Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])=[O:7].[N-:20]=[N+:21]=[N-:22].[Li+]>CS(C)=O>[N:20]([CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[CH3:16])=[O:7])=[N+:21]=[N-:22]
Reactant: Cc1cccc(NC(=O)c2cccc(CCl)c2)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1cccc(NC(=O)c2cccc(CN=[N+]=[N-])c2)c1C
Reaction time: 3 h

Procedure:
To solution of 19 (1.0 g) in dimethylsulfoxide was added lithium azide (0.20 g). The resulting solution was stirred for 3 h, partitioned between ethyl acetate and water. The ethyl acetate layer was several times with water, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to obtain the product. NMR (300 MHz, DMSO-d6) δ 10.0 (1H, s), 7.95 (2H, s), 7.55 (2h, m), 7.08 (3H, s), 4.55 (2H, s), 2.26 (3H, s), 2.07 (3H, s).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1>O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([C:10]([CH3:11])=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ncc(C(C)=O)n1Cc1ccccc1Cl
Reaction time: 17 h
Yield: 59.2 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole (1.07 g, 3.65 mmol), activated maganese dioxide (6 g) and toluene (75 mL) was heated at 90° to 100° C. under a slight vacuum with a Dean-Stark water separator for 17 hours. The inorganics were filtered, the concentrated filtrate was applied to a flash silica gel column, and the product was eluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].O.Cl[C:13]([O:15][CH2:16][CH2:17][CH2:18][Cl:19])=[O:14]>O1CCOCC1.C(OCC)(=O)C>[NH:10]=[C:8]([NH:9][C:13](=[O:14])[O:15][CH2:16][CH2:17][CH2:18][Cl:19])[S:7][CH3:6]
Reactant: O=C(Cl)OCCCCl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSC(=N)NC(=O)OCCCCl
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (5.56 g, 20.0 mmol) in water (50 mL) sodium bicarbonate (6.73 g, 80.0 mmol) was added and the reaction mixture was cooled to 0° C. A solution of 3-chloropropyl chloroformate (2.41 mL, 20.0 mmol) in 1,4-dioxane (20 mL) was added dropwise and it was stirred for 15 hour at room temperature. The reaction mixture was diluted with ethyl acetate (250 mL) and the organic layer was separated. It was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting crude product was purified by silica gel flash chromatography (hexane:ethyl acetate 7:3 to 1:1 eluent) to give 3-chloropropyl [imino(methylthio)methyl]carbamate (2.70 g, 64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 8.58 (br.s, 1H), 4.06 (t, 2H), 3.67 (t, 1H), 2.32 (s, 3H), 2.02 m, 2H); MS (EI) for C6H11ClN2O2S: 211 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH:5]=[C:6]([C:16](OCC)=[O:17])[C:7]([CH3:15])=[N:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:16]=[O:17])[C:7]([CH3:15])=[N:8]2
Reactant: CCOC(=O)c1cc2c(OC)ccc(OC)c2nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(OC)c2nc(C)c(C=O)cc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
A solution of ethyl 5,8-dimethoxy-2-methylquinoline-3-carboxylate (4.0 g, 0.0145 mol) in tetrahydrofuran is added to a slurry of lithium aluminum hydride (0.72 g, 0.019 mol) in ether. The reaction is stirred for 16 hours at 50° C. After cooling, the reaction is quenched by the sequential addition of water and 15% aqueous sodium hydroxide. Additional ether and anhydrous magnesium sulfate are added and the reaction mixture is filtered. The product is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant. The resulting alcohol (1.50 g) is dissolved in methylene chloride and added to a slurry of pyridinium chlorochromate in methylene chloride. The resulting solution is stirred for 3 hours at room temperature. Diatomaceous earth is added, the reaction mixture is diluted with ether and filtered. The filtrate is concentrated in vacuo and the product purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (0.10 g, 5%) as a yellow solid, identified by IR and NMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH:15]1([C@H:18]([NH2:20])[CH3:19])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:20][C@@H:18]([CH:15]3[CH2:17][CH2:16]3)[CH3:19])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C1CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 474.3 mg, 1.728 mmol), (R)-1-cyclopropylethylamine (162 mg, 1.901 mmol) and DIPEA (0.453 mL, 2.59 mmol) in NMP (Volume: 5 mL) was heated to 100° C. for 4 hr. The reaction was cooled and 10 mL of water was added and the resulting mixture was stirred for 10 minutes. The solid was collected by vacuum filtration and dried to afford the title compound (470 mg, 80%). HPLC (Method N): retention time=3.258 min. LC/MS (M+H)+=325.1. 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.60 (dd, J=1.8, 0.7 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 4.12-3.73 (m, 1H), 1.39 (d, J=6.4 Hz, 3H), 1.18-1.04 (m, 1H), 0.64-0.49 (m, 2H), 0.41-0.27 (m, 2H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([N:8]2[CH2:9][CH2:10][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)=[O:17]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(c2ccc(C=O)cc2)CC1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a solution of 4-acetamidopiperidine (2.5 g, 17.5 mmol) in DMF (10 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol) and K2CO3 (2.9 g, 21.2 mmol). The reaction was heated at 120° C. for 4 hours, diluted with H2O, and extracted with EtOAc. The organics were washed sequentially with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (3.1 g, 92%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:33])([F:32])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH3:27])[CH:18]=[C:17]([C:28]([F:31])([F:30])[F:29])[N:16]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>COCCOC.O>[F:33][C:14]([F:32])([F:13])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26][CH3:27])[C:18]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:17]([C:28]([F:31])([F:30])[F:29])[N:16]=1
Reactant: CCOC(=O)c1c(OC)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
To a cold (-78° C.) solution of NDA, from 0.02 mol (2.8 ml) of diisopropylamine, 0.0208 mol of n-BuLi, and 30 ml of DME was added a solution of 4.65 g (0.015 mol) of product of Example 4 in 20 ml of DME. The resulting greenish solution was stirred at -78° C. for 10 minutes and treated with 2.7 ml (0.035 mol) of ethyl chloroformate. The reaction mixture was warmed to room temperature in 40 minutes, then poured into a mixture of 20 ml of concentrated HCl and 50 ml of water. The mixture was extracted with ether (200 ml). The ether extract was dried and concentrated. The residue was kugelrohr distilled at 13 Pa. The earlier fraction (pot temperature 50°-65° C.) was discarded. The later fraction (pot temperature 90° C.) was an oil (5.47 g) which was crystallized from hexane at low temperature to give 4.4 g (75%) of product; mp 46.5°-47.5° C.
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].[CH2:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCOCC>[Cl:1][C:2]1([Cl:7])[C:3](=[O:4])[CH2:8][C:9]21[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)C2(Cl)Cl)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
28.42 mL (254.65 mmol) of trichloroacetyl chloride dissolved in 70 mL of dimethoxyethane are added dropwise, at 0° C., to a mixture containing 7.98 g (47.16 mol) of tert-butyl 3-methyleneazetidine-1-carboxylate (WO 2008/124 085) and 36.48 g (282.94 mmol) of zinc-copper amalgam suspended in 200 mL of ether. The reaction medium is stirred at room temperature for 12 hours. The mixture is then poured portionwise into a sodium carbonate solution at 0° C. The solution obtained is filtered through Celite and rinsed thoroughly with water and ether. The aqueous phase is then separated out and extracted several times with ether. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the product obtained, in the form of a brown oil, is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[OH:23])=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:42]Cl)[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH2:42][O:23][CH:9]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:14][CH:13]3[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:10]2[CH2:11][CH2:12]3)[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(O)C(c1ccc(F)cc1)C2
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Product: CC(C)(C)OC(=O)N1C2CCC1C(OCc1cc(OCc3ccccc3)c3ccccc3c1)C(c1ccc(F)cc1)C2

Procedure:
Alkylation of tert-butyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylate with 1-benzyloxy-3-chloromethyl-naphthalene (Example 19) analogously to the procedure described in Example 1 (g) yielded tert-butyl (1RS,2RS,3RS,5SR)-2-(4-benzyloxy-naphthalen-2-yl-methoxy)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylate as a colourless solid; MS: 568 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C@@H:13]2[C@@H:8]([C:9]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6]1.[CH2:20]([N:22]([CH2:25]C)[CH2:23]C)C.CC(N(C)Cl)=[O:29].O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:20][N:22]([CH3:25])[C:23](=[O:29])[O:18][C:14]1[C:10]2[CH2:11][CH2:12][C@H:13]3[C@H:8]([CH2:7][CH2:6][N:5]3[CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: CC(C)CCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Reactant: CC(=O)N(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCN1CC[C@@H]2c3cccc(OC(=O)N(C)C)c3CC[C@@H]21
Yield: 84.3 %

Procedure:
2.71 g (0.01045 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(3-methyl-butyl)-1H-benzo[e]indol-6-ol were dissolved in 60 ml of toluene. 2.1 g (2.90 ml, 0.0208 mol) of triethylamine and 128 mg (1045 mmol, 0.1 eq.) of 4-dimethylaminopyridine were added thereto in succession and then 1.92 ml (0.02088 mol) of dimethyl chloroformamide were added dropwise thereto. The mixture was boiled under reflux for 2 hours, then cooled, poured into water and extracted with toluene. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated. By chromatography of the residue over silica gel with ethyl acetate there were obtained 2.91 g (84%) of oily rac-cis-2,3,3a, 4,5,9b-hexahydro-3-(3-methyl-butyl)-1H-benzo[e]indol-6-yl dimethylcarbamate.
Reaction SMILES: [CH2:1]([O:3][C:4]1(CCNC)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH3:2].[CH2:23]([N:25]([CH2:28]C)CC)[CH3:24].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH2:24][CH2:23][N:25]([CH3:28])[S:31]([CH3:30])(=[O:33])=[O:32])[C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH3:2]
Reactant: CCOC1(CCNC)c2ccccc2CCc2ccccc21
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC1c2ccccc2CCc2c(CCN(C)S(C)(=O)=O)cccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48.5 %

Procedure:
Dissolved N-[2-(5-ethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]-N-methylamine (150 mg, 0.508 mmol) in 5 mL of dry dichloromethane. Cooled to 0° C. under a nitrogen atmosphere, and added triethylamine (0.14 mL, 0.10 g, 1.0 mmol) and then methanesulfonyl chloride (0.06 mL, 0.089 g, 0.76 mmol) dropwise via syringe. Stirred at 0° C. for 90 mins. Added water, and extracted with dichloromethane. Washed the combined organic extracts with sodium phosphate monobasic, 1N NaOH, and then saturated NaCl. Dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography eluting with 9:1 hexane:ethyl acetate. Combined appropriate fractions, and evaporated to solid. Recrystallized from ethyl acetate-hexane to give 92 mg (48% yield) of N-[2-(5-ethoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptenyl)ethyl]-N-methyl-methanesulfonamide as a white, solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([N:17]([CH3:18])[CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl) thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while cooling in a water bath and treated with 2.5 ml (0.02 mole) of 40% dimethylamine in water. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the resulting product collected ny filtration (2.6 g). Recrystallization from acetone/isopropyl ether yielded 2 g (74.1%) of fine white crystals, m.p. 96°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:11].[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[S:11][CH3:21]
Reactant: O=C(NC(=S)Nc1c(Cl)cccc1Cl)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(=O)c1ccccc1)Nc1c(Cl)cccc1Cl
Yield: 85 %

Procedure:
19.5 g (0.06 M) of N-(2,6-dichlorophenyl)-N'-benzoyl thiourea, 5.5 g (0.04 M) of ground potassium carbonate, 5.1 ml (0.08 M) of methyliodide and 200 ml of acetone are boiled in a reflux for 4 hours under energetic shaking. The acetone is distilled off. 200 ml of water are added to the residue and it is then filtered. The sediment on the filter is washed to a neutral pH. After drying 20.2 g (99% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-benzoyl-S-methylisothiourea are obtained with melting point 127-129° C. This product being recrystallized from ethyl alcohol gives the corresponding isothiourea with a melting point of 128°-130° C. and 85% yield of the theoretical one.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].COC[C:21]([Cl:23])=O>[N+](C)([O-])=O>[Cl:23][CH2:21][C:13]1[CH:12]=[C:9]([CH:8]=[CH:7][C:6]=1[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:10]=[O:11]
Reactant: CC(C)COc1ccc(C=O)cc1
Reactant: COCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(C)COc1ccc(C=O)cc1CCl
Temperature: 0 °C
Yield: 59.5 %

Procedure:
To a mixture of 4-isobutoxybenzaldehyde (6.9 g, 38.7 mmol), aluminum chloride (12.9 g, 96.8 mmol) and nitromethane (39 mL) was added methoxyacetyl chloride (4.1 mL, 44.5 mmol), with stirring at 0° C., and the mixture was stirred at the same temperature for 3 hr. After completion of the reaction, the reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (5.22 g, yield 60%) as colorless crystals. 1H NMR (CDCl3) δ: 1.08 (6H, d, J=6.9 Hz), 2.19 (1H, m), 3.89 (2H, d, J=6.0 Hz), 4.68 (2H, s), 6.98 (1H, d, J=8.4 Hz), 7.84 (1H, dd, J=2.1, 8.4 Hz), 7.91 (1H, d, J=2.1 Hz), 9.89 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH:17](O)([CH3:19])[CH3:18].[Cl-].[Na+]>CN(C)C=O.S(Cl)(Cl)=O>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([O:9][CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: Cc1nnsc1C(=O)O
Reactant: CC(C)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1nnsc1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To 1.0 g (6.9 mmoles) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid were added 40 ml of thionyl chloride and 2 drops of dimethylformamide at room temperature, and the resulting mixture was refluxed with heating or 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the excess thionyl chloride was distilled off and 7.0 ml of tetrahydrofuran was added to the residue. Then, 2.1 g (21 mmoles) of triethylamine and 0.83 g (13.8 mmoles) of isopropanol were added and the resulting mixture was stirred at room temperature for 18 hours, after which a saturated aqueous sodium chloride solution was added. The desired compound was extracted with ethyl acetate and the organic layer was washed successively with diluted hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain 1.0 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([O:16][CH3:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C[O-].[Na+].[CH:24](OCC)=O.Cl>COCCOC.O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:18]([OH:20])=[CH:19][CH:24]=[N:1]2)=[CH:4][C:5]=1[O:16][CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC=O
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To a solution of 1-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HCl. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7-benzyloxy-6-methoxy-quinolin-4-ol. 1H NMR (CDCl3): 10.7 (1H, br), 7.703 (1H, s), 7.493-7.461 (1H, t), 7.431-7.413 (2H, br d), 7.372-7.333 (2H, t), 7.296-7.283 (1H, d), 6.839 (1H, s), 6.212-6.193 (1H, d), 5.212 (2H, s), 3.965 (3H, s). LC/MS (M+1=282).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:7][C:8](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[N:2]1.[OH:37]O.[Li+].[OH-].Cl>C1COCC1.O>[O:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:7][C:8]([OH:9])=[O:37])=[N:2]1
Reactant: O=C(C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-4-benzyl-3-((R)-3-(3-(benzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)oxazolidin-2-one (94.1C) (0.558 g, 1.16 mmol) in THF (12 mL) was cooled to 0° C. H2O2 (30% w/w, 0.50 mL) was added, and was followed by addition of LiOH, monohydrate (0.0643 mL, 2.31 mmol) in water (4 mL). The resulting mixture was stirred at 0° C. for 2 hours. The organic solvent was blown away by nitrogen, and the aqueous mixture was acidified with 1N HCl to pH 3-5. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4. After removing solvent, crude product (94.1D) (491 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][C:13]([C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH2:25])[CH:24]=1)=[CH:12]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][C:13]([C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([NH:25][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH:24]=1)=[CH:12]2
Reactant: O=Cc1cccs1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
2-Thiophenecarboxaldehyde (0.112 g, 1.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.29 g, 1.06 mmol) in methylene chloride (125 mL), followed by acetic acid (0.1 g, 1.67 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.23 g, 1.09 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken and the organic layer separated. The solvent was evaporated to give a brown gum. Recrystallization from methanol/water gave the product as a brown solid (120 mg), mp 190-192° C.