Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][CH:20]1[CH2:22][O:21]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([O:16][CH2:19][CH:20]2[O:21][CH2:22]2)=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(O)cc(C)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cc(OCC2CO2)cc(C)c1OCc1ccccc1

Procedure:
Using 4.22 g of the compound of Example 15, 2.7 ml of chloromethyloxirane, 2.42 g of anhydrous potassium carbonate and 100 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 4.80 g of 1-(4-benzyloxy-3,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 4.04 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup carried out as in Example 1-A followed by purification by column chromatography (silica gel, eluted with ethyl acetate:hexane=1:1) gave 5.96 g of white crystals, m.p. 93-94° C.
Reaction SMILES: ClCCl.Cl[C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:6].[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][CH2:21]2>N1C=CC=CC=1>[C:31]([O:30][C:28]([N:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([NH:17][C:5]([O:7][C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:6])[CH:19]=2)[CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a dichloromethane (10 mL) solution of 4-nitrophenyl chloroformate (812 mg), a dichloromethane (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (1.00 g) and pyridine (0.33 mL) was gradually added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2 hours and then concentrated. The residue was vigorously stirred in a mixed solution of diisopropyl ether and water (diisopropyl ether/water). The precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (1.46 g, 88%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH3:25][O:26][C:27](OC)(C)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCOC(C)=O.ClCCl>[CH3:25][O:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(-c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
To an oven-dried flask containing a stirbar was added 4-hydroxybiphenyl (1.70 g, 10 mmol), toluenesulfonic acid (190 mg, 1.1 mmol), dichloromethane (DCM, 5 mL), and dimethoxypropane (5 mL). The solution was heated and stirred at 40° C. for 48 h. Solid NaHCO3 (200 mg) was added, followed by EtOAc (100 mL) and NaOH (1N, 20 mL). The layers were separated and the organic layer was further extracted with NaOH (1N, 12×20 mL), brine (30 mL), and was dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (385 mg, 18%) which was used without further purification. 1H-NMR (CDCl3); δ 7.56 (m, 4H), 7.44 (m, 2H), 7.34 (m, 1H), 7.14 (m, 2H), 5.24 (s, 2H), 3.54 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=1.O.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>CCOC(C)=O>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=1)=[O:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-amino-3-t-butyl-1-p-tolylpyrazole hydrochloride (300 g, 1.13 mol), water (0.9 L), EtOAc (2.1 L) and NaOH (117 g, 2.84 mol) was stirred between 5-15° C. for 30 min. To this mixture, 2,2,2-trichloroethyl chloroformate (342 g, 1.58 mol) was added over 1 h between 5-15° C. The mixture was stirred at room temperature for 2 h, and then the aqueous layer was separated from the EtOAc layer. The EtOAc layer was washed with brine (2×0.9 L) and dried over MgSO4 (60 g). The EtOAc layer was collected by filtration. To this solution, heptane was added. A part of the solution was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 409 g, 90%. 1H NMR (CDCl3) δ 7.40 (d, 2H), 7.30 (d, 2H), 6.40 (s, 1H), 4.80 (s, 2H), 2.40 (s, 3H), 1.40 (s, 9H). MS (EI) m/z 404 (M+).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH:12]1[NH:16][CH:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:14]2([CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[S:13]1)[C:5]([O:7]C(C)(C)C)=[O:6]>[N+](C)([O-])=O>[ClH:1].[NH2:3][CH:4]([CH:12]1[NH:16][CH:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:14]2([CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[S:13]1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)C(N)C1NC(C(=O)OCc2ccccc2)C2(CCOCC2)S1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: NC(C(=O)O)C1NC(C(=O)OCc2ccccc2)C2(CCOCC2)S1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Dry gaseous hydrogen chloride is bubbled into a suspension of 6.6 g (0.0144 mole) of tert-butyl alpha-amino-4-benzyloxycarbonyl-8-oxa-1-thia-3-azaspiro[4,5]decane-2-acetate hydrochloride in 150 ml of anhydrous nitromethane at 0° C. After 15 minutes, most of the product has dissolved and the bubbling of hydrogen chloride is continued for 1 hour. Insoluble material is filtered off and the nitromethane solution is degassed at a pressure of 20 mm Hg in a rotary evaporator at ambient temperature to eliminate as much gaseous hydrogen chloride as possible. 700 ml of anhydrous diethyl ether are added, followed by cooling to -5° C for 4 hours. In this way, a precipitate is obtained which is filtered off, washed with diethyl ether and dried in vacuo to give 4.2 g (0.0104 mole) of alpha-amino-4-benzyloxycarbonyl-8-oxa-1-thia-3-azaspiro[4.5]decane-2-acetic acid hydrochloride (yield: 72.5% of theory); M.P. 152-153° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.Cl.[CH:25]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:32]2[CH2:33][CH2:34][N:29]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[CH2:30][CH2:31]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: C1CC(N2CCNCC2)C1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CCC2)CC1
Temperature: 65 °C
Yield: 59.2 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 1-cyclobutylpiperazine dihydrochloride (0.087 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.44 g, 1.4 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give the desired product (69.2 mg, 59%). LCMS calculated for C19H23ClN3O (M+H)+: m/z 344.2; Found: 344.1
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C(OC(C)C)(=O)C>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNC1
Solvent: CC(=O)OC(C)C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in isopropyl acetate were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in isopropyl acetate at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH3:13])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-methylaniline (32 mg, 0.30 mmol) by a procedure similar to Example 1b and was isolated as white powder (15 mg, 30%). 1H NMR (CDCl3): 7.97-7.89 (m, 3H), 7.71 (d, J=6.6 Hz, 2H), 7.64 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 2.47 (s, 3H).
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]([CH3:14])[CH2:5]1)(=O)C.C(O[CH:18]=[C:19]([C:25]([O:27]CC)=O)[C:20]([O:22]CC)=[O:21])C.O.[OH-].[Na+]>C(O)(=O)C>[CH3:14][CH:6]1[N:7]2[CH:18]=[C:19]([C:20]([OH:22])=[O:21])[C:25](=[O:27])[C:9]3[C:8]2=[C:13]([CH:12]=[CH:11][CH:10]=3)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)Nc2ccccc21
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1CNc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 120 °C

Procedure:
A mixture of 0.0894 mole (1.7 g) of optically purified (+) 1-acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline and 0.009 mole (1.9 g) diethyl ethoxymethylenemalonate was heated over one hour to 200° C. and maintained at that temperature for 1.5 hours. After cooling, 5 g of polyphosphoric acid were added and the mixture was heated at 120° C. until foaming stops. The mixture was stirred into water and the solution was made strongly basic with 25 percent sodium hydroxide. The solution was stirred and heated on a steam bath for one hour, then neutralized with acetic acid. Cooling, followed by filtration provided an olive green solid R(+) 2,3-dihydro-3-methyl-7-oxopyrido-[1,2,3-de]quinoxaline-6- carboxylic acid, m.p. >250° C. Analysis: Calculated for C13H12N2O3 : %C, 63.9; %H, 5.0; %N, 11.5; Found: %C, 63.4; %H, 5.0; %N, 11.6. Optical rotation [α]21 D = 93±3° (C=0.594, N,N-dimethylformamide:ethanol, 1/1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=O)([O-])[O-].[K+].[K+].C=O.O>CN1CCCC1=O>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccccc1
Agent: C=O
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C(C(=O)OCC)c1ccccc1
Yield: 53.5 %

Procedure:
94 g of ethyl phenylacetate (methyl ester content 0.01%) were stirred in 300 ml of N-methylpyrrolidone with 120 g of potassium carbonate and 25 g of paraformaldehyde at 75 to 80° C. for 1.5 h. After cooling, 150 ml of water were added, and the aqueous phase was separated off. The N-methylpyrrolidone phase was extracted twice with 75 ml of diisopropyl ether each time. The combined diisopropyl ether phases were washed with 50 ml of water and concentrated in vacuo. 58 g of product were obtained, corresponding to 54 g of ethyl atropate (53% of theory) with a methyl atropate content of 0.03%.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Ni]>[N:1]1([S:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11][NH2:12])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccccc1S(=O)(=O)N1CCCC1
Agent: [Ni]
Solvent: CO
Product: NCc1ccccc1S(=O)(=O)N1CCCC1
Yield: 68.8 %

Procedure:
(Step 2) A solution of 2-(pyrrolidin-1-ylsulfonyl)benzonitrile obtained in Step 1 (0.1 g) and Raney-nickel (5 mg) in methanol (2.2 ml) was stirred at room temperature for 19 hr under a hydrogen atmosphere (50 psi). The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=5:1) to give 1-[2-(pyrrolidin-1-ylsulfonyl)phenyl]methanamine (70 mg).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>CN(C=O)C.[Cl-].[NH4+]>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]1)[N:19]=[CH:18][N:17]=[C:16]2[O:12][C:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][N:9]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: O=C1CC(c2ccccc2)=NN1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4ccccc4)[nH]n3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
3-Phenyl-4,5-dihydro-1H-pyrazol-5-one (182 mg, 1.14 mmol), (J. Org. Chem., 1967, 32, 3321-3324), was added in portions to a suspension of sodium hydride (46 mg, 1.14 mmol, prewashed with pentane) in DMF (3 ml). After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (200 mg, 0.57 mmol) was added. The mixture was stirred for 30 minutes at 60° C. After cooling, the mixture was diluted with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic layer was passed through an ISOLUTE (trade mark of IST) SPE column. The column was thoroughly washed with methanol. The product was recovered from the column by washing with a mixture of 0.1M solution of ammonia in methylene chloride/methanol (1/1). The volatiles were removed by evaporation and the solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-4-(5-phenylpyrazol-3-yloxy)quinazoline (206 mg, 76%).
Reaction SMILES: CS(OCC1C(C2CCCC=2)=CSC=1C(F)(F)F)(=O)=O.FC1C=C(O)C=C(F)C=1CCC(OCC)=O.[C:37]1([C:42]2[C:43]([CH2:51][O:52][C:53]3[C:58]([F:59])=[CH:57][C:56]([CH2:60][CH2:61][C:62]([O:64]CC)=[O:63])=[CH:55][C:54]=3[F:67])=[C:44]([C:47]([F:50])([F:49])[F:48])[S:45][CH:46]=2)[CH2:41][CH2:40][CH2:39][CH:38]=1>>[C:37]1([C:42]2[C:43]([CH2:51][O:52][C:53]3[C:58]([F:59])=[CH:57][C:56]([CH2:60][CH2:61][C:62]([OH:64])=[O:63])=[CH:55][C:54]=3[F:67])=[C:44]([C:47]([F:49])([F:50])[F:48])[S:45][CH:46]=2)[CH2:41][CH2:40][CH2:39][CH:38]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(C3=CCCC3)csc2C(F)(F)F)c(F)c1
Agent: CCOC(=O)CCc1c(F)cc(O)cc1F
Agent: CS(=O)(=O)OCc1c(C2=CCCC2)csc1C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(C3=CCCC3)csc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of (4-(cyclopent-1-en-1-yl)-2-(trifluoromethyl)thiophen-3-yl)methyl methanesulfonate and ethyl 3-(2,6-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(cyclopent-1-en-1-yl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=7.8 Hz, 2H), 6.27 (m, 1H), 5.18 (s, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.70 (m, 4H), 2.61 (m, J=7.0 Hz, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:12][CH:7]([CH:8](CO)[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH:4](CO)[CH2:5]1>C(O)CO>[CH3:8][CH2:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:12]
Reactant: OCC1CC2C3CC(CO)C(C3)C2C1
Solvent: OCCO
Product: CCCCCCCCCC

Procedure:
The same procedure as in Example 2 was repeated except that 6.2 parts of ethylene glycol was replaced with 19.6 parts of tricyclo[5,2,1,02,6 ]decane-4,8-dimethanol, thereby obtaining 54.8 parts of 4,8-bis[N-(4-isopropenyl-α,α-dimethylbenzyl)carbamoylmethyl]tricyclo[5,2,1,02,6 decane in the form of a colorless transparent liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].C.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22]>C(OCC)(=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:14])([CH3:15])[O:16]2)=[CH:4][C:3]=1[O:17][CH3:18])=[C:21]=[O:22]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N=C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To 4-amino-3-methoxyphenylboronic acid pinacol ester (24.08 mmol, 6 g) and charcoal (0.29 g) in ethyl acetate (50 ml), was added trichloromethyl chloroformate (48.2 mmol, 5.81 mL) and the mixture was stirred at 70° C. for two hours. After cooling to room temperature the solids were removed by filtration and the filtrate concentrated in vacuo to give 6.7 g of 2-(4-isocyanato-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][F:28])C>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][F:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#CCF
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Product: O=c1cc(CF)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.464 g, 1.69 mmol), (see Example 28) in ethanol (25 mL) was added 4-fluoro-but-2-ynoic acid ethyl ester (0.22 g, 1.69 mmol) (see Poulter, J Org Chem 1981, 46, 1532). The reaction mixture was heated at reflux for 14 hrs and then gradually cooled to room temperature. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, 0-2% 7N NH3 in MeOH /CH2Cl2) to afford 0.358g of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-fluoromethyl-2,3-dihydro-oxazolo[3,2 a]-pyrimidin-7-one. [α]D25 −28.20 (c 0.5, CHCl3).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]3[O:24][N:28]=[C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=NO)c1cccnc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccnc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 37 mg (43% of theory)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12](OCC)=[O:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(Cl)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 5-(5-chloro-2-thienyl)isoxazole-4-carboxylate (9.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.5 M toluene solution, 52 ml) at 0° C. and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into dilute hydrochloric acid, and the precipitated 5-(5-chloro-2-thienyl)-4-isoxazolylmethanol (7.00 g, yield 93%) was filtrated and recrystallized from ethyl acetate-hexane to give a colorless needle. melting point: 80–81° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
(2S)-1-(Benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylpropan-2-amine (3.02 g, 5.62 mmol) was dissolved in 60 mL of anhydrous CH2Cl2 and 9.1 mL of glacial acetic acid. The reaction mixture was cooled to 0° C. under an atmosphere of N2 and boron trifluoride diethyl etherate (0.75 mL, 5.92 mmol) was added dropwise over several minutes. After stirring for 5 hours, the reaction mixture was treated with 85 mL of cold, aqueous 10% NaOH solution. The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×20 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-5% methanol/CHCl3) gave 1.57 g of (2S)-1-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-amine as a white solid.
Reaction SMILES: [ClH:1].CS[C:4]1[N:5]2[CH:17]=[CH:16][N:15]=[C:6]2[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)CCCC>>[ClH:1].[ClH:1].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:4]2[N:5]3[CH:17]=[CH:16][N:15]=[C:6]3[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:23][CH2:22]1
Reactant: CSC1=Nc2ccccc2Sc2nccn21
Reactant: OCCN1CCNCC1
Agent: Cl
Solvent: CCCCCO
Product: OCCN1CCN(C2=Nc3ccccc3Sc3nccn32)CC1

Procedure:
A mixture of 5 g of 5-methylthio-imidazo[2,1-b][1,3,5]-benzothiadiazepine hydrochloride, 2.86 g of N-β-hydroxyethylpiperazine, and 175 ml of amyl alcohol is refluxed under nitrogen for 48 hrs. with stirring. The solvent is removed under vacuum, the residue is triturated with methylene chloride, washed with 2 N sodium hydroxide solution, dried over MgSO4, and evaporated to dryness. The residue is dissolved in 5 ml of methanol and treated with 2 N ethereal hydrochloric acid solutions to give 5-(4-β-hydroxyethylpiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine dihydrochloride melting at 212°-214°.