Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[CH2:29]([NH2:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>COCCO.C(O)(C)C>[S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=1)([OH:45])(=[O:44])=[O:43].[C:23]1(/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:35][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:6][CH:7]=2)=[C:12](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[C:13]([F:16])([F:15])[F:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCCN
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Solvent: CC(C)O
Product: CCCCCCNCCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
2.23 g (5 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, are dissolved in a mixture of 5.0 g (50 mmoles) of n-hexylamine and 10 ml of 2-methoxyethanol. The mixture is boiled for 30 minutes, then evaporated, and the residue is passed through a chromatographic column filled with 50 g of silica gel. The column is eluted with benzene. The fractions which are chromatographically uniform are combined and evaporated, the residue is dissolved in 5 ml of isopropanol, and a solution of 1.20 g (6 mmoles) of p-toluenesulfonic acid in 6 ml of isopropanol is added. The separated crystals are filtered off and washed with ether. 2.14 g (91.8%) of the aimed compound are obtained; m.p.: 151°-153° C.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]#[N:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:15][CH2:16][CH3:17]>C(O)C>[C:2]([NH:5][C:6]([C:12]#[N:13])([CH2:15][CH2:16][CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCCBr
Reactant: CCOC(=O)C(C#N)NC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCCC(C#N)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.35 g of sodium (58.8 mmol) are dissolved in 200 ml of ethanol and the resulting solution is cooled down to 0° C. 10 g (58.8 mmol) of ethyl acetamidocyanoacetate are added. After a clear solution has formed, a solution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol is added dropwise and the reaction mixture is stirred at room temperature for 2 hours. A solution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol is added once again and the reaction mixture is heated under reflux for 16 hours. The solvent is removed in vacuo and the residue is taken up in dichloromethane; the solution is washed with water and dried over magnesium sulfate. The solvent is removed in vacuo and the residue is stirred up with petroleum ether. After filtering off with suction, 7.5 g (60%) of ethyl 2-acetylamino-2-cyanopentanoate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:24][CH3:25])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: CCI
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: CCn1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=353.3, 355.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>CCOC(C)=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(Br)c1F
Yield: 92 %

Procedure:
To a stirred solution of 3-bromo-2-fluorobenzoic acid A1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound A2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([N:18]=[C:19]=[O:20])([CH3:17])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:30][OH:31]>>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([NH:18][C:19]([O:31][CH3:30])=[O:20])([CH3:17])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CO
Reactant: CC1(N=C=O)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Product: COC(=O)NC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1

Procedure:
A solution of 20 g (47 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-isocyanato-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 1d) in 200 ml of methanol was refluxed for 2 hours, concentrated in vacuo and recrystallized from ethyl acetate/hexanes yielding 19.8 g (92%) of a white solid, mp 179°-181° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:27])=[C:17]2[C:25]=1[C:24](=[O:26])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1>C(O)(=O)C>[OH:12][C:13]1[C:14]([N+:8]([O-:11])=[O:9])=[CH:15][C:16]([CH3:27])=[C:17]2[C:25]=1[C:24](=[O:26])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1C1CCCCC1C2=O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A mixture of 15 ml of acetic anhydride and 50 ml of acetic acid was ice-cooled and thereto was added dropwise 10 ml of nitric acid (d=1.38). After stirring for 1 hour, thereto was added dropwise an acetic acid solution containing 10 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of acetic acid. After stirring for 30 minutes, the ice bath was removed and the solution was warmed to an inner temperature of 15° C. To this solution was added 150 ml of diethyl ether, followed by stirring under ice-cooling. The resulting precipitate was collected by filtration to obtain 8 g of 8-hydroxy-5-methyl-7-nitro-1,2,3,4,4a,9a-hexahydro-9-fluorenone of yellowish green powdery crystal.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([CH2:15][CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][C:18]1=[S:23])(O)=[O:13]>O1CCCC1>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:12]([CH2:15][CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][C:18]2=[S:23])=[O:13])=[CH:3][CH:4]=1
Reactant: Oc1ccnc2ccccc12
Reactant: O=C(O)CCN1C(=O)CSC1=S
Solvent: C1CCOC1
Product: O=C(CCN1C(=O)CSC1=S)Oc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three g of 4-hydroxyquinoline and 2 g of 3-carboxyethylrhodanine were added to 200 ml of tetrahydrofuran. Two g of N,N-dicyclohexylcarbodiimide was added to the solution. The material was stirred at room temperature for 8 hours. The resulting insoluble matters were removed by filtration. One l of ethyl acetate was added to the filtrate. The resulting crystal was filtered off to obtain 2.2 g of 3-(4-quinolyloxycarbonylethyl)rhodanine.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([O:17]C)=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)#[N:4]>O.CCO.C(Cl)Cl>[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([OH:17])=[O:16])=[CH:12]2)=[CH:7][CH:6]=1)#[N:4]
Reactant: COC(=O)c1ccc2ccc(C#N)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1ccc2ccc(C(=O)O)cc2c1
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A solution of NaOH (1.36 g, 34 mmol) in water (35 mL) was added dropwise to a solution of 191 (4.95 g, 24 mmol) in EtOH (100 mL) and CH2Cl2 (30 mL) and the mixture was stirred for 15 h. Water was added to dissolve the white solid and the mixture was extracted with CH2Cl2 (×2) and EtOAc. The aqueous portion was acidified (pH 2) with aqueous HCl (2N) and the resulting precipitate was filtered off, washed with water, and dried in a vacuum desiccator to give 7-cyano-2-naphthoic acid (192) (4.60 g, 99%), as a colorless powder: mp 279-283° C.; lit. mp [Aust. J. Chem., 1965, 18, 1351] 286-288° C.; 1H NMR [(CD3)2SO] δ 13.25 (br s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.17 (d, J=8.5 Hz, 2H), 8.15 (d, J=8.5 Hz, 2H), 7.92 (dd, J=8.5, 1.3 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:14]=1)=O.[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[O:13]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:23]=[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[S:22][CH:2]=3)=[CH:14][C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: O=C(CCl)c1ccc2c(c1)CCCO2
Reactant: NC(=S)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(-c2nc(-c3ccc4c(c3)CCCO4)cs2)cc1
Yield: 94.1 %

Procedure:
A solution of 2-chloro-1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (9b) (250 mg, 1.19 mmol) and thiobenzamide (180 mg, 1.3 mmol) in dioxane (10 mL) was refluxed for 15 hours, then the reaction mixture was concentrated. The residue was diluted with dichloromethane (20 mL), washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/cyclohexane 60/40) to afford the desired thiazole (9c) as a white solid (330 mg, 1.12 mmol, 94%).
Reaction SMILES: CN(C)[N:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][CH3:8].Br[C:11]1[C:12](=[O:22])[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CC1C=CN=C2C(=O)C3C=CC=CC=3C(=O)C=12>C1(C)C(C)=CC=CC=1>[CH3:8][CH2:7][C:6]1[CH:5]=[CH:4][N:3]=[C:11]2[C:12]([C:13]3[C:18]([C:19](=[O:21])[C:20]=12)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:22]
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Reactant: CC/C=C/C=NN(C)C
Agent: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Solvent: Cc1ccccc1C
Product: CCc1ccnc2c1C(=O)c1ccccc1C2=O
Yield: 15.3 %

Procedure:
A solution of trans-2-pentenal N,N-dimethylhydrazone (49.15 g, 0.39 mol) in xylene (100 mL) was quickly added to a xylene (600 mL) solution of 2-bromo-1,4-naphthoquinone (71.12 g, 0.30 mol) and the dark reaction heated at reflux for 6 h. Workup followed the procedure described above for cleistopholine. Chromatography provided pure homocleistopholine (13) (10.90 g, 14%). An analytical sample was obtained by crystallization from EtOAc: mp 157°-158° C.; IR (KBr) 1680, 1665, 1590, 1575, 1450, 1340, 1300, 1280, 1260, 1225, 1200, 1000, 955, 870, 850, 800, 790, 730 cm-1 ; 1H NMR (CDCl3) δ 1.29 (t, 3H, J=7.4 Hz), 3.28 (q, 2H, J=7.4 Hz), 7.48 (d, 1H, J=5.0 Hz), 7.71-7.78 (m, 2H), 8.14-8.18 (m, 1H), 8.25-8.28 (m, 1H), 8.87 (d, 1H, J=5.0 Hz); 13C NMR (CDCl3) 14.1 (3), 28.0 (2), 127.1 (1), 127.2 (1), 128.5 (0), 129.3 (1), 132.4 (0), 133.9 (0), 134.0 (1), 134.5 (1), 150.2 (0), 153.6 (1), 157.2 (0), 181.8 (0), 184.5 (0) ppm; Anal. calcd for C15H11NO2 : C 75.94, H 4.67, N 5.90; found C 75.85, H, 4.68, N 5.91.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.P(Br)(Br)[Br:16].O>ClCCl>[Br:16][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1
Reactant: COc1ccc2c(c1)C(CCO)CC2
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(CCBr)CC2
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-6-methoxyindan (4.95 g, 25.7 mmol) in dichloromethane (100 ml) was added dropwise at −5° C. phosphorus tribromide (0.86 ml, 2084 27.0 mmol). The mixture was stirred for 30 minutes. To the reaction mixture was added water, which was subjected to extraction with chloroform. The extract solution was washed with brine and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 7:3→1:1) to give 1.80 g (yield 27%) of the above-titled compound as an oily product.
Reaction SMILES: O1CCCC1.[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([CH3:23])[CH:11]=[CH:10][C:9]([O:12][C:13]2[S:17][C:16]([CH2:18][C:19]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(Oc2ccc(CC(Cl)=NO)s2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(Oc2ccc(Cc3cc(-c4cccnc4N)on3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 1.6 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (5-p-tolyloxy-thiophen-2-yl)-acetohydroximoyl chloride (191 mg, 0.678 mmol) described in Manufacturing Example 48-1-5 and 3-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (189 μL, 1.36 mmol) at room temperature, which was stirred for 4 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (2.03 mg, 1.65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10](=[O:18])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.O>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([O:18][CH2:31][C:32]([F:35])([F:34])[F:33])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(=O)[nH]n1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of ethyl 1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate (i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15 mL) at −5° C. was added potassium carbonate (0.85 g, 6.15 mmol). The suspension was stirred for 15 minutes at 20° C. The stirred suspension was then cooled to 5° C., and 2,2,2-trifluoro-ethyl trifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. The reaction mixture was warmed to room temperature and then heated to reflux, at which time thin layer chromatography showed the reaction to be complete. Water (25 mL) was added to the reaction mixture, which was then extracted with ethyl ether. The ether extract was dried over magnesium sulfate and concentrated to yield the title product compound (1.05 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:19][CH2:18]1)[S:3]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)(=[O:5])=[O:4].CC[Cl:36]>C(#N)C>[ClH:36].[ClH:36].[CH3:1][N:2]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:19][CH2:18]1)[S:3]([C:6]1[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)(=[O:4])=[O:5]
Reactant: CCCl
Agent: CN(CC1CCN(CCCOc2ccc(F)cc2)CC1)S(=O)(=O)c1cccc2cnccc12
Solvent: CC#N
Product: Cl

Procedure:
5.5 g of the compound obtained in stage A is taken up in 10 cm3 of acetonitrile. 7.5 cm3 of a 3.3N solution of hydrochloric ether are added to this solution. 3.1 g of a solid which corresponds to the title compound are obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]1[C:32]2=[N:33][C:34]3[C:35](=[C:36]([CH:40]=[O:41])[CH:37]=[CH:38][CH:39]=3)[N:31]2[CH2:30][CH2:29][CH2:28]1.C[Si](C)(C)[C:44]([F:47])([F:46])[F:45]>O1CCCC1.Cl>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]1[C:32]2=[N:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([OH:41])[C:44]([F:47])([F:46])[F:45])[C:35]=3[N:31]2[CH2:30][CH2:29][CH2:28]1
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.1 %

Procedure:
Tetra-n-butylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.3 mL, 1.3 mmol) was added dropwise to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.50 g, 4.33 mmol) and trimethyl(trifluoromethyl)silane (1.83 g, 12.9 mmol) in tetrahydrofuran (11 mL) at 0° C., and the mixture was stirred at room temperature for 10 hr. The mixture was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.19 g, 2.86 mmol, 66%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:9][C@@H:10]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][OH:29])=[CH:21][C:20]=2[CH3:30])=[C:16]([CH:31]([CH3:33])[CH3:32])[NH:15][N:14]=1)(=[O:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:29][CH2:28][CH2:27]/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[C:13]([O:12][C@@H:11]3[O:34][C@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:10]3[O:9][C:6](=[O:8])[CH3:7])=[N:14][NH:15][C:16]=2[CH:31]([CH3:33])[CH3:32])=[C:20]([CH3:30])[CH:21]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Add methanesulfonyl chloride (0.54 mL, 7 mmol) to a solution of 4-{4-[(1E)-4-hydroxybut-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (3.7, 5.87 mmol) in dichloromethane (15 mL) and triethylamine (4 mL, 29 mmol) at 0° C. After refluxing at room temperature for 30 min, concentrate to remove the solvent under the reduced pressure. Purify residue by flash chromatography to yield the title compound (2.9 g, 4.1 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([CH3:12])[N:5]=1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[N:34]=1>CN(C)C=O.CN1CCCC1=O>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][C:46]([F:47])=[C:25]([NH:24][C:9]([C:7]5[N:6]([CH3:12])[N:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:8]=5)=[O:11])[CH:26]=4)=[N:34][N:33]3[CH:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: CCOc1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 38.4 %

Procedure:
Using 3-ethoxy-1-methyl-1H-pyrazole-5-carboxylic acid (170 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (15 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (92 mg, yield 38%) was obtained.
Reaction SMILES: [Na:1].C1C2C(=CC=CC=2)C=CC=1.[F:12][C:13]1([CH2:19][CH:20]([NH:31]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[C-]1C2C(=CC=CC=2)C=CC=1.[Na+].CC1C=CC(S(N)(=O)=O)=CC=1>COCCOC.C(=O)=O.C(O)(C)C>[Na:1].[C:25]([O:24][C:23](=[O:29])[N:22]([CH2:21][C@@H:20]([NH2:31])[CH2:19][C:13]1([F:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH3:30])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OC(C)(C)C)CC2(F)CCCCC2)cc1
Agent: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C=O
Agent: [Na+]
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Solvent: CC(C)O
Product: CN(C[C@@H](N)CC1(F)CCCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution of sodium naphalenide in anhydrous DME was prepared by adding anhydrous DME (20 mL) to a mixture of sodium (0.3 g, 13 mmol) and naphthalene (2.1 g, 16 mmol) and stirring the resulting mixture at rt for 2 h. A solution of tert-butyl 3-(1-fluorocyclohexyl)-2-(4-methylphenylsulfonamido)propyl(methyl)carbamate (200 mg, 0.43 mmol) in anhydrous DME (15 mL) was cooled in dry ice-isopropyl alcohol bath. The sodium naphthalenide solution was added dropwise to the well-stirred tosylamide solution until a light green color persisted. The reaction was quenched with water, diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was basified with K2CO3, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (S)-[2-amino-3-(1-fluoro-cyclohexyl)-propyl]-methyl-carbamic acid tert-butyl ester (50 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.[H][H].N>[Ni].C(OCC)C.CCCCCC>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (93 g, 321 mmol) and ethanol (400 mL) in a 2 gallon pressure reactor. Add Raney nickel (280 g). Heat to 50° C. and charge with 200 psi of hydrogen. After 15 minutes, vent the reactor and add aqueous concentrated ammonia solution (120 mL). Charge the reactor with 200 psi of hydrogen. After 7 hours, vent the reactor and allow to stand for 18 hours. Filter through a celite pad and rinse the solids with ethanol. Evaporate the filtrate in vacuo to obtain a residue. Combine the residue and 1/5 diethyl ether/hexane (500 mL) and cool to -20° C. After 18 hours, decant and add 1/5 diethyl ether/hexane (500 mL) and cool to -20° C. to give a solid. Collect the solid by filtration and triturate with 1/5 diethyl ether/hexane (500 mL). Filter and dissolve in diethyl ether (300 mL) and add hexane (700 mL) to give a solid. Collect the solid by filtration and dry to give the title compound. Elemental Analysis calculated for C14H17NO3 : C 68.00; H 6.93; N 5.66; Found: C 67.63; H 6.99; N 5.81.