Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OCCCN(C(C)=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (1.2 g) was dissolved in pyridine (15 ml), and acetic anhydride (0.71 ml) was added thereto. The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was separated into layers by adding ethyl acetate and diluted hydrochloric acid. The organic layer was washed successively with-water, saturated aqueous sodium bicarbonate solution and water, and concentrated under reduced pressure to give the desired product (1.38 g). mp. 68°-69° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (100 mg; 0.432 mmol) and 3-amino-5-t-butylisoxazole (58.9 mg; 0.42 mmol) in anhydrous pyridine (1.2 mL) is added phosphorous oxychloride (0.039 mL; 0.432 mmol). The reaction mixture is left stirring at room temperature for 1 hour. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 354 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
2-Bromobenzyl alcohol (25.0 g) was dissolved in N,N-dimethylformamide (150 ml) and imidazole (20.0 g) and tert-butyldimethylchlorosilane (22.2 g) were added. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 5% aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (40.9 g).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:54])[NH:46][C:47]1C=CC=C(N)C=1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:54])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-phenyl)-carbamic acid tert-butyl ester was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 11.28 (1H, br s), 8.85 (1H, s), 7.69 (1H, s), 7.57-7.27 (6H, m), 7.04 (1H, m), 4.76 (1H, d), 4.63 (1H, d), 4.21 (2H, m), 2.80 (1H, m), 2.18-1.35 (6H, m), 1.32-1.22 (13H, m). The product was further characterised as the hydrochloride salt. Found: C, 59.71; H, 7.33; N, 12.48%; C28H35N5O3.HCl.2.0H2O requires: C, 59.83; H, 7.17; N, 12.46%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl) -6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH2:9][CH2:8][CH2:7]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[NH:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH2:9][CH2:8][CH2:7]2
Reactant: CN1CCCC1CCN1CCCc2cc(N)cc(F)c21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCCC1CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a stirred solution of 8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (580 mg, 2.091 mmol) in ethanol (15 ml) was added methyl thiophene-2-carbimidothioate hydroiodide (1193 mg, 4.18 mmol) as a solid. The resulting suspension was stirred overnight at room temperature under argon. The reaction mixture was then quenched with water and sodium carbonate (sat) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated. The residue was then chromatographed in ethyl acetate, followed by 0-10% (2M NH3 in methanol) in dichloromethane, giving the desired N-(8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (485 mg, 1.255 mmol, 60.0% yield). 1H NMR (DMSO-d6) δ 7.71 (d, J=3 Hz, 1H), 7.57 (d, J=4.5 Hz, 1H), 7.07 (dd, J=4.8, 3.9 Hz, 1H), 6.44 (brs, 2H), 6.39-6.34 (m, 2H), 3.07-3.02 (m, 4H), 2.95-2.89 (m, 1H), 2.69-2.65 (m, 2H), 2.21 (s, 3H), 2.03-1.99 (m, 2H), 1.94-1.87 (m, 2H), 1.76-1.74 (m, 2H), 1.63-1.59 (m, 2H), 1.46-1.40 (m, 2H).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].C(O[C:14]([C:16]1[C:25]([N:26]=[CH:27]N(C)C)=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:40][CH3:41])=[C:21]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:22]=2)[CH:17]=1)=[O:15])(C)(C)C>O1CCCC1>[CH3:41][O:40][C:20]1[C:21]([O:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[CH:22][C:23]2[CH:24]=[C:25]3[C:16]([C:14](=[O:15])[C:7]([C:6]#[N:8])=[CH:27][NH:26]3)=[CH:17][C:18]=2[CH:19]=1
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N=CN(C)C)cc2cc1OCCN1CCOCC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCN1CCOCC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To 15 mL of tetrahydrofuran at −78° C. is added 2.6 mL of n-butyllithium (1.6M in hexane) and the reaction mixture is stirred for 5 minutes. To this is added 0.36 mL (6.8 mmol) of acetonitrile dropwise, followed by stirring for 15 minutes. Finally, a solution of 3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)naphthalene-2-carboxylic acid tert-butyl ester in 5 mL of tetrahydrofuran is added dropwise over a period of 15 minutes. The resulting mixture is stirred at −78° C. for 1 hour, then at room temperature for 1 hour. After cooling again to −78° C., the reaction is quenched with 0.5 mL of glacial acetic acid, the dry ice bath is removed and the resulting thick slurry is stirred for 1 hour. The solid is collected by filtration, washed with ethyl acetate and dried. Purification is carried out by silica gel chromatography, utilizing a gradient of 95:5 to 89:11 of methylene chloride/methanol to give 0.38 g of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 275° C. (dec).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:15][CH2:16][C@:17]1([CH3:30])[C@H:21]([CH:22]=[CH2:23])[O:20][C@H:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18]1)[CH2:10][C:11]([O:13]C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1.CO.O>[Si:1]([O:8][C@H:9]([CH2:15][CH2:16][C@:17]1([CH3:30])[C@H:21]([CH:22]=[CH2:23])[O:20][C@H:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:18]1)[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CC[C@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Methyl (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S,4R,5S)-4-methyl-2-phenyl-5-vinyl-1,3-dioxolan-4-yl]pentanoate (14.6 g, 33.6 mmol) was dissolved in a mixed solution of THF (140 ml)-methanol (140 ml)-water (70.0 ml) and anhydrous lithium hydroxide (4.02 g, 168 mmol) was added. The reaction solution was stirred at room temperature for four and a half hours. The reaction solution was poured into 0.5N hydrochloric acid, which was then extracted with ethyl acetate. After the organic layer was washed with water and brine sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=4:1→2:1) to obtain the title compound (14.1 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6])#[N:2].[Cl:9][CH2:10][C:11]([N:13]([CH3:17])[C:14](Cl)=[O:15])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]([CH3:8])([CH3:7])[CH:4]=[N:5][OH:6])#[N:2].[Cl:9][CH2:10][C:11]([N:13]([CH3:17])[C:14](=[O:6])[O-:15])=[O:12]
Reactant: CN(C(=O)Cl)C(=O)CCl
Agent: CC(C)(C#N)C=NO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)[O-])C(=O)CCl
Reaction time: 2 h
Yield: 137 %

Procedure:
To a mixture of 3.24 g (0.029 m) of 2-cyano-2-methylpropionaldoxime, 5.0 g (0.029 m) of N-chloroacetyl-N-methylcarbamoyl chloride in 50 ml of toluene was added 2.92 g (0.029 m) of triethylamine. After stirring for 2 hours, the solid was filtered. The filter cake was washed with water and hexane and air dried to afford 5.2 g of a white solid with a melting point of 115° C.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13](OC(C)(C)C)=[O:14])[C:8]([C:20]1C(Cl)=[N:22][C:23]3[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7]2)(=O)C.[C:31](O)(=[O:33])[CH3:32]>O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:20]([C:8]1[C:13](=[O:14])[NH:9][C:10]3[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:12][CH:11]=3)=[CH:29]2)(=[O:33])[CH3:32]
Reactant: CC(=O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc2[nH]c(-c3cc4ccccc4[nH]c3=O)cc2c1

Procedure:
A solution of tert-butyl 5-acetyl-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (8-3, 400 mg, 0.95 mmol) was heated in a 3:1 mixture of acetic acid and water at reflux for 20 hours. The reaction mixture was cooled, then concentrated to dryness. The residue was suspended in ethyl ether (50 mL) with the aid of sonication, then filtered and air dried to give 3-(5-acetyl-1H-indol-2-yl)-2(1H)-quinolinone (8-4) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 11.94 (s, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 7.76 (d, 2H, J=7.9 Hz), 7.60 (d, 1H, J=8.6 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.49 (s, 1H), 7.39 (d, 1H, J=7.9 Hz), 7.26 (t, 1H, J=7.5 Hz), 2.62 (s, 3H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1>CCOCC>[Br:1][CH:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:13][CH2:12][CH2:11]1)=[O:23]
Reactant: O=C(CCc1ccccc1)C1(c2ccc(Cl)cc2)CCC1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(C(Br)Cc1ccccc1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.52 ml) was added dropwise over 20 minutes at ambient temperature to a stirred solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one (3 g) in ether (50 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 1 hour then it was washed with water (30 ml), saturated aqueous sodium hydrogen carbonate solution (2×30 ml) and water (30 ml), dried (MgSO4), and the solvent removed in vacuo to give 2-bromo-1-[1-(4-chlorophenyl)cyclobutyl]-3-phenylpropan-1-one as an oil which was used without purification.
Reaction SMILES: CS(OCC([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)C)(=O)=O.N1CCCC1>C1(C)C=CC=CC=1>[CH:21]1[C:22]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:16][C:17]=2[CH:18]=[CH:19][C:20]=1[C:23]#[N:24]
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)Nc1ccccc1S2
Reaction time: 24 h
Yield: 87.6 %

Procedure:
A mixture of (2RS)-2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate (10 g) and pyrrolidine (11.6 cc) in toluene (50 cc) is brought to 90° C. with stirring for 24 hours. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the residue is taken up with ethyl ether (200 cc) and 4N aqueous sodium hydroxide solution (15 cc). After stirring for 10 minutes, settling is allowed to take place and the organic phase is washed with saturated aqueous sodium chloride solution (3×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. The residual oil (11.3 g) is dissolved in 0.5N aqueous hydrochloric acid solution (60 cc). This solution is washed with ethyl ether (100 cc), then alkalinized with an excess of N aqueous sodium hydroxide solution and extracted with ethyl ether (100 cc). The organic phase is washed with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. The residual yellow oil (9.5 g) is purified on a column (height: 30 cm; diameter: 5.8 cm) on silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (95:5 by volume) (one litre) of methylene chloride and methanol and collecting 100-cc fractions. Fractions 3 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[2RS]-1-(1-Pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (5.45 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:15][C:16]2=[O:18]>C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH3:23])[C@H:17]2[C@@H:13]1[C@H:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:15][C@H:16]2[OH:18]
Reactant: CC(C)(C)[C@@H]1OC(=O)[C@@H]2[C@H]1C2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@@H]1O[C@@H](O)[C@@H]2[C@H]1C2(C)C
Yield: 98.9 %

Procedure:
15.5 ml of a toluene solution of 20% of diisobutyl aluminum hydride were slowly added at -70° C. to a solution of 2.5 g of the product of Step B in 25 ml of toluene with stirring and the mixture was poured over ice. The mixture was filtered and the filtrate was extracted with ether and was evaporated to dryness under reduced pressure to obtain 2.5 g of (1R,2R,4R,5S) 6,6-dimethyl-4-(2-methyl-prop-2-yl)-3-oxa-bicyclo(3,1,0)hexan-2-ol melting at 126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][C:14]=1[CH3:31])[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:15][C:14]=1[CH3:31])[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Oc1cc2c(cc1Cl)C(C(=O)O)CCO2
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylate (0.022 g, 0.042 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.087 ml, 0.087 mmol). The reaction was stirred overnight and then concentrated. The residue was taken up in water and acidified with 1M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by preparatory thin layer chromatography eluting with 95:5:1 dichloromethane/methanol/glacial acetic acid to yield 11 mg of the title compound (53% yield).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccc(F)cc1
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2ccc(F)cc2)c2ccc(O)cc21
Reaction time: 7 h
Yield: 45 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(4-fluorophenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate and being stirred for 7 h to obtain the title compound (45%).
Reaction SMILES: [CH3:1][N:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:23]1([C:29]2[O:30]C(=O)[CH:32]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[C:29]([NH:33][CH:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:4](=[O:6])[CH2:3][N:2]([CH3:1])[C:7](=[O:8])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C1OC(c2ccccc2)=NC1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-methyl-N-[(phenylmethoxy)carbonyl]-glycine (2.23 g., 10 mmole) is dissolved in 30 ml. of tetrahydrofuran and cooled in an ice-bath. Oxalyl chloride (1 ml., 11.5 mmole) is added followed by 2 drops of dimethylformamide. After stirring for 30 minutes in the ice-bath, the mixture is then stirred at room temperature for an hour. To this 0.25 ml. of oxalyl chloride is added. The mixture is evaporated, redissolved in 15 ml. of tetrahydrofuran, and stirred in an ice bath. A solution of 2-phenyl-4-(phenylmethyl)-5-(4H)-oxazolone (3.1 g., 12.4 mmole) dissolved in 15 ml. of tetrahydrofuran is added to the above solution stirring in the ice-bath. Triethylamine (1.4 ml., 10 mmole) is added and the solution is stirred at room temperature overnight. The precipitated triethylamine hydrochloride salt is filtered off. Tetrahydrofuran is removed from the residue and it is then redissolved in pyridine (5 ml.) and p-dimethylamino pyridine (20 mg.) is added. After stirring at room temperature for 3 hours, acetic acid (5 ml.) is added and the reaction mixture is kept at 105° for 30 minutes. The reaction mixture is then evaporated, the residue is dissolved in ethyl acetate, and washed with aqeuous sodium bicarbonate and water. After trituration with ethyl acetate/hexane, 2.2 g. of homogeneous [3-(benzoylamino)-2-oxo-4-phenylbutyl]methylcarbamic acid, phenylmethyl ester is obtained; m.p. 140°-141°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: Oc1ccc(F)c(Br)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(OC2CCCCO2)cc1Br
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of 3-bromo-4-fluorophenol (1.2 g) in toluene (62.8 mL) were added 3,4-dihydro-2H-pyran (1.15 mL) and pyridinium p-toluenesulfonate (0.237 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 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 (1.63 g) as a colorless oil.