Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=3)[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[CH:33]/[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[N:25]=[C:24]2[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)[CH3:14]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(C=O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2c(c1)c(-c1cccc(F)c1)nn2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.11 ml ethyl diethylphosphonoacetate in 5 ml N,N-dimethylformamide was added 20 mg of sodium hydride (60% oily) under ice-cooling, and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 150 mg of tert-butyl 3-(3-fluorophenyl)-5-formyl-1H-1-indazolecarboxylate in 1 ml N,N-dimethylformamide, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.16 g of tert-butyl 5-[(E)-3-ethoxy-3-oxo-1-propenyl]-3-(3-fluorophenyl)-1H-1-indazolecarboxylate as a colorless oil. This product was dissolved in 2 ml of tetrahydrofuran, 0.1 ml of 5 N hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 0.14 g of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([F:13])=[C:6](F)[C:3]=1[CH2:4][OH:5].[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(N(CC)CC)C>C(O)C.O>[F:13][C:7]1[C:6]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:25][CH2:24]2)=[C:3]([C:2]([F:1])=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)[CH2:4][OH:5]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(CO)c1F
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g) in ethanol (64 ml) and water (7 ml) is added a mixture of 4-ethoxycarbonylpiperazine (11 g), triethylamine (12.5 g) and ethanol (18 ml) at one time. The mixture is stirred at room temperature overnight, and the resulting precipitates are separated by filtration. The crystals are washed with a small amount of diethyl ether and recrystallized from ethanol to give 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (8.7 g), as yellow needles, m.p. 147°-149° C.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH2:22])=[N:17][CH:16]=[CH:15]3)[CH2:7][CH2:6]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.O>[CH2:23]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([NH2:22])=[N:17][CH:16]=[CH:15]3)[CH2:7][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nccc2cc(OC3CCNCC3)ccc12
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Nc1nccc2cc(OC3CCN(Cc4ccccc4)CC3)ccc12
Reaction time: 2 h

Procedure:
A drop of glacial acetic acid was added to a solution of 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (20 mg, 0.082 mmol) in N, N-dimethylformamide (0.5 ml), followed by addition of benzaldehyde (20 mL). The mixture was then treated with sodium triacetoxyborohydride (50 mg) and shaken for 2 h. Water (0.5 ml) was added, the mixture was stirred overnight and then purified by prep-HPLC to give 6-(1-benzyl-piperidin-4-yloxy)-isoquinolin-1--ylamine (28 mg), El-MS: m/z=334.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:15])=[CH:8]2.[OH-].[Na+]>>[Br:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([CH2:4][C:3]([OH:16])=[O:2])=[CH:14][CH:13]=2
Reactant: COC(=O)Cc1ccc2ncc(Br)cc2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of (3-bromo-quinolin-6-yl)-acetic acid methyl ester (14.8 g, 52.8 mmol) and aqueous 2 N NaOH (80 ml, 160 mmol) was heated under reflux for 1.5 hours until reaction mixture became clear. After cooling down to room temperature the reaction mixture was washed with dichloromethane then the water layer was acidified with concentrated hydrochloric acid to pH 4. A white precipitate was filtered off the stirred in refluxing methanol, filtered and dried in vacuo to give the product title compound as a white solid (10.3 g, 74%). (300 MHz, DMSO-d6): 12.52 (b, 1H), 8.91 (d, 1H), 8.69 (d, 1H), 7.99 (d, 1H)), 7.82˜7.70 (m, 2H), 3.80 (s, 2H). ES-MS m/z: 266 (M+H+).
Reaction SMILES: O.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+].[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C([O-])=O>C(Cl)Cl>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:28][C@@H:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]2[NH2:29])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
1-Benzyl-3-piperidone hydrochloride monohydrate (5.93 g, 26.3 mmol) was partitioned between a saturated aqueous NaHCO3 solution (30 ml) and CH2Cl2 (50 mL). The organic layer was separated and dried over Na2SO4 and filtered. The filtrated was collected and (1R,2R)-cyclohexane-1,2-diamine (3 g, 26.3 mmol) was added followed by sodium triacetoxy borohydride (8.35 g, 39.4 mmol). The reaction was stirred at rt overnight. After this time, the reaction was quenched with water (2 ml). The resulting solution was washed with saturated aqueous NaHCO3 (50 ml) and saturated NaCl (50 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified by RP Prep-HPLC. The desired fractions containing the product were concentrated to give the product, (1R,2R)—N1-(1-benzylpiperidin-3-yl)cyclohexane-1,2-diamine (3.01 g, 10.47 mmol, 40% yield) as a trifluoroacetate salt and as a white solid. 1H NMR (500 MHz, MeOH-d3) δ ppm 7.54-7.36 (m, 5H), 4.27-3.99 (m, 2H), 3.24-2.94 (m, 3H), 2.69 (d, J=9.90 Hz, 2H), 2.46-2.27 (m, 1H); 2.25-2.02 (m, 2H); 2.03-1.83 (m, 2H); 1.83-1.62 (m, 4H); 1.47-1.19 (m, 4H); 1.05 (d, J=11.55 Hz, 1H). 13C NMR (126 MHz, MeOH-d3) δ ppm 132.27, 130.75, 130.25, 62.31, 58.81, 56.46, 53.57, 32.76, 31.33, 25.99, 25.73, 25.40
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:4]([NH:6][CH3:7])=[O:5].[C:21](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:21][O:1]/[N:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:4]([NH:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 94.4 %

Procedure:
To E-2-hydroxyimino-N-methyl-2-(2-phenoxyphenyl)acetamide (10.00 g, 0.037 mole) were added acetone (200 ml), potassium carbonate (15.34 g, 0.111 moles) and dimethylsulfate (9.33 g, 0.074 moles) and the mixture was stirred at room temperature for 9 hours. After completion of the reaction, the reaction mixture was filtered, washed with acetone and concentrated under reduced pressure. The oil thus obtained was dissolved in toluene (50 ml) and to this was added an aqueous 1N sodium hydroxide solution (50 ml), followed by stirring at room temperature for 30 minutes. The mixture was extracted with toluene, washed with water and concentrated, and then the resulting residue was recrystallized (methanol/water) to obtain E-2-methoxyimino-N-methyl-2-(2-phenoxyphenyl)acetamide (9.93 g, yield: 94.4%) as colorless crystals (melting point: 81.5°-83° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:31][NH2:32]>C(Cl)Cl>[OH:31][NH:32][C:13](=[O:14])[CH2:12][CH:11]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(CCCCc1ccccc1)Sc1ccccc1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(CC(CCCCc1ccccc1)Sc1ccccc1)NO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7-Phenyl-3-phenylsulfanylheptanoic acid (2 g; 6.5 mmol) is dissolved in CH2Cl2 (20 mL) and cooled to 0° C. Oxalyl chloride (1.1 mL, 13 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 20° C. for 2 hours. The reaction is then concentrated in vacuo and azeotroped with CH2Cl2. The resulting oil is dissolved in CH2Cl2 (20 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (1.7 g, 16 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (100 mL) and 1 N HCl (50 mL), the organic layer is then separated and washed with water (40 mL), dried (MgSO4) and concentrated in vacuo to yield 7-phenyl-3-phenylsulfanylheptanoic acid hydroxyamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([OH:12])[C:5]=2[C@@H:4]2[CH2:18][C:19]([CH3:22])=[CH:20][CH2:21][C@@H:3]12.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:5]=2[C@@H:4]2[CH2:18][C:19]([CH3:22])=[CH:20][CH2:21][C@@H:3]12
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C)C[C@@H]21
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C)C[C@@H]21
Yield: 77 %

Procedure:
A mixture of 1.73 g (5.50 mmol) of (6aR-trans)-6a,7,10,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, 10 ml of dimethylsulfoxide, 3 ml of ethyl 4-bromobutyrate and 1.73 g of potassium carbonate was degassed and then heated under reflux under argon over night. The reaction was cooled, diluted with 250 ml of water and extracted with ether. The extracts were passed over a column of silica gel, and the fractions containing the intermediate ester were combined and concentrated under vacuum. The residue was dissolved in 100 ml of methanol, the solution was heated to boiling and 20 ml of water, followed by 2.2 g of sodium carbonate, was added. The mixture was heated under reflux for 3 hrs. The methanol was evaporated under vacuum, and the aqueous residue was acidified with hydrochloric acid and extracted with dichloromethane. The extracts were concentrated, and the residue was dissolved in hexane and adsorbed onto silica gel. Elution with 15% ethyl acetate in benzene, followed by evaporation, gave 1.70 g (77%) of (6aR-trans)-4-[(6a,7,10,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid as a colorless oil: ir (CHCl3) 1710 cm-1 ; uv max (C2H5OH) 225 nm (infl) (ε17,830), 274 (1090), and 282 (1120); nmr (CDCl3) δ11.3 (br, CO2H), 6.20 and 6.20 (two sharp d, H-2 and H-4), 5.41 (m, H-8), 4.01 (t, OCH2C), 3.18 (m, H-10a), 2.59 (t, ArCH2C), 2.48 (t, CCH2CO), 1.69 (s, 9-CH3), 1.34 and 1.06 (two s, 6,6-diCH3), and 0.87 (t, ω-CH3); mass mol wt 400; [α]D25° -195.3° (c 1.104, CHCl3).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Solvent: C1CCOC1
Product: CN1CCC(NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (252 mg, 1.26 mmol) and 1-methyl-4-piperidone (0.16 mL, 1.38 mmol) in THF (10 mL) MP-(OAc)3BH resin (Argonaut; 2.33 mmol/g; 1.35 g, 3.15 mmol) was added and the reaction mixture was agitated at room temperature for 24 hours. Then, the reaction mixture was filtered and concentrated in vacuo to afford (R)-3-[(1-methyl-piperidin-4-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (370 mg, 99%) as an orange oil. The product was used without further purification.
Reaction SMILES: O[CH:2]([CH:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:20]3[N:21]([CH:25]=[CH:26][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>N1C=CC=CC=1.C(OC(=O)C)(=O)C.ClCCl>[CH:2](=[C:8]1[O:12][C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:20]3[N:21]([CH:25]=[CH:26][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)C1OC(=O)N(CCCCOc2cccn3ccnc23)C1=O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC=C1OC(=O)N(CCCCOc2cccn3ccnc23)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 386 mg (0.99 mmol) of 5-(1-hydroxyhexyl)-3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]oxazolidine-2,4-dione in 8 ml of pyridine, 4 ml of acetic anhydride was added, followed by stirring at room temperature for 2 hours and then at 90° C. for 21 hours. The mixture was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate/hexane=4/1→ethyl acetate) to yield 79.2 mg (22%, yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:21][CH3:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:23]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:23])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[O:21][CH3:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nc3ccccc3c(OC)c2CC1
Reactant: OO
Product: CCOC(=O)N1CCc2c(OC)c3ccccc3[n+]([O-])c2CC1
Yield: 15 %

Procedure:
11-Methoxy-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester-6-oxide was prepared from 11-methoxy -1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide analogous to Example 163. Yield: 15% of theory; m.p. 135° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:19][C:20]1[C:25]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:18]=[CH:17][C:5]=4[N:6]=3)=[CH:15][CH:14]=2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Oc1ccc(Nc2nc3ccc(F)cc3s2)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc2nc(Nc3ccc(Oc4nccnc4Cl)cc3)sc2c1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol (7.5 g, 0.028 mol) and 2,3-dichloropyrazine (5.0 g, 0.034 mol) in DMSO (35 mL) was added cesium carbonate (11.0 g, 0.034 mol). The mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT and diluted with water (350 mL). The aqueous layer was extracted with EtOAc (4×300 mL). The combined organic extract was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (silica 100-200 mesh; 30-60% ethyl acetate in hexane) to give N-(4-(3-chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine as a white solid. [M+H]=372.8. IC50 (uM) +.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A suspension of 1.30 g (3.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 13 ml of N,N-dimethylformamide was treated with 1.24 g (0.017 mol) of diethylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 39:1 as the eluent. The product was recrystallized from ether/n-hexane. There was obtained 1.3 g (91%) of 7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 140°-144° (dec.).
Reaction SMILES: COC[O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1.Cl.[Na+].[Cl-].O>O1CCCC1.C(OC)(C)(C)C>[OH:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([CH2:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7]1
Reactant: COCOC[C@@H]1CCC[C@H](COCC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)COC[C@H]1CCC[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
1.9 g of tert-butyl [cis-3-(methoxymethoxymethyl)cyclohexylmethoxy]-acetate are dissolved in 10 ml of tetrahydrofuran, 5 ml of conc. HCl are added and the mixture is stirred at room temperature for 2 h. 10 ml of sat. NaCl solution, 10 ml of water and 30 ml of methyl tert-butyl ether are then added, the phases are separated and the aqueous phase is extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. Flash chromatography on silica gel (heptane/ethyl acetate 3/1) gives 600 mg of tert-butyl (cis-3-hydroxymethyl-cyclohexylmethoxy)acetate as a colorless oil (TLC (heptane/ethyl acetate 2/1): Rf, starting material=0.68, Rf, product=0.18). 260 mg of this are dissolved in 5 ml of dimethylformamide, and 170 mg of tert-butyidimethylsilyl chloride are added. The solution is then cooled to 0° C., and 160 mg of imidazole are added. The solution is stirred at room temperature for 15 h, and 20 ml of sat. NaCl solution, 10 ml of water and 30 ml of methyl tert-butyl ether are then added. The phases are separated and the organic phase is washed with sat. NaCl solution, dried over MgSO4 and concentrated. This gives 350 mg of tert-butyl [cis-3-(tert-butyldimethyl-silanyloxymethyl)cyclohexylmethoxy]acetate as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([S:12][CH3:13])(=[S:11])[CH2:9][CH3:10].C(O[C@H:18]1[NH:21][C:20](=[O:22])[C@@H:19]1[C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH3:24])(=O)C.Cl>C(#N)C.[Cl-].[Zn+2].[Cl-].ClCCl>[Si:26]([O:25][C@@H:23]([C@@H:19]1[C@@H:18]([C@H:9]([C:8]([S:12][CH3:13])=[S:11])[CH3:10])[NH:21][C:20]1=[O:22])[CH3:24])([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28]
Reactant: CCC(=S)SC
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a suspension of anhydrous zinc chloride (45.3 g) in acetonitrile (450 ml) cooled to 0° C. was added triethylamine (101 g). After stirring for 30 minutes at 0° C., the solution was cooled to -35° C. and a mixture of methyl dithiopropionate (20.0 g) and (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-oxoazetidine (23.9 g) in acetonitrile (90 ml) was added thereto. The reaction mixture was stirred at -20° C. for 2 hours, warmed to 0° C., and additionally stirred for 30 minutes at 0° C. The mixture was poured into a stirred mixture of dichloromethane (800 ml) and 1N hydrochloric acid (1000 ml). The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and brine, and dried. The solution was concentrated under reduced pressure and the solid residue was washed with n-hexane to afford (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine (20.1 g) as a yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Fc1ccc2c(c1)NCC2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(F)cc43)c2cc1OC

Procedure:
To 6-fluoroindoline (274 mg, 2.0 mmol) in dry i-PrOH (10mL) was added 4-chloro-6,7-dimethoxy-quinazoline (225 mg, 1.0 mmol). The mixture was refluxed for 16 hours under an atmosphere of dry N2(g) and then the solvent was removed in vacuo. The residue was partitioned between CHCl3 and 1M NaOH, and the organic phase was washed with brine, dried over Na2SO4(g) and concentrated in vacuo. The residue (535 mg) was purified by flash chromatography on silica using 80%EtOAc/CH2 Cl2 to yield 4-(6-fluoro-2,3-dihydro-indol-1-yl)-6,7-dimethoxyquinazoline as its free base (293 mg) (GC/MS: 325 (M+); LC-MS: 326 (MH+); anal. RP18-HPLC RT: 4.37 min.).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[C:13]([O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O[Li].O>C1COCC1>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[C:13]([O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OC(=O)[C@@H]2CCCC[C@@H]2c2ccccc2)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(=O)[C@@H]2CCCC[C@@H]2c2ccccc2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(cis-2-phenyl- 1-cyclohexanoyloxy)-2-methoxybenzoate (230 mg, 0.64 mmol) in THF:H2O (5 mL:1 mL) was added LiOH.H2O (113.5 mg, 2.7 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 90:10 CH2Cl2 :MeOH(NH3) and eluted with same. The solvent was removed under reduced pressure to afford 4-(cis-2-phenyl-1-cyclohexanoyloxy)-2-methoxy-benzoic acid as a foam.