Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:41]=[CH:40][C:39]([O:42]COC)=[CH:38][CH:37]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:25][CH2:24]2)=[O:22])=[CH:7][CH:6]=1>O1CCCC1.C(O)C.Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[CH2:27][CH2:28]2)=[O:22])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1[nH]c2ccccc2c1C(c1ccc(O)cc1)c1ccc(O)cc1)N1CCN(c2ccccc2Cl)CC1
Yield: 89.7 %

Procedure:
Compound 1 (1.43 g, 2.28 mmol) obtained in Example 1 was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and ethanol (20 ml), and 5 ml of 2N hydrochloric acid was added thereto, followed by heating under reflux for 0.5 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added thereto followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under pressure. The resulting residue was washed with diethyl ether/ethyl acetate and crystallized to give 1.1 g (yield: 88%) of the title compound.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].O=O>CO>[CH3:11][O:10][C:1](=[O:9])[CH:2]([CH3:3])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: O=O
Solvent: CO
Product: COC(=O)CC(C)C(=O)OC

Procedure:
A solution of dimethyl itaconate (158 mg, 1 mmol) and the catalyst (I) (6 mg, 1 mmol, 1 mol %) in degassed methanol (10 ml) was prepared under exclusion of oxygen in a Schlenk flask. After hydrogenation of the mixture overnight at 3.41 MPa (500 psi), the solvent was evaporated to give the 2-methylsuccinic acid dimithyl ester (complete conversion, 11.7% ee, configuration unknown).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Br[CH2:12][C:13](OC)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][OH:14])[CH:2]=[CH2:3]
Reactant: COC(=O)CBr
Reactant: C=CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1ccccc1OCCO
Temperature: 100 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-Allylphenol (5.066 g) was dissolved in N,N-dimethylformamide (70 ml), followed by the addition of methyl 2-bromoacetate (6.931 g) and potassium carbonate (7.88 g), and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was dissolved in tetrahydrofuran (40 ml), followed by the addition of lithium aluminium hydride (1.442 g) in small portions under ice-cooling. The resulting mixture was stirred for 5 min. To the reaction mixture were sequentially added water (1.5 ml), 5N sodium hydroxide (1.5 ml) and water (4.5 ml), and the resulting insoluble matters were filtered off through Celite. The resulting filtrate was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless oil (5.248 mg, yield; 76%).
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)=O.[C-]#N.[K+].CN(C)[C:18]1([C:23]#[N:24])[CH2:22]CC[CH2:19]1>O>[N:2]1([C:18]([CH3:22])([CH3:19])[C:23]#[N:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C1(C#N)CCCC1
Reactant: C1CCCNCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)N1CCCCCC1
Yield: 80 %

Procedure:
The title compound (6.6 g: 80%) was prepared from homopiperidine hydrochloride (6.7 g; 49 mmol), acetone (3.67 ml; 50 mmol), and potassium cyanide (3.25 g; 50 mmol) in water (25 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ 1.43 (6H, s), 1.50-1.65 (8H, m), 2.66 (4H, m).
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[S:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22](#[N:25])[CH:23]=[CH2:24]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]3([CH:23]([C:22]#[N:25])[CH2:24]2)[N:7]1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=13
Reactant: C=CC#N
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CC1CC2(c3ccccc3)SC13c1ccccc1CCN3C2=O

Procedure:
4.08 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo-[2,3-a]isoquinolinium hydroxide (internal salt) and 1.95 ml of acrylonitrile were heated together under reflux overnight in 250 ml of toluene. After evaporation of the solvent in vacuo, the residue was recrystallized from acetonitrile. There was obtained 1,2,3,4,6,7-hexahydro-4-oxo-3-phenyl-3,11b-epithio-11bH-benzo[a]quinolizine-1-carbonitrile of m.p. 225°-226°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: OCCCSc1cccc2nccn12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCSc1cccc2nccn12
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (2.00 g, 9.60 mmoles) and triethylamine (1.60 ml, 11.5 mmoles) in methylene chloride (50 ml) was added acetic anhydride (1.10 ml, 11.6 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 7.5 hours. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent:hexane/acetone (1:1)] to obtain 2.40 g of the desired product (100%, brown oily product).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=O)=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:26])[C:22]#[N:24])=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(N)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)CCCCOc1ccc(OCCCCCn2ccnc2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 0.97 g 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanamide in 50 ml dichloromethane was added 0.94 ml pyridine, the solution was cooled down to -20° C., 1.57 g phosphorus pentachloride was added, and the resulting mixture was stirred to allow the temperature to rise to 15° C. over a period of about one hour. Chloroform (30 ml) and ice water (30 ml) were admixed in that order, and the organic layer was collected and washed with 5% aqueous solution of sodium bicarbonate until the pH of aqueous layer rose to 7.5 to 8.0 and then with saturated sodium chloride solution. After dehydration, the solvent was distilled off, and the residue was purified by silica gel column chromatography, affording 0.82 g of 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexane-nitrile.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[C:15]([O:16]C)=[C:14]([O:18]C)[C:13]([N+:20]([O-:22])=[O:21])=[CH:12][C:11]=1[C:23]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[C:28]([O:34]C)=[C:27]([O:36]C)[C:26]=1[C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1)=[O:24].Cl.N1C=CC=CC=1>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[C:15]([OH:16])=[C:14]([OH:18])[C:13]([N+:20]([O-:22])=[O:21])=[CH:12][C:11]=1[C:23]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[C:28]([OH:34])=[C:27]([OH:36])[C:26]=1[C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1)=[O:24]
Reactant: COc1c([N+](=O)[O-])cc(C(=O)c2cc([N+](=O)[O-])c(OC)c(OC)c2-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1OC
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1cc([N+](=O)[O-])c(O)c(O)c1-c1nc2ccccc2[nH]1)c1cc([N+](=O)[O-])c(O)c(O)c1-c1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
1.0 g of 2-benzimidazolyl(3,4-dimethoxy-5-nitrophenyl)ketone and 8.0 g of pyridine hydrochloride are held at 200° for 60 minutes. The dark solution is poured while still warm into ice-water and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethyl acetate/hexane, there is obtained 2-benzimidazolyl(3,4-dihydroxy-5-nitrophenyl)ketone in the form of yellow crystals of m.p. 249°-250°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1[NH2:23])=[S:11])=[O:8]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1[NH:23][C:1](=[O:3])[CH3:2])=[S:11])=[O:8]
Reactant: CC(=O)Cl
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c(N)c1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(=S)NC(=O)OC)c(NC(C)=O)c1
Yield: 62 %

Procedure:
Acetyl chloride (4.53 g.; 0.058 mole) was added to a suspension of 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)-thiourea (16.0 g; 0.057 mol3) in dry toluene (230 ml) and the stirred mixture was refluxed for ninety minutes. During this time the solid gradually dissolved to give a slightly turbid solution. On cooling to laboratory temperature a solid separated which was filtered off and recrystallised to give 1-methoxycarbonyl-3-(2-acetamido-4-n-butylphenyl)thiourea (11.4 g), m.p. 173°-174° C. (with decomposition).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([CH3:16])[CH:4]=1)=[O:2].[OH:17]OS([O-])=O.[K+].C(OCC)(=O)C>CN(C=O)C.O.CCCCCC>[C:10]([O:9][C:7]([C:6]1[CH:14]=[CH:15][C:3]([C:1]([OH:17])=[O:2])=[CH:4][C:5]=1[CH3:16])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 27 %

Procedure:
To a solution of tert-butyl 4-formyl-2-methyl-benzoate (390 g, ˜78% purity, 1.8 mol) in DMF (2.0 L) was added oxone (270 g, 1.8 mol) over a period of 15 min at 10° C. After complete addition, the reaction mixture was warmed to room temperature and stirred for 12 h. After complete conversion of starting material, the reaction mixture was diluted with water at 10° C. The aqueous layer was extracted with ethyl acetate (2×5 L), washed with water (3×1 L) dried over sodium sulphate and concentrated to yield a crude residue (217 g). Pure 4-tert-butoxycarbonyl-3-methyl-benzoic acid (115 g) was obtained by column chromatography with ethyl acetate (6%) in hexane.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=O>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:8][C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:13]/[C:12]/2=[N:7]\[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C1\CC2(CCCCC2)Oc2ccc(Br)cc21
Yield: 51.4 %

Procedure:
The compound of 2-methylpropane-2-sulfinamide (29.54 g, 244.2 mmol) was added the solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (78.97 g, 268.6 mmol) in dry THF (900 mL), and then tetraisopropoxytitanium (193.1 g, 488.3 mmol) was added, The reaction mixture was reflux overnight. The mixture was removed in vacuo, and then quenched by brine, extracted with ethyl acetate. The ethyl acetate was dried over anhydrous Na2SO4, filtered, and evaporated to give (E)-N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)-2-methylpropane-2-sulfinamide (50 g, 40%). 1H NMR (CDCl3): 1.30 (s, 10H), 1.51 (m, 5H), 1.62 (m, 4H), 1.83 (d, 2H), 3.07 (d, 1H), 3.43 (d, 1H), 5.29 (s, 2H), 6.79 (d, 1H), 7.41 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[H-].[Na+].[CH3:16][Si:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([CH2:19][CH2:18][Si:17]([CH3:25])([CH3:24])[CH3:16])(=[O:22])=[O:21])[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1H-indole-5-carboxylic acid methyl ester (3.6 g, 20.6 mmol) in tetrahydrofuran (180 mL) at 0° C., was added sodium hydride (0.65 g, 21.9 mmol). After 10 min., 2-trimethylsilanylethanesulfonyl chloride (4.4 g, 21.9 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 3 h, acetic acid (1.6 mL, 26.8 mmol) was added and the reaction mixture was concentrated. The crude product was chromatographed (Biotage 40M column, 2.5% ethyl acetate-hexanes) to afford 1-(2-trimethylsilanylethanesulfonyl)-indole-5-carboxylic acid methyl ester (5.43 g) as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:21])[CH2:10][N:11]1[CH2:15][CH:14]2[CH2:16][CH2:17][C:18](=[O:19])[N:13]2[C:12]1=[O:20])C1C=CC=CC=1>O1CCCC1.[Pd]>[O:20]=[C:12]1[N:13]2[C:18](=[O:19])[CH2:17][CH2:16][CH:14]2[CH2:15][N:11]1[CH2:10][C:9]([OH:21])=[O:8]
Reactant: O=C(CN1CC2CCC(=O)N2C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CN1CC2CCC(=O)N2C1=O

Procedure:
A solution of tetrahydro-3,5-dioxo-1H-pyrrolo[1,2-c]imidazole-2(3H)-acetic acid benzyl ester (2.9 g, 0.01 mol) in tetrahydrofuran, 250 ml, is treated with H2 gas in the presence of a Pd/C catalyst. After H2 uptake is complete, the solution is filtered through filter aid and concentrated in vacuo to yield tetrahydro-3,5-dioxo-1H-pyrrolo[1,2-c]-imidazole-2(3H)-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][C:3]=1[NH:11][NH2:12].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C.C>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:21][C:20]1[N:11]([C:3]2[CH:4]=[C:5]([Cl:10])[C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:12]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1cc(Cl)c(Cl)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2cc(Cl)c(Cl)c(Cl)c2Cl)c1N
Yield: 32.9 %

Procedure:
2,3,4,5-Tetrachlorophenylhydrazine (12.3 g) was heated with ethoxymethylenemalononitrile (6.4 g) in dimethylformamide (25 ml) at reflux for 10 minutes in the presence of sodium carbonate (0.1 g). The hot solution was treated with charcoal and filtered and evaporated to dryness. The residue was triturated with diethyl ether and the ether solution was decanted and diluted with hexane to precipitate dark yellow crystals which were recrystallised from toluene to give 5-amino-4-cyano-1-(2,3,4,5-tetrachlorophenyl)pyrazole (5.3 g), m.p. 168°-169° C., in the form of off-white crystals.
Reaction SMILES: Cl.[C:2]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([O:27][CH3:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH3:16])=[CH:10][CH:9]=1)(OC)=[O:3].[CH3:29][NH2:30].Cl>CO.[Cl-].[Na+]>[ClH:26].[CH3:29][NH:30][C:2]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([O:27][CH3:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH3:16])=[CH:10][CH:9]=1)=[O:3]
Reactant: CN
Reactant: COC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(3-chlorophenyl)ethanamine hydrochloride (0.63 g, diastereoisomeric ratio 92:8) in methanol was added 5 ml of a 30% aqueous solution of methylamine. This mixture was boiled under reflux for 6 hours during which time 3 further 5 ml portions of the methylamine solution were added. The solution was cooled to room temperature, a further 5 ml of methylamine solution added and the reaction mixture allowed to stand at room temperature overnight. After diluting with saturated sodium chloride solution the mixture was extracted with dichloromethane, washed with saturated sodium chloride solution, dried (magnesium sulphate), filtered and evaporated to give an oil which was converted to its hydrochloride salt by addition of ethereal hydrogen chloride. Recrystallisation from methanol-ethyl acetate gave the title compound, mp 217°-9° C., as single diastereoisomer.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:26](O)(=O)[CH3:27]>>[CH2:26]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH3:23])[CH3:27]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
This compound was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (16 mg, 0.049 mmol) and NaBH4 pellets (large excess, >10 equiv) in 5 mL acetic acid (0.01 M stirred at rt for 12 h, to afford 18 mg (100%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (18 mg, 0.050 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 2.5 mL acetic acid and 2.5 mL concentrated HCl and heated at 90° C. for 4 h to afford 9 mg (57%) of Compound 103, after purification by column chromatography (3:1 hexanes: EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 12.02 (bs, 1H), 7.12 (s, 1H), 7.04 (d, J=8.8, 1H), 6.97 (d, J=9.3, 1H), 4.10 (dd, J=10.2, 3.4, 1H), 4.02 (dd, J=10.3, 2.9, 1H), 3.53 (m, 1H), 3.43 (m, 1H), 3.32 (m, 1H), 1.22 (d, J=6.9, 3H), 1.18 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2=[O:14])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2=[O:14])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O

Procedure:
5 g of 2-(4-chlorobenzylidene)-5,5-dimethylcylopentanone (prepared in Example 5) was dissolved in 40 ml of ethanol, and 60 mg palladium-carbon (10%) was added to the mixture. The hydrogenation reaction was carried out under normal pressure until theoretical amount of hydrogen was absorbed.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1)[CH3:2].[Br-:15].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:15][CH2:12][C:11]([C:7]1[C:8]([CH3:10])=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[CH3:14])=[O:13]
Reactant: [Br-]
Reactant: CCOc1cc(C)c(C(C)=O)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCOc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.5 %

Procedure:
To a solution of 1-(4-ethoxy-2,6-dimethylphenyl)ethanone (4.00 g, 20.8 mmol) in acetonitrile (41.6 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.0 g, 20.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-ethoxy-2,6-dimethylphenyl)ethanone (6.40 g), which was used directly for the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5](C)=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[CH:20](C1OC=CC(=O)C=1O)C.C(Br)C1C=CC=CC=1>>[OH:1][CH:2]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Reactant: CC(O)c1occc(=O)c1O
Agent: BrCc1ccccc1
Product: CC(O)c1occc(=O)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 4.68 g (30 mmol, 1 eq.) of 2-(1 -hydroxyethyl)-3-hydroxy-pyran-4(1H)-one and 5.64 g benzyl bromide (33 mmol, 1.1 eq.) to yield the pure product 6.1 g (82%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p 97-100° C.
Reaction SMILES: [N:1]1([C:8]2[C:9](=[O:22])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[N:1]1([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCCC3)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (100 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol) and then Tf2O (186 mg, 0.66 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 3-(azepan-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc2ccc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
10 g (62.4 mmol) of 7-methyl-coumarin were suspended in 115 ml of carbon tetrachloride. After the addition of 12.2 g (68.7 mmol) of N-bromosuccinimide and 0.122 g (0.5 mmol) of benzoyl peroxide the reaction mixture was boiled under reflux for 7 hours. After cooling to room temperature the mixture was filtered. The residue was washed in succession with carbon tetrachloride and a small amount of diethyl ether and subsequently digested in 500 ml of water. The crude product was filtered off, dried and recrystallized from about 150 ml of acetone. After drying in a water-jet vacuum at 60° C. there were obtained 11 g of 7-bromomethyl-2H-1-benzopyran-2-one as white crystals.