Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH3:28])[C:5]2[C:6]([CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)C3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH:29][Li].O.O>CO.C(Cl)(Cl)Cl>[O:29]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[CH:27]=[C:19]1[C:6]1[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:28])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=2)[N:7]=1
Reactant: [Li]O
Reactant: COC(=O)c1ccc2nc(C3Cc4ccccc4C3)c(N(C)C3CC3)nc2c1
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(2,3-dihydro-1H-inden-2-yl)quinoxaline-6-carboxylate (95.0 mg, 0.25 mmol) in methanol (15 mL) and CHCl3 (10 mL) was added LiOH.H2O (35.0 mg, 0.83 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted pH to 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(benzofuran-2-yl)-3-(cyclopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (43.6 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14](=[O:16])[CH3:15])[C@H:10]([F:17])[C@H:9]1[C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14](=[O:16])[CH3:15])[C@H:10]([F:17])[C@H:9]1[C:18]([OH:20])=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc2ccccc2)[C@H]1F
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F

Procedure:
A solution of (2R,3S,4R)-4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (315 mg, 0.82 mmol) in methanol (2 mL) was hydrogenated with palladium on carbon 10% (88 mg, 0.82 mmol) overnight. The reaction mixture was filtered over glass fiber and was concentrated. The residue was used as was for the next step.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:15]([CH3:19])[C@H:16]([NH2:18])[OH:17])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[C:8]([CH:15]([CH3:19])[C@:16]([NH2:18])([S:21]([CH3:20])(=[O:23])=[O:22])[OH:17])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C(=O)OC(C)(C)C)[C@H](N)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)OC(C)(C)C)[C@@](N)(O)S(C)(=O)=O
Reaction time: 1 h

Procedure:
DCM (400 mL) and triethylamine (83.9 mL, 0.60 mol) were added to a flask containing (R)-2-boc-amino-propan-1-ol. The reaction mixture was cooled in an ice bath for 30 min, and methanesulfonyl chloride (37.0 mL, 0.478 mol) was added dropwise over a five min period. The resulting mixture was stirred for 1 hour, the ice bath removed, and the mixture stirred for 18 h at RT. The resulting mixture was washed with aqueous NaOH (10%), and the organic layer dried over MgSO4, filtered, and concentrated under reduced pressure to give (R)-2-boc-amino-1-methanesulfonyl-propan-1-ol (91.93 g).
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:14]([S:18]([NH2:20])=[O:19])([CH3:17])([CH3:16])[CH3:15]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH:1]1([CH2:4][S:5][C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:15]/[C:14]([CH3:17])([S:18]([NH2:20])=[O:19])[CH3:16])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(SCC2CC2)cc1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(/C=C/c1ccc(SCC2CC2)cc1)S(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[(cyclopropylmethyl)thio]benzaldehyde (5.64 g, 29.4 mmol) in THF (250 mL) was added tert-butyl sulphinamide (5.4 g, 44 mmol) and titanium(IV) ethoxide (12.6 mL, 60 mmol). The reaction mixture was stirred at room temperature for 3 d then quenched with water (250 mL) and ethyl acetate (250 mL). The mixture was stirred vigorously for 30 min then filtered through Celite, washing well with ethyl acetate. The organic phase was separated, dried (MgSO4) and concentrated to give the title compound as an oil. 1H NMR δ (360 MHz, CDCl3) δ 8.52 (1H, s), 7.74 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.4 Hz), 2.95 (2H, d, J=7.0 Hz), 1.26 (9H, s), 1.14-1.06 (1H, m), 0.66-0.60 (2H, m), 0.34-0.29 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=2.Br[C:24]([Br:27])([CH3:26])C.[C:28](=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:27][CH2:24][CH2:26][CH2:28][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1OC
Reactant: CC(C)(Br)Br
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3ccc(OCCCBr)cc3o2)cc1OC

Procedure:
This compound (61) was prepared from 3′,4′-dimethoxy-7-hydroxy-flavone, 27 (3 g, 10 mmol), dibromo propane (4 mL, 39.2 mmol) and potassium carbonate (2.8 g, 20 mmol) in dry dimethyl formamide (150 mL) using the identical procedure as described for 56. Yield 3.4 g (80%); mp 148-149° C.; MS (FAB) 419/421 (M++1); IR (KBr) 1630; 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=9.5 Hz, 1H), 7.53 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 6.99-6.95 (m, 3H), 6.68 (s, 1H), 4.24 (t, J=5.8 Hz, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.64 (t, J=6.3 Hz, 2H), 2.39 (q, J=6.1 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added phenylacetyl chloride (285 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (578 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:3](=[O:31])[NH:4][N:5]=[C:6]([O:20][CH2:21][CH2:22][S:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:40])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc(CNc2c(OCCSc3ccccc3Cl)n[nH]c(=O)c2Br)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2c(OCCS(=O)c3ccccc3Cl)n[nH]c(=O)c2Br)cc1OC
Yield: 82.5 %

Procedure:
To a solution of 0.4 g of 4-bromo-6-[2-(2-chlorophenylthio)ethyloxy]-5-(3,4-dimethoxyphenylmethylamino)-3(2H)-pyridazinone in 30 ml of dichloromethane was added dropwise a solution of 0.15 g of metachloroperbenzoic acid in 5 ml of dichloromethane at 0° C. The excess peracid was decomposed by the addition of saturated aqueous sodium thiosulfate. The mixture was diluted with dichloromethane, washed with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel to give 0.34 g of the objective compound. Yield, 83%, Melting point, 183°-185° C.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16]=2[OH:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[OH:17][C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][C:12]=1[S:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2oc3ccccc3c2O)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2oc3ccccc3c2O)n[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(3-hydroxy-benzofuran-2-sulfonyl)-pyridazine (2.7 mmol, 820 mg), conc. HCl (2 mL), and dioxane (10 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. The dried residue was extracted with EtOAc (2×20 mL). The extract was dried, filtered, and the filtrate was evaporated to a residue, which was purified by silica gel chromatography (eluent:EtOAc:n-hexanes::3:1), triturated with water (10 mL), and filtered to obtain the desired product: 6-(3-hydroxy-benzofuran-2-sulfonyl)-2H-pyridazin-3-one (35%, 284 mg); mp 186° C.-189° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.C=O.[C:18](=[O:21])([O-])[O-].[K+].[K+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:21][CH2:18][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1)[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: C=O
Agent: [K+]
Product: CCOCN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of tert-butyl (piperidin-4-ylmethyl)carbamate (7.0 g, 33 mmol) in ethanol (19 mL), paraformaldehyde (1.2 g, 39 mmol) and potassium carbonate (5.4 g, 39 mmol) were added at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was filtered and the filter cake was washed with ethanol (50 mL). The volatile components were removed by evaporation to give the title compound 8.9 g (quant.) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[I-].[Mg+2].[I-].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:25][CH3:26])=[C:16]([CH:18]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]2=[O:24])[CH:17]=1>ClCCl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:25][CH3:26])=[C:16]([CH:18]2[C:22](=[O:23])[CH:21]3[CH:20]([C:2]4([CH3:1])[O:3][C:4]3([CH3:7])[CH:5]=[CH:6]4)[C:19]2=[O:24])[CH:17]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C=CC1=O
Reactant: Cc1ccc(C)o1
Agent: [I-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C1C(=O)C2C(C1=O)C1(C)C=CC2(C)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,5-Dimethylfuran (2.3 ml, 21.6 mmol) and magnesium iodide (0.40 g, 1.4 mmol) are added to a solution of 2-(5-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione (2.0 g, 7.2 mmol) in dichloromethane (10 ml) and the mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-1,7-dimethyl-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.C1N2CCN(CC2)C1.[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])[CH2:23][CH2:22][CH2:21][CH:20]=1>C(Cl)Cl>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:35])(=[O:31])=[O:32])[CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C1=CCCC1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C2=CCCC2)n1

Procedure:
A mixture of 2-amino-4-methoxy-6-methylpyrimidine (0.45 g, 3.2 mmol), methylene chloride and DABCO (ca. 10 mg) was contacted with 2-(1-cyclopentenyl)benzenesulfonyl isocyanate in methylene chloride solution at ambient temperature. After approximately 20 minutes the product crystallized from the reaction mixture and was collected by filtration and rinsed with ether. In this manner, 0.35 g of product was obtained, m.p. 235°-236°. The infrared spectrum exhibited a carbonyl absorption at 1710 cm-1 indicating the title compound.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26][CH2:27]CCl>CS(C)=O.O>[CH:7]1([NH:13][CH2:27][CH2:26][CH:25]([O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH3:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(CCNC1CCCCC1)Oc1ccc2ccccc2c1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.28 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 5 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[3-(naphthalen-2-yloxy)-butyl]amine, solid. m.p., 94° C., (yield 0.61 gm, 92%).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.Cl[Si](C)(C)C.CO[CH:31](OC)[N:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[N:32]1([CH:31]=[N:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([C:10]4[NH:11][N:12]=[N:13][N:14]=4)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(OC)N1CCCCCC1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(N=CN3CCCCCC3)C(=O)N2C1c1nnn[nH]1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a stirred solution of 1.2 g (5 mmoles) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10 mmole) of triethylamine and 30 ml of dichloromethane, cooled to 0° C., is added 0.54 g (5 mmole) of chlorotrimethylsilane. After 15 minutes, 0.86 (5 mmole) of 1-(dimethoxymethyl)hexahydroazepine (British Patent No. 1,293,590) is added, and stirring is continued for a further 1 hour. The volatile components are removed by evaporation in vacuo, and then the residue is extracted with 25 ml of acetone. The insoluble material is filtered off, and the acetone is evaporated in vacuo to a yellow foam, which changes to a white powder on trituration with ether. This affords 1.44 g (82% yield) of 6-([hexahydro-1-azepinyl]methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorption bands at 1795 cm-1 (β-lactam), 1706 cm-1 and 1645 cm-1. The NMR spectrum (CDCl3) shows absorption bands at 8.00 ppm (singlet, 1H, N--CH=N), 5.90 and 5.60 ppm (two doublets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 5.40 ppm (singlet, 1H, C-3 hydrogen), 3.90-3.50 (multiplet, 4H, CH2 --N--CH2), 2.00-1.50 ppm (multiplet, 11H, C-2 methyl hydrogens and [CH2 ]4) and 1.20 ppm (singlet, 3H, C-2 methyl hydrogens). Examination of the product by thin-layer chromatography (0.2M NaOAc: acetone; 1:6) showed a single spot (Rf 0.23).
Reaction SMILES: [Cl-].[C:2]1([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH:42]=[CH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C=Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried 500 ml three-neck round bottom flask was equipped with a magnetic stir bar, addition funnel and nitrogen inlet connector. The flask was charged with (1-napthylmethyl)triphenylphosphonium chloride (12.07 g, 27.5 mmol) and 200 ml of anhydrous THF. Sodium hydride (1.1 g, 25 mmol) was added in one portion. The mixture became bright orange and was left to stir overnight at room temperature. A solution of 4-tert-butyl-benzaldehyde (7.1 g, 25 mmol) in anhydrous THF (30 ml) was added to the addition funnel with a cannula. The aldehyde solution was added to the reaction mixture dropwise over 45 minutes. Reaction was left to stir at room temperature for 24 hours (orange color went away). Silica gel was added to the reaction mixture and volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica gel using 5-10% dichloromethane in hexanes. The product was isolated as a mixture of cis- and trans-isomers (6.3 g, 89%) and used without separation. The structure was confirmed by 1H NMR.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1ccc(CCN2CCCC[C@@H]2CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 14 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-dimethylaminophenethyl)piperidine (452 mg, 1.72 mmol) was dissolved in 10 ml of dichloromethane. Triethylamine (226 mg, 2.26 mmol) and methanesulfonyl chloride (260 mg, 2.26 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-dimethylaminophenethyl) homo-piperidine in the form of a light yellow oil (470 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>O1CCCC1.O>[F:35][C:12]1[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([CH2:22][OH:23])[CH:20]=2)(=[O:17])=[O:18])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
To a solution of 3-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}benzoic acid (256 mg) in tetrahydrofuran (2 mL) was added a 1.9 mol/L toluene solution (0.53 mL) of borane dimethylsulfide complex at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a pale-yellow oil (yield 207 mg, 83%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
A mixture of 4-(3-chloromethylphenoxy)methyl-5-methyl-2-phenyl-1,3-oxazole (2.10 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-({3-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate as colorless crystals (2.78 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:16]N(C=O)C>>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:15])[CH2:8][CH2:9][CH2:10][C:11]=3[N:12]2[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2[nH]c3cc(F)ccc3c21
Reactant: CN(C)C=O
Product: Cn1c2c(c3ccc(F)cc31)C(=O)CCC2
Reaction time: 1.5 h

Procedure:
A solution of 7-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (1.0 g) in dry DMF (8 ml) was added dropwise to a stirred, ice-cooled suspension of pre-washed (hexane:2×10 ml) sodium hydride (78% dispersion in oil; 175 mg) in dry DMF (5 ml) under nitrogen and stirring was continued at room temperature for 1.5 h. The solution was cooled to 0°, iodomethane (0.35 ml) was added dropwise and stirring was continued at 0° for 2 h. The suspension was poured into 8% aqueous sodium bicarbonate (30 ml) extracted with dichloromethane (2×30 ml) and the combined, dried organic extracts were evaporated and dried in vacuo at 100° for 18 h to give the title compound (1.03 g) as a solid, m.p. 174°-175°.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[CH3:7][N:8]1[C:12]([S:13][CH3:14])=[N:11][N:10]=[C:9]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[OH-:21].[Na+].C(Cl)(Cl)Cl>O.C(O)(=O)C>[CH3:7][N:8]1[C:12]([S:13]([CH3:14])(=[O:1])=[O:21])=[N:11][N:10]=[C:9]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: [OH-]
Reactant: CSc1nnc(-c2cccnc2)n1C
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2cccnc2)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
KMnO4 (5 g, 32 mmol) was added to a solution of 3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine (6.0 g, 29 mmol) in H2O (40 mL) and acetic acid (100 mL). After 1 h stirring at r.t. the reaction was basified with 4M NaOH. CHCl3 was added and the mixture was filtrated through celite. The layers were separated and the water phase was washed with CHCl3. The combined organic phase was dried and concentrated to give 3.67 g (53%) of the title compound. 1H NMR: 3.59 (s, 3H) 3.99 (s, 3H) 7.52 (m, 1H) 8.02 (dt, 1H) 8.83 (dd, 1H) 8.91 (m, 1H)