Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO.CC(O)=O.Cl>[O:16]=[C:15]1[C:14]2[NH:2][C:4]3[C:11](=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[C:13]=2[CH2:12][CH2:19][CH2:17]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
4-Hydrazinylbenzonitrile hydrochloride (3 g, 17.6 mmol) dissolved in MeOH (30 mL), was heated to 60° C., and 1,2-cyclo hexadione (1.98 g, 17.6 mmol) in AcOH (30 mL) and HCl (12 mL) were added while maintaining the temperature at 60° C. The reaction mixture was stirred at 60° C. for 12 h and then cooled to room temperature. The volatiles were removed in vacuo and the residue was diluted with water, neutralized with saturated NaHCO3 solution and extracted with EtOAc (2×40 mL). The combined organic extracts were concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography [EtOAc-hexane (1:3) as eluant] to provide the title compound (3.3 g, 89%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.80 (bs, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.45 (dd, J=12.0, 2.0 Hz, 1H), 7.30 (d, J=12.5 Hz, 1H), 2.90 (t, J=9.0 Hz, 2H), 2.62 (t, J=9.0 Hz, 2H), 2.25 (m, 2H).
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:5][CH2:4][CH:3]([C:6]([O:8]C(C)(C)C)=[O:7])[NH:2]1.[OH-].[Na+]>Cl>[C:17]1([CH2:16][O:15][C:13]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[NH:2]2)=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 35 °C
Yield: 84 %

Procedure:
To a solution of hydrogen chloride (10 L, 12.2% wt) charged into a 20-L, round-bottomed flask was added 3-(1,1-dimethylethyl) 1-(phenylmethyl) 1,3-pyrazolidinedicarboxylate (1000 g, 3.27 mol at room temperature. The mixture solution was heated at 35° C. for 4 h. The mixture solution was poured into 10 kg of ice and the pH was adjusted to 4 using aqueous NaOH (5M) solution. The product precipitated out and a filtration was performed to give the product (690 g, 1.32 mol, 84%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])[C:2]#[CH:3].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])[C:2]#[CH:3]
Reactant: C#CCN(CC(OCC)OCC)C(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN(CC1OCCCO1)C(=O)CCl

Procedure:
N-Propargyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), propandiol-1,3 (3 ml) and trace amounts of toluenesulfonic acid are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated until no more ethanol is given off. After this time sodium carbonate (1 gram) is added to the mixture with stirring and the resulting mixture is distilled to yield the desired product N-propargyl-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:23])[CH2:8][O:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)=[N:5]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:3][C:4]1([CH3:23])[CH2:8][O:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[CH:17][C:18]([CH2:21][O:22][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=3)(=[O:32])=[O:31])=[CH:19][CH:20]=2)=[N:5]1
Reactant: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ccc(-c3ccccc3C3=NC(C)(C)CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
0.34 g (8.5 mmol) of a 60% oily sodium hydride was suspended in tetrahydrofuran (20 ml). A solution of 2.0 g (7.1 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline in tetrahydrofuran (30 ml) was dropwise added thereto at room temperature, followed by further stirring at room temperature for one hour. After the reaction liquid was cooled with ice, a solution of 1.6 g (8.4 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran (20 ml) was dropwise added thereto. After stirring for 3 hours as such, the reaction liquid was poured into a saturated aqueous solution of ammonium chloride, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.7 g of the title compound as an oil (yield 55%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[C:14]([O:16]CC)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].[OH-].[Li+].Cl>C1COCC1.CCO.O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[C:14]([OH:16])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H]1COCCN1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1COCCN1Cc1ccccc1
Temperature: 50 °C
Yield: 94 %

Procedure:
Ethyl (3R)-4-(phenylmethyl)-3-morpholinecarboxylate (D46, 2.33 g, 9.36 mmol) was dissolved in a mixture of THF/EtOH/H2O (1:1:1 45 mL) before treating with Lithium Hydroxide monohydrate (0.432 g, 10.29 mmol) and heating at 50° C. overnight. Reaction not finished. Added more Lithium Hydroxide monohydrate (0.200 g, 4.76 mmol) and left heating for a further 24 hours. Added more Lithium Hydroxide (0.100 g, 2.38 mmol) and heated for a further 6 hours. Added more Lithium Hydroxide (0.100 g, 2.38 mmol) and heated for a further 16 hours. Cooled to R.T. Reaction neutralised using 2N HCl solution. Solvent evaporated. Residue partitioned between DCM and Water. Aqueous layer extracted with 10% MeOH/DCM ×5. Combined extracts dried (MgSO4). Filtered. Solvent evaporated under reduced pressure to afford the title compound as a white foam in a 94% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)=[CH:22][N:23]=1
Reactant: CNC(=O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ccc(-c2cnc(N)nc2)cc1F
Temperature: 110 °C
Yield: 91.4 %

Procedure:
A mixture of 4-bromo-2-fluoro-N-methylbenzamide (900 mg, 3.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (710 mg, 3.2 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.1 mmol) and potassium carbonate (1.3 g, 9.7 mmol) in toluene (6.0 mL) and ethanol (3.0 mL) and water (3.0 mL) was heated at 110° C. for 2 hours. After cooling to RT, the reaction mixture was quenched with water and extracted with diethyl ether. The solid was filtered and washed with water and diethyl ether to afford the desired product (720 mg).
Reaction SMILES: [CH3:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][N:15]=1)([CH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:3](=[O:6])[CH:4]=[CH2:5].C(O)C.O1CCCC1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36]=[O:37]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][N:15]=1)([CH2:7][CH:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:3](=[O:6])[CH2:4][CH2:5][C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=1)=[O:37]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(C)(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(C(C)(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)nc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 4-methyl-4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (77.8 mg) in a mixed solvent of ethanol (0.6 mL) and tetrahydrofuran (0.6 mL) were added pyridine-2-carbaldehyde (48.5 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (6.9 mg) and triethylamine (14.2 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60.7 mg, yield 58%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=O)=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[CH:12][N:11]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)cn1

Procedure:
11.9 g. of o-phenylenediamine, 13.7 g. of 2-methylpyridine-5-carboxylic acid and 100 g. of polyphosphoric acid were stirred under nitrogen gas current at 180° C. to 200° C. for 4 hours. To the reaction mixture were added 800 ml. of water and then a concentrated aqueous solution of sodium carbonate to neutrality. The resulting crystals were filtered off, dried and recrystallized from acetonitrile to give 15.7 g. of colorless needles of the product (75% of theory), M.P. 265.5°-266.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:28]N1C(=O)CCC1=O>O1CCCC1>[I:28][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I

Procedure:
5-Amino-2-nitrobenzotrifluoride (16.25 g, 78.8 mmol) was dissolved in tetrahydrofuran (100 mL) and methanol (100 mL) and to this solution was added p-toluenesulfonic acid (0.18 g, 0.95 mmol) and N-iodosuccinimide (17.8 g, 78.8 mmol). The solution was stirred all day. N-iodosuccinimide (0.78 g, 3.47 mmol) and p-toluenesulfonic acid (0.2 g, 1.05 mmol) were then added and the solution stirred overnight at room temperature under nitrogen. The solution was concentrated under vacuum to a small volume. Water (200 mL) was added to the reaction mixture and a brown solid precipitated out. The solid was filtered and washed with water, then dissolved in ethyl acetate (100 mL) and diethyl ether (60 mL). The organic solution was washed with 10% sodium thiosulfate solution (50 mL). This created an emulsion which was alleviated by adding diethyl ether and water and filtering undissolved material. The layers were separated and the organic layer was washed with 10% sodium thiosulfate solution (50 mL), water was then added to the aqueous layer and the layers separated. The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated to yield the title compound as a brown solid that was dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Yield: 11.4 %

Procedure:
N-(1-(3-Chlorophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (522 mg, 1.8 mmol), t-butyl piperazine-1-carboxylate (329 mg, 1.8 mmol), N,N-diisopropylethylamine (457 mg, 3.5 mmol) were stirred at 90° C. in dry acetonitrile (50 mL) for 24 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (95 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.06 (d, 1H), 7.33-7.21 (m, 4H), 6.15 (d, 1H), 5.58 (s, 1H), 4.53 (m, 1H), 3.43 (m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 1.63 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C23H29ClN4O4: 460.19; Observed: 483.3 (M++Na).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:47])([F:48])[C:40]([F:45])([F:46])[C:41]([F:42])([F:43])[F:44])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A solution of ethyl 10-[(3RS,4RS)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (0.5 g, 0.67 mmol) in dichloromethane (10 mL) was cooled to −78° C. To this solution, a solution of boron tribromide in dichloromethane (1M, 5.37 ml) was slowly added dropwise, and the resulting mixture was stirred for 1 hour. The reaction vessel was then transferred to an ice-bath and the reaction mixture was further stirred for 3 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (0.4 g, Yield 84%) as a foam.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[CH2:9]([Mg]Br)[CH3:10]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([OH:8])[CH2:9][CH3:10])[O:4][N:3]=1
Reactant: Cc1cc(C=O)on1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)no1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methylisoxazole-5-carbaldehyde (0.801 g, 7.21 mmol) in 10 mL of THF at −78° C. was added ethylmagnesium bromide (3.60 mL, 10.81 mmol) slowly. The reaction mixture was stirred at −78° C. for 2 h, then quenched with saturated aq. NH4Cl solution, and extracted with ether (3×80 mL). The combined organic layers were dried over Na2SO4 filtered and the filtrate was evaporated to provide the crude product. The crude product was purified by chromatography on silica gel, eluting with 10 to 60% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI) m/z=142.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.Cl.Cl.[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].COC(OC)OC>ClCCCl.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([CH:21]4[CH2:23][CH2:22]4)[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2cc(CN3CCN(C4CC4)CC3)sc2n1
Yield: 61.5 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (254 mg), 1-cyclopropyl-piperazine di-HCl (264 mg), sodium triacetoxyborohydride (619 mg) and trimethylorthoformate (968 μL), was stirred in anhydrous 1,2-dichloroethane (25 mL) for 12 hours at room temperature, then diluted with dichloromethane (50 mL), and washed with 50% sodium bicarbonate solution. The organic phase was dried (MgSO4) and the solvents removed in vacuo to give a residue which was purified using flash silica chromatography to yield the title compound (217 mg) as a buff solid.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:28])[N:11]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])[CH2:17][CH2:16]2)[CH3:12])=[CH:5][CH:4]=1.C1(=O)OC(=[O:35])C2=CC=CC=C12.OO.NC(N)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC.O>[CH2:26]([N+:22]([CH2:23][CH2:24][OH:25])([CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH2:14][CH2:13][N:11]([CH3:12])[C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:30])[F:1])=[CH:4][CH:5]=2)=[O:28])[CH2:16][CH2:17]1)[O-:35])[CH3:27]
Reactant: CCN(CCO)C[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C1OC(=O)c2ccccc21
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC[N+]([O-])(CCO)C[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 702 mg (1.63 mmol) [trans-(2-(4-{[ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, 256.6 mg (1.8 mmol) of phthalic anhydride and 335 mg (3.54 mmol) of Hydrogen peroxide•Urea adduct in 7 ml of CH2Cl2, was stirred for two days at RT. Additional 100 mg (1.06 mmol) of Hydrogen peroxide•Urea adduct and 50 mg (0.34 mmol) of phthalic anhydride were added to the reaction mixture. After another 3 h at RT, 10 ml of aqueous saturated NaHCO3 were added. After stirring for 10 min at RT, the reaction-mixture was taken up in ether/water. The ether phase was dried and evaporated under reduced pressure. The residue was chromatographed on silica gel with a 9:1 v/v mixture of methylenchloide/methanol as eluent giving 449 mg (62%) of pure rac-trans-ethyl(2-hydroxyethyl)({4-[2-(methyl{[4-(trifluoromethyl)phenoxy]carbonyl}amino)ethyl]cyclohexyl}methyl)ammoniumolate, MS: 447 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][CH:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Product: Clc1nccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
53.0 g (236, mmol) of 6-bromo-isoquinoline 2-oxide (4) were heated in 400 ml of POCl3 under reflux conditions in two portions. After 4 h, the reaction was cooled to room temperature and poured carefully on ice with mechanical stirring. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated, which gave 42.8 g of the title compound, which was used without further purification. Rt=1.64 min (Method C). Detected mass: 242.1/244.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O.[O-]CC.[Na+].Cl>C(=O)(OCC)OCC.C(O)C>[S:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CCCSc1ccccc1C=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: CCOC(=O)C1=Cc2ccccc2SCC1
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Ethyl 4-(2-formylphenylthio)butyrate (537 mg) was dissolved in 11 ml of diethyl carbonate and a 20% sodium ethoxide solution (1 ml) in ethanol was dropped at room temperature. Stirring was conducted at room temperature for 2 hours. During cooling in ice, 4 ml of a 1N hydrochloric acid was added. Extraction with 10 ml of ethyl acetate was conducted. The organic layer was washed with 20 ml of water three times. After drying with anhydrous sodium sulfate, the mixture was concentrated. The concentrated matter was purified by silica gel chromatography (toluene). The resulting effective fractions were concentrated to yield ethyl 2,3-dihydro-1-benzothiepine-4-carboxylate (352 mg, Yield 71%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[CH:6]=[CH:5]2.IC1C=C2C(=CC=1)N(C)C(=O)C=C2.C(I)C>CI>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:14])[CH3:13]
Reactant: CCn1c(=O)ccc2cc(I)ccc21
Agent: Cn1c(=O)ccc2cc(I)ccc21
Solvent: CI
Solvent: CCI
Product: CCn1c(=O)ccc2ccccc21

Procedure:
The 1,2-dihydro-6-iodo-1-ethylquinolin-2-one used as a starting material was obtained using a similar procedure to that described in the portion of Example 1 which is concerned with the preparation of the starting material 1,2-dihydro-6-iodo-1-methylquinolin-2-one, except that ethyl iodide was used in place in methyl iodide. There were thus obtained in turn 1,2-dihydro-1-ethylquinolin-2-one, m.p. 52°-54° C., and the required starting material as an oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.[Cl-].[NH4+]>CO>[CH3:36][C:33]([CH3:34])([CH3:35])[C:32](=[O:37])[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:11]3[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=3)=[C:14]([CH3:39])[CH:15]=2)([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:25][C:26]=1[CH3:38]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.3 mL) was added to a solution of [5-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 105-(1); 52.8 mg, 0.10 mmol) in methanol (1.7 mL), and the mixture was stirred for two hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (10% methanol/dichloromethane) to give the title compound (43.2 mg, 84%).