Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]2[CH3:32])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH3:32])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CCCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of potassium tert-butoxide (0.65 g) in DMF (4 mL) was added dropwise a solution of 2-(benzyl{[3-chloro-5-(2-methylpiperidin-1-yl)pyrazin-2-yl]methyl}amino)ethanol (1.63 g) in DMF (4 mL) at 0° C., and the mixture was stirred for 2 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5-433% ethyl acetate/hexane) to give the title compound (1.27 g, 78%) as a pale-yellow oil.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=O)=O.O[C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:29]=[C:25]1[CH:24]=[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH:28]=[CH:27][NH:26]1
Reactant: O=c1cc(O)cc[nH]1
Reactant: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 140 °C
Yield: 37.2 %

Procedure:
A stirring suspension of benzyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.97 g, 6.30 mmol), 4-hydroxypyridin-2(1H)-one (0.50 g, 4.5 mmol, Aldrich), potassium carbonate (1.43 g, 10.6 mmol, EMD) and DMF (25 mL) was heated at 140° C. for 2.5 h and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo to a light yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 10% MeOH in CH2Cl2) to yield 550 mg of desired product as a white solid. MS (ESI) 329 (M+H).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17])([O:3][CH2:4][CH3:5])=[O:2].[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19].N1CCCCC1>C(O)C>[C:18]([C:20](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[C:9]([O:16][CH3:17])[CH:10]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]
Reactant: CCOC(=O)COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)COc1ccc(C=C(C#N)C(=O)OCC)cc1OC
Yield: 93.9 %

Procedure:
A mixture of 4-carbethoxymethoxy-3-methoxybenzaldehyde (23.8 g, 0.10 mol), ethyl cyanoacetate (11.3 g, 0.10 mol), ethanol (150 mL) and piperidine (2 mL) is heated at reflux for 4 hours. The reaction mixture is allowed to cool, and the solid is collected by filtration, washed with ethanol and dried in air. A yield of 31.3 g (93%) of product is obtained which has the following structure as supported by mass spectrometry: ##STR21## An absorption maximum at 355 nm is observed when the product is dissolved in methylene chloride.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:38][C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: O=C1CN(CCC2CCOCC2)c2nc(Br)cnc2N1
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCC2CCOCC2)CC(=O)N3)cc1
Temperature: 120 °C
Yield: 25.9 %

Procedure:
6-Bromo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.250 g, 0.733 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (0.192 g, 0.733 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.030 g, 0.037 mmol) were combined in dimethylformamide (1.0 mL). Sodium carbonate (0.311 g, 2.93 mmol) in water (0.2 mL) was added and the reaction solution was then heated in a Biotage Emrys Optimizer microwave reactor at 120° C. for 15 min. The cooled reaction solution was filtered through Celite and the filter cake was washed with ethyl acetate. Filtrate and ethyl acetate wash were combined and solvent removed under reduced pressure. The resulting material was purified using Biotage column chromatography (0-5% methanol in ethyl acetate) followed by trituration with dimethylformamide and water to afford the title compound (0.074 g, 0.19 mmol, 25%) 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.39 Hz, 2H), 7.53 (d, J=8.39 Hz, 1H), 5.04 (s, 1H), 4.16 (s, 1H), 3.82 (dd, J=11.1, 2.39 Hz, 2H), 3.61 (t, J=7.59 Hz, 2H), 3.25 (t, J=9.59 Hz, 3H), 1.70 (s, 1H), 1.66 (s, 1H), 1.58 (m, 3H), 1.44 (s, 6H), 1.25 (m, 2H); MS (ESI) m/z 397.2 [M+1]+; mp 210-212° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([N:20]1[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[O:9]1[CH:23]2[CH:24]1[CH2:25][N:20]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:21][CH2:22]2
Reactant: O=C(c1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of metachloroperbenzoic acid (12 mmole) in methylene chloride is added dropwise to a solution of 39 at 4 C. The reaction mixture is allowed to stir overnight at room temperature. It is made basic and then extracted with methylene chloride. Following work-up and flash chromatography affords 40.
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 120 °C
Yield: 12.3 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z:E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. One mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P)2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 120° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 17 percent and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 12.3 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:15][C:16]1[N:46]=[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:25]3[CH:26]=[C:27]([NH:32][C:33](=[O:45])[C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([C:43]#[N:44])([CH3:42])[CH3:41])[CH:35]=4)[CH:28]=[CH:29][C:30]=3[CH3:31])=[CH:23][N:18]2[N:17]=1.C(=O)([O-])O.[Na+]>O1CCCC1.N1C=CC=CC=1.CN(C)C=O>[C:43]([C:40]([C:36]1[CH:35]=[C:34]([C:33]([NH:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH:26]=2)[O:24][C:22]2[CH:21]=[CH:20][C:19]3[N:18]([N:17]=[C:16]([NH:15][C:6]([C:4]4[N:3]=[CH:2][O:1][CH:5]=4)=[O:8])[N:46]=3)[CH:23]=2)=[O:45])[CH:39]=[CH:38][CH:37]=1)([CH3:42])[CH3:41])#[N:44]
Reactant: O=C(O)c1cocn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)c3cocn3)nn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 1,3-oxazole-4-carboxylic acid (107 mg, 946 μmol) in tetrahydrofuran (3 mL) were added oxalyl chloride (123 μL, 1.42 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (202 mg, 473 μmol) were dissolved in pyridine (5 mL), and the mixture was stirred at room temperature for 15 hr. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→98/2), and fractions containing the desired product were concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (196 mg, 79%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[CH2:14][CH2:15][OH:16].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S]>C(O)(C)C.O>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[CH2:14][CH2:15][OH:16]
Reactant: Nc1c(CCO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Agent: [S]
Solvent: O
Solvent: CC(C)O
Product: Nc1cc([N+](=O)[O-])cc(CCO)c1N

Procedure:
To a suspension of 0.119 mole (27 g) of 2-(2-amino-3,5-dinitrophenyl)ethanol obtained in Example 1 in 67.5 ml of isopropanol to which an equal volume of water has been added, a solutionof 38.4 g of sodium sulphide nonahydrate and 5.4 g of sulphur in 10 ml of water is added dropwise at 60°-65° C. Heating is maintained for 20 minutes after the addition is complete. When the mixture is cooled, a precipitate of the expected product is obtained, and this is drained, made into a paste in water and then recrystallized from 96° strength alcohol. It melts at 172° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:20]([C:14]2[CH:13]=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[C:15]=2[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:25][CH2:26]1
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCSc1c(C(=O)NC2CCOCC2)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h
Yield: 56.5 %

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7), (160 mg, 0.5 mmol), 4-aminotetrahydropyran (61 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (174 μL, 1.0 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and volatiles removed by evaporation. The residue was purified by chromatography on silica gel (12 g silica, 0-100% EtOAc/isohexane) to give the title compound as a white solid (114 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15]C(C)=O)=[C:4]2[O:14][CH2:13][CH2:12][O:11][C:5]2=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[OH-].[Na+]>CO>[NH2:15][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[O:11][CH2:12][CH2:13][O:14][C:4]=12
Reactant: CC(=O)Nc1c(Cl)cc(C(C)=O)c2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1cc(Cl)c(N)c2c1OCCO2
Yield: 73.2 %

Procedure:
A mixture of 5'-chloro-2',3'-ethylenedioxy-4'-(methylcarbonylamino)-acetophenone (152 mg, 0.56 mmol) and sodium hydroxide (4N, 1.4 mL, 5.6 mmol) in 5 mL of methanol was heated at reflux for 3.5 hours. The mixture was concentrated by rotary evaporation and the residue was stirred into water. The residue was isolated by filtration and washed with water. Drying gave 4'-amino-5'-chloro-2',3'-ethylenedioxyacetophenone (95 mg, 0.41 mmol), m.p. 133°-136° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH3:36])([CH3:35])[C:7](=[O:34])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:35][C:6]([CH3:36])([CH:7]([OH:34])[CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:19]=2)[CH2:13][CH2:14]1)[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC(C)(C)C(=O)CN1CCN(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CC(O)C(C)(C)CCO)CC4)n3)ccc21
Reaction time: 1 h

Procedure:
90 mg (0.171 mmol) of 3,3-dimethyl-4-oxo-5-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazin-1-yl}pentanoic acid ethyl ester from step a was dissolved in 8 ml of THF. 1.71 ml (1.71 mmol) of a 1M lithium aluminium hydride solution in THF was added dropwise with ice-cooling. The mixture was stirred for a further 1 h with cooling, then stirred at room temperature and subsequently at 40° C. overnight, decomposed using a saturated sodium sulfate solution with cooling and extracted twice with EA. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, evaporated to dryness and purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: C([O:3][C:4]([C:6]([CH:14]([CH2:23][C:24]#[CH:25])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[OH:7])=[CH2:5])C.Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:14]([CH2:23][C:24]#[CH:25])[C:6]([OH:7])([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:4](=[O:3])[CH3:5]
Reactant: C#CCC(c1ccc(Cl)cc1Cl)C(O)(C(=C)OCC)c1cccnc1
Agent: Cl
Solvent: CO
Product: C#CCC(c1ccc(Cl)cc1Cl)C(O)(C(C)=O)c1cccnc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A mixture of 2.0 g of α-(1-ethoxyvinyl)-α-[2,4-dichloro-α-(2-propynyl)-benzyl]-3-pyridinemethanol (see Example 3, 1st end product), 1 ml of concentrated hydrochloric acid and 15 ml of methanol as a clear yellow solution is held at room temperature for 1 hour. Thereafter, the mixture is evaporated under reduced pressure in order to remove methanol and the residue is neutralized with saturated aqueous sodium bicarbonate solution. The aqueous mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution and evaporated. Finally, the residue is recrystallized from methylene chloride/n-hexane. There are obtained 1.8 g of 4-(2,4-dichlorophenyl)-3-hydroxy-3-(3-pyridyl)-6-heptyn-2-one, m.p. 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1COCC1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>B>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)NCC2
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
6-Chloroindole (1.0 g, 6.6 mmol) was dissolved in a solution of borane in THF (1 M, 9.83 mmol) at 0° C. and stirred for 30 min. TFA (9.83 mL) was added dropwise and the solution stirred at 0° C. for 30 min. 6 M aqueous NaOH was added until the solution was basic (pH 11). The aqueous solution was extracted with DCM (3×25 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (864 mg, 86%) as a yellow oil. 1H NMR (Me-d3-OD): 6.99 (1H, d), 6.64-6.55 (2H, m), 3.50 (2H, t), 2.95 (2H, t).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH3:7])([O-])=[O:2].C1(N=C=O)C=CC=CC=1.[C:17]([C:19]12[CH2:26][CH2:25][CH2:24][N:23]1[CH2:22][CH2:21][CH2:20]2)#[CH:18]>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:18]=[C:17]([C:19]23[CH2:26][CH2:25][CH2:24][N:23]2[CH2:22][CH2:21][CH2:20]3)[O:2][N:1]=1)[CH2:6][CH3:7]
Reactant: CCCC[N+](=O)[O-]
Reactant: C#CC12CCCN1CCC2
Solvent: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CCCc1cc(C23CCCN2CCC3)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Nitrobutane (0.705 mL, 6.66 mmol) and phenylisocyanate (1.50 mL, 13.3 mmol) were dissolved in benzene (13.5 mL) and added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (450 mg, 3.33 mmol, from step 13a). The solution was stirred at ambient temperature for 1 hour and at reflux for 5 hours. The mixture was cooled, filtered, concentrated and diluted with EtOAc. The solution was extracted with 6N HCl. The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford an amber oil (392 mg, 53%). 1H NMR (CDCl3, 300 MHz) δ0.97 (t, J=7.5 Hz, 3H), 1.61-1.92 (m, 8H), 2.15-2.26 (m, 2H), 2.55-2.69 (m, 4H), 3.13-3.20 (m, 2H), 5.96 (s, 1H); MS (CI/NH3) m/z: 221 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:26])(=[O:25])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=2)=[CH:6][CH:5]=1>C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:24])([F:22])[F:23])[CH:13]=2)(=[O:26])=[O:25])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccc(CO)cc2)cc1C(F)(F)F
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of compound iii (3.26 g, 8.06 mmol) in dry THF (50 mL), LAH pallet (0.46 g, 12.10 mmol) was added at 0° C. The resulting reaction mixture was stirred for 4 h, quenched by the addition of water (5 mL), concentrated, diluted with ethyl acetate (50 mL), and washed, in tandem, with 1N HCl, water, 10% Na2CO3 aqueous solution, and brine. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexane, 3:7) to afford 4-hydroxymethyl-N-(4-nitro-3-trifluoromethyl-phenyl)-benzenesulfonamide (iv) as light yellow solid with 71% yield. 1H NMR (300 MHz, CDCl3) δ 2.06 (br, 1H), 4.75 (s, 2H), 6.96 (br, 1H), 7.59 (d, J=10.17 Hz, 2H), 7.84 (d, J=8.19 Hz, 2H), 7.88 (d, J=8.43 Hz, 1H), 8.03 (d, J=8.43 Hz, 1H), 8.16 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13]O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.I([O-])(=O)(=O)=O.[NH:42]1[CH2:47][CH2:46][CH2:45][C@@H:44]([CH2:48][N:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:51][CH2:50]2)[CH2:43]1.CO>C(Cl)Cl.S([O-])([O-])(=O)=O.[Mg+2]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][N:42]2[CH2:47][CH2:46][CH2:45][C@@H:44]([CH2:48][N:49]3[CH2:50][CH2:51][N:52]([C:55]([O:57][CH2:58][C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)=[O:56])[CH2:53][CH2:54]3)[CH2:43]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CCCO)cc1
Reactant: O=C(OCc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCN(C(=O)OCc4ccccc4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
3-[4-(Methylsulfonyl)phenyl]propan-1-ol (4.02 g, 18.8 mmol) and Dess-Martin periodate (8.49 g, 20.0 mmol) were stirred in DCM (50 ml) at room temperature overnight. The reaction was washed with NaOH solution (1N, 3×25 ml). Sodium triacetoxyborohydide (5.28 g, 25 mmol) was added to the mixture followed by benzyl 4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxylate (3.97 g, 12.5 mmol) and magnesium sulphate (20.0 mg). The reaction was stirred at room temperature overnight then washed with water (20 ml) and dried using a phase separation cartridge. Silica was added and the solvent removed under reduced pressure to provide a cake which was added to the top of a silica column. Flash column chromatography (silica, 1%-10% MeOH:DCM) gave the title compound as a yellow oil (5.47 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=4[Cl:30])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:23]=1
Reactant: ClCc1ccccc1Cl
Reactant: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCCCc3cc(Cl)ccc32)ccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1-(3-methoxy-4-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.7 g) in dry dimethylformamide (20 ml) are added potassium carbonate (0.35 g) and 2-chlorobenzyl chloride (0.32 ml), and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and evaporated to remove the solvent. The residue is recrystallized from acetone/diethyl ether to give 7-chloro-1-[3-methoxy-4-(2-chlorobenzyloxy)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.76 g) as white powder.