (1.000 g, 3.8 mmol) in POCl3 (7.0 ml, 75.1 mmol) was refluxed under N2 for 24 hr, then the cooled reaction mixture was slowly added to ice-water (30 ml) with stirring. The resulting mixture was extracted with EtOAc (3×20 ml), then the remaining aqueous layer was basified to pH 10 with concentrated ammonia (40 ml). This was extracted with CHCl3 (4×20 ml), then the combined extracts were dried over MgSO4 and concentrated in vacuo to give 0.270 g (93% yield) of yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[NH2:8].CCN(CC)CC.[H][H]>CO.[Pd]>[F:10][C:5]1[C:6]([F:9])=[C:7]([NH2:8])[CH:2]=[C:3]([F:11])[N:4]=1
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1cc(F)nc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of 3-chloro-2,5,6-trifluoro-pyridin-4-ylamine (1.82 g, 10 mmol), 5% Pd/C (0.5 g), and Et3N (3.04 g, 30 mmol) in 50 mL of MeOH was equipped with a balloon of hydrogen gas and stirred at room temperature overnight. The solution was filtered through diatomaceous earth (Celite®). The filtrate was concentrated under vacuum and the residue was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 1.33 g (90%) of the desired product. MS (DCI) m/e 149 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[O:11])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a mixture of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (12.9 g, 81.6 mmol), 4-fluorobenzenamine (9.06 g, 81.6 mmol, Alfa-Aesar) and HOAt (2.22 g, 16.3 mmol, Shanghai Medped Co. Ltd.) in DCM (80 mL) was added EDCI (18.76 g, 97.9 mmol, Shanghai Medped Co. Ltd.) in portions at rt. The reaction was warmed up to 45° C. and stirred for 3 h. The mixture was extracted with water (150 mL×5), followed by brine (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized in n-hexane to give the title compound as a pale yellow solid (12.83 g, 63%).
Reaction SMILES: [Cl-].[NH4+:2].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=O)=[CH:6][CH:5]=1>>[CH:6]1[C:7]([C:8]#[N:2])=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Product: N#Cc1ccc(Cl)cc1
Temperature: 215 °C
Yield: 1211.4 %

Procedure:
The reaction was carried out as described in Example 1. PCBTC (230 g, 1.0 mol), ammonium chloride (56.2 g,1.05 eq), and p-chlorobenzoic acid (11.5 g) were charged to the reactor. The mixture was heated at 215° C. for 9 h. Distillation of the reaction mixture gave PCBN (122.4 g, 89%, melting point: 92°-93° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:47]=[CH:46][C:24]([C:25]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH3:37])[C:32](=[O:38])[CH:31]=[C:30]3[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[OH:26][C:25]([C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:47][CH:46]=1)([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[C:32](=[O:38])[CH:31]=[C:30]2[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C

Procedure:
Herein, in step 1, the intermediate 1-methyl imidazole in tetrahydrofuran, is mixed with a solution of n-butyllithium in a hexane solvent to which is added chlorotriethylsilane (triethylsilyl chloride), followed by a further addition of n-butyllithium in hexane, the resulting mixture being cooled to −78° C. before the addition of a solution of a compound of formula (I), i.e. 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone in tetrahydrofuran. The reaction mixture is subsequently brought to room temperature, and then hydrolysed, extracted with ethyl acetate and the organic layer worked up to obtain a compound of formula (II), i.e. (±)-6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:25][CH:26]=[CH2:27])[C@:9]([NH:18][S@@](C(C)(C)C)=O)([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:25][CH:26]=[CH2:27])[C@@:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)([NH2:18])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(N)c1ccc(Cl)cc1

Procedure:
A solution of (R)—N-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-yl)-2-methylpropane-2-sulfinamide (Example 418, Step C, 5.96 g, 14.04 mmol) in THF (56.2 ml) was treated with. hydrochloric acid in water (36-38% wt, 6.40 ml, 211 mmol) for three hours. The reaction was diluted with 300 mL ether and the acidic aqueous layer made alkaline with sat. aq. NaHCO3 solution. The organic layer was washed with sat. aq. NaHCO3 solution, dried over MgSO4 and concentrated to provide the title compound as a colorless glass.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:16])[O:8][C:9]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:10]=1)(=O)[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=[O:26])[CH:19]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>ClCCl.CCOCC.C(OC(=O)C)C>[CH:2]([C:1]1[C:6]2[C:7](=[O:16])[O:8][C:9]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:10]=2[C:19]2[C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]=2[N:17]=1)([CH3:4])[CH3:3]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: CC(C)C(=O)C1=CC2(CCOCC2)OC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)C(=O)CC(C)(C)C2
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
3.12 g 3-Isobutyryl-1,8-dioxaspiro[4.5]dec-3-en-2-one and 2.13 g 3-amino-5,5-dimethylcyclohex-2-enone are mixed and heated to 200° C. for 10 minutes under a vacuo of 20 mbar. The mixture is cooled to room temperature, 15 ml ethylacetate are added and the mixture is stirred for 30 minutes. Then 15 ml petrole ether are added and the precipitate is isolated by filtration. The crude product is dissolved in 350 ml dichloromethane, treated with 2.46 g 2,3dichloro-5,6-dicyano-p-benzoquinone and stirred for 18 hours. 2 g Ascorbic acid are added and the mixture is stirred for 10 minutes. The it is washed for three times with water. The organic phase is dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[Na].Br[CH2:15][CH2:16][C@@H:17]1[O:23][C@:22](/[CH:28]=[CH:29]/[CH:30]2[CH2:32][CH2:31]2)([C:24]([F:27])([F:26])[F:25])[C:21]2[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:20]=2[NH:19][C:18]1=[O:38]>C1COCC1.C(O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:20]2[NH:19][C:18](=[O:38])[C@H:17]([CH:16]=[CH2:15])[O:23][C@:22](/[CH:28]=[CH:29]/[CH:30]3[CH2:32][CH2:31]3)([C:24]([F:25])([F:26])[F:27])[C:21]=2[CH:33]=1
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](/C=C/C2CC2)(C(F)(F)F)O[C@H]1CCBr
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@@H]1O[C@](/C=C/C2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
To a room temperature solution of 238 mg (1.05 mmol) of 2-nitrophenylselenocyanate in 3.0 mL of THF was added 9 mL of ethanol and 66 mg of sodium borchydride. After stirring 1.5 h, a solution of 153 mg of rel-(3S,5S)-trans-3-(2-bromoethyl)-7-chloro-5-cyclopropylethenyl-1,5-dihydro-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one in 1.5 mL of dry THF and 5 mL of ethanol was added, and the resulting mixture was stirred at ambient temperature for 32 h. The reaction mixture was partitioned between water and ether, and the organic layer was washed with aqueous bicarbonate and brine, dried and evaporated. The crude product was purified by column chromatography over silica gel (elution with 10-25% ethyl acetate in hexanes) to give 73 mg of the title compound as a pure solid which can be recrystallized from ethanol-hexanes: mp 165.5-166.5°; HRMS Calcd. for C17H16NO2F3Cl (M+H)+ : 358.082166. Found: 358.081658.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1.C([Li])CCC.C1C[O:22][CH2:21][CH2:20]1>>[CH:1]1[C:13]2[N:12]([CH2:20][CH2:21][OH:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: OCCn1c2ccccc2c2ccncc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a −30° C. cooled solution of 9H-β-carboline (1.0 g, 5.95 mmol) in dry THF (30 mL) was added butyllithium (4.12 mL, 6.55 mmol) over a 15 min period. After 30 min at −30° C., the reaction mixture was cooled to −50° C. Ethylene oxide (1.6 mL in a cooled measuring cylinder) was then bubbled into the reaction mixture, in a stream of nitrogen. The temperature was slowly raised to −5° C. over a 2 h period, and stirring was continued for 84 h. The mixture was acidified with 1 N HCl (50 mL) and extracted with diclormethane (2×100 mL). The combined extracts were dried (MgSO4), and concentrated in vacuo. The product was chromatographed eluted with dichloromethan/methanol (20:1) to give 660 mg (53%) of 2-β-carbolin-9-yl-ethanol. 1H NMR (300 MHz, CDCl3): δ 3.62 (s, 1H), 4.10 (t, 2H), 4.50 (t, 2H), 7.30 (t, 1H), 7.50-7.65 (m, 2H), 7.80 (d, 1H), 8.10 (d, 1H), 8.22 (d, 1H), 8.78 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>Cl>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:26])=[O:5])=[CH:8][CH:9]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(c3ncccn3)CC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(NC2CCN(c3ncccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 120.7 %

Procedure:
A solution of (11) (0.009 g, 0.025 mmol) in HCl (5 mL, 4M in 1,4-dioxane) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a pale yellow oily residue (0.009 g, quantitative yield); 1H NMR (DMSO) δ 8.42 (d, 2H, J=4.8), 7.67 (d, 2H, J=8.7), 6.70 (t, 1H, J=4.8), 6.67 (d, 2H, J=9.3), 4.54 (d, 2H, J=13.2), 3.72 (m, 1H), 3.20 (t, 2H, J=11.1), 1.98 (d, 2H, J=10.7), 1.34 (m, 2H); 13C NMR (CDCl3) δ 167.4, 158.9, 157.7, 151.0, 131.2, 117.4, 111.7, 109.7, 48.9, 43.6, 30.9; HRMS (FAB) m/z 299.1518 (M+H)+ (C16H18N4O2 requires 299.1508).