Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])O.[Na+].[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15]
Reactant: COc1ccc(OC)c(CCCC(=O)O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CCCc1cc(OC)ccc1OC
Reaction time: 5 h

Procedure:
To an ethanol solution (180 ml) of 4-(2,5-dimethoxyphenyl)butyric acid (52.4 g, 0.23 mole), several drops of conc. sulfuric acid are added, and the mixture is boiled for 5 hours. After cooling in the air, a saturated aqueous solution of sodium hydrogen carbonate is added for neutralization, and the mixture is concentrated under reduced pressure. The residue is diluted with ether (300 ml), washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml×2), water (50 ml×2) and a saturated aqueous solution of sodium chloride (50 ml×1) and dried over anhydrous magnesium sulfate. After filtration and evaporation, a dark red oil (55 g) is obtained, which is subjected to distillation under reduced pressure twice for purification to obtain the objective compound as a pale yellow oil (37 g, 63%). B.P. 155°-158° C. (3 mmHg). IRνmaxfilm cm-1 : 1720 (CO2Et). NMR (in CDCl3): 1.19 (3H, t, J=7.5Hz, CO2CH2CH3), 1.56-2.06 (2H, m, CH2CH2CO2Et), 2.06-2.46 (2H, m, CH2CH2CO2Et), 2.46-2.76 (2H, broad t, J=6.6Hz, CH2CH2CH2CO2Et), 3.67 (6H, s, OCH3 ×2), 4.15 (2H, q, J=7.5Hz, CO2CH2CH3), 6.15 (3H, s, aromatic proton).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[N:6]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([C:29]2[C:34]3[O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>C(Cl)Cl>[CH3:25][C:24]1[CH:23]=[CH:22][C:21]([NH:26][C:27]([C:29]2[C:34]3[O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:28])=[CH:20][C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1N
Reactant: Cc1nc(COc2ccc(C(=O)O)cc2)cs1
Solvent: ClCCl
Product: Cc1nc(COc2ccc(C(=O)Nc3cc(NC(=O)c4cccc5c4oc4ccccc45)ccc3C)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
4-(2-Methylthiazol-4-ylmethoxy)benzoic acid (0.095 g) was added to a stirred mixture of N-(3-amino-4-methylphenyl)dibenzofuran-4-carboxamide (0.12 g), diisopropyethyllamine (0.2 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.134 g) and methylene chloride (22 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column) using initially a 1:1 mixture of ethyl acetate and methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. The product so obtained was triturated under ethyl acetate. There was thus obtained the title compound (0.051 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 2.65 (s, 3H), 5.2 (s, 2H), 7.15 (d, 2H), 7.25 (d, 1H),7.4-7.65 (m, 5H), 7.8-7.9 (m, 3H), 7.98 (d, 2H), 8.2 (d, 1H), 8.35 (d, 1H), 9.8 (d, 1H), 10.4 (s, 1H); Mass Spectrum: M+H+ 548.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[CH:7]=1.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:7]=1
Reactant: CCOC(=O)c1csc(-c2cc(Br)ccc2F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1csc(-c2cc(Br)ccc2F)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of ethyl 2-(5-bromo-2-fluoro-phenyl)thiazole-4-carboxylate (8.97 mmol, 2960 mg) in methanol (40 mL) and water (10 mL) was added lithium hydroxide (1.6 equiv., 14.2 mmol, 347 mg). The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, suspended in water, and then quenched with 2N HCl(aq.). The solid was collected, washed with water, and dried under high vacuum to afford 2-(5-bromo-2-fluoro-phenyl)thiazole-4-carboxylic acid (2410 mg, 89% Yield) as a white solid.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:21])[O:12][CH2:13][C:14]2[O:15][C:16](=[O:20])[O:17][C:18]=2[CH3:19])=CC=1)([O-])=O.[NH2:22][C:23]1[S:27][N:26]=[C:25](/[C:28](=[N:56]/[OH:57])/[C:29]([NH:31][C@@H:32]2[C:39](=[O:40])[N:38]3[C@@H:33]2[S:34][CH2:35][C:36](/[CH:44]=[C:45]2/[C:46](=[O:55])[N:47]([C@@H:50]4[CH2:54][CH2:53][NH:52][CH2:51]4)[CH2:48][CH2:49]/2)=[C:37]3[C:41]([OH:43])=[O:42])=[O:30])[N:24]=1.CC(C)=O>CS(C)=O>[NH2:22][C:23]1[S:27][N:26]=[C:25](/[C:28](=[N:56]/[OH:57])/[C:29]([NH:31][C@@H:32]2[C:39](=[O:40])[N:38]3[C@@H:33]2[S:34][CH2:35][C:36](/[CH:44]=[C:45]2/[C:46](=[O:55])[N:47]([C@@H:50]4[CH2:54][CH2:53][N:52]([C:11]([O:12][CH2:13][C:14]5[O:15][C:16](=[O:20])[O:17][C:18]=5[CH3:19])=[O:21])[CH2:51]4)[CH2:48][CH2:49]/2)=[C:37]3[C:41]([OH:43])=[O:42])=[O:30])[N:24]=1
Reactant: Cc1oc(=O)oc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of 13.2 g (44.72 mmol) of carbonic acid 5-methyl-2-oxo-[1,3]dioxol4-ylmethyl ester 4-nitro-phenyl ester in 200 ml of dimethylsulfoxide are added 20.0 g of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamino]-8-oxo-3-[(E)-(R)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The mixture is stirred under argon at room temperature for 4 hours and 1000 ml of acetone are added. The slightly turbid solution is clarified by filtration over a fluted filter. To the clear motherliquour are added 34.0 ml (34 mmol) of a 1N solution of sodium-2-ethylcaproate in acetone at room temperature during 20 minutes. The slightly yellow suspension is stirred for 10 minutes at room temperature, the solid is collected by filtration, washed with 1000 ml of acetone and 1000 ml of n-pentane and dried under high vacuum. The product is suspended in 600 ml of acetone and stirred at room temperature for 2 hours. The product is collected by filtration and dried under high vacuum to yield 23.94 g of the title compound as an off-white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:37]2[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCN(Cc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cc2)CC1
Product: CN1CCN(Cc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cc2)CC1
Yield: 83 %

Procedure:
Following general procedure D, {6-bromo-4-[4-((4-methylpiperazin-1-yl)methyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (42 mg, 0.088 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.132 mmol) to afford the desired product (41 mg, 83%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.27 (s, 1H), 7.93-7.85 (m, 2H), 7.74 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.19-7.10 (m, 4H), 3.61 (s, 2H), 2.95-2.88 (m, 1H), 2.74-2.68 (m, 4H), 2.57-2.46 (m, 7H), 1.23-1.10 (m, 4H); ESI MS m/z 561 [C31H30Cl2N4O2+H]+; HPLC 94.4% (AUC), tR=8.57 min.
Reaction SMILES: O1CCOCC1.[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21](=[O:26])[C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[K+]>C(O)C>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([C:19](=[O:27])[CH2:20][C:21](=[O:26])[C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)C(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 20 ml of ethanol and 2.4 ml of dioxane there was suspended 1.15 g (4 mMol) of the ester product prepared in Step B above. There was then added 3 ml of 2 N potassium hydroxide, whereupon a precipitate formed. The reaction mixture was stirred overnight at room temperature. The mixture was evaporated to dryness, an then water was added, whereupon most of the solid dissolved. The mixture was then made acidic to pH 1.0 using 6 N hydrochloric acid. A white solid was obtained which was filtered off, washed with water and dried. The solid was crystallized from benzene to give product, m.p. 140°-142° C. Analysis:
Reaction SMILES: [Br:1][C:2]1N=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(Br)nc1N1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: O=c1[nH]cc(Br)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3-morpholinopyrazin-2(1H)-one (1.0 equiv.) in DMF (0.1 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.0 equiv.) at 0° C. and the solution was allowed to warm to room temperature and stirred for 2 hours. Upon completion, the reaction was partitioned between water and ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude material was used for the next step without further purification. Isolated 5-bromo-1-methyl-3-morpholinopyrazin-2(1H)-one in 91% yield. LCMS m/z (M+H)=274/276, Rt=0.60 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.42 (s, 3H) 3.66-3.83 (m, 4H) 3.85-4.00 (m, 4H), 6.77 (s, 1H).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([OH:17])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.Cl.Cl.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:44]=[CH:43][C:34]3[C:35]4[CH2:42][CH2:41][CH2:40][C:36]=4[C:37](=[O:39])[O:38][C:33]=3[CH:32]=2)[CH2:23][CH2:22]1.[OH-].[Na+]>O.C(N(CC)CC)C.ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:44]=[CH:43][C:34]4[C:35]5[CH2:42][CH2:41][CH2:40][C:36]=5[C:37](=[O:39])[O:38][C:33]=4[CH:32]=3)[CH2:23][CH2:22]2)=[O:17])[CH:11]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1)c1cccnc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
1.3 ml. (0.01 mole) Isobutyl chloroformate, dissolved in 10 ml. dichloromethane, is added dropwise at -5° C. to -10° C. to a mixture of 1.23 g. (0.01 mole) nicotinic acid, 40 ml. dichloromethane and 1.4 ml. triethylamine. After stirring the reaction mixture for 15 minutes at -10° C., a slurry of 4.15 g. (0.01 mole) 7-[3-(4-aminopiperidino)-propoxy]-2,3-dihydrocyclopenta[c][1]benzopyran-4(1H)-one dihydrochloride in 30 ml. dichloromethane and 2.8 g. triethylamine is added thereto and the reaction mixture is further stirred for 30 minutes at -10° C., washed with water, mixed with an excess of ethereal hydrogen chloride solution, filtered and the precipitate obtained taken up in water and rendered alkaline with an aqueous solution of sodium hydroxide. There are thus obtained 2.8 g. (62% of theory) of the desired compound; m.p. 199°-200° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl-].[OH:8][NH3+:9].[C:10]([C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13])#[N:11]>O.C(O)C>[NH2:11]/[C:10](=[N:9]\[OH:8])/[C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13]
Reactant: [NH3+]O
Reactant: CC(C)(C#N)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)/C(N)=N/O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
Potassium carbonate (3.64 g) was dissolved in water (12 mL) and hydroxylammonium chloride (CAN: 5470-11-1, 1.7 g, mmol) was added. A solution of tert-butyl 2-cyanopropan-2-ylcarbamate (4.84 g, 26 mmol) in ethanol (42 mL) was added and the resulting reaction mixture was stirred for 18 h at ambient temperature. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The mixture was filtered and the filtrate was concentrated to yield the crude product (5 g, 87.6%) as yellow solid. MS: m/e=218.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, off-white solid (59 mg, 79%), MS (ISP) m/z=299.3 [(M+H)+], mp 304° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C(OCC)C>[F:19][C:20](=[CH2:24])[C:21]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)=[O:22]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 83.3 %

Procedure:
16.2 g (0.1 mol) of 4-trifluoromethylphenol were dissolved in 80 ml of anhydrous diethyl ether, and 10.1 g (0.1 mol) of triethylamine were added in portions to the solution; 12 g (0.11 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were then added dropwise, at a temperature of 10° C., with stirring, and in the course of 20 minutes, and the reaction mixture was stirred for a further 60 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of diethyl ether. The mixture of filtrate and wash solution was distilled, after adding 0.005 g of hydroquinone monomethyl ether. 19.5 g (83% of theory) of 4-trifluoromethylphenyl α-fluoroacrylate were obtained, boiling point 69° to 70° C. (under 3 mbar).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28](O)=[O:29])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:63][CH:64]([CH3:67])[CH2:65][OH:66]>CN(C)C=O.C(OCC)(=O)C.O>[OH:66][CH2:65][CH:64]([NH:63][C:28]([C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[C:19]([C:6]3[C:5]4[CH2:4][CH2:3][C:2]([CH3:39])([CH3:1])[CH2:10][C:9]=4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[N:7]=3)[N:20]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])=[CH:25][CH:24]=1)=[O:29])[CH3:67]
Reactant: CC1(C)CCc2c(-c3cc4ccc(C(=O)O)cc4n3COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c2C1
Reactant: CC(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CO)NC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid obtained in Example 1, Step 4 (500 mg, 0.88 mmol) in N,N-dimethylformamide (5 ml) were added 1-hydroxybenzotriazole monohydrate (161 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.1 mmol) and 2-amino-1-propanol (84 mg, 1.1 mmol) at room temperature, and the mixture was stirred at room temperature for 7 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (511 mg, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([F:29])[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:27]([F:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(Cl)nc1F
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)c(F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (45 mg, 0.14 mmol) and 6-chloro-2-fluoro-3-(methylsulfonyl)pyridine (30 mg, 0.14 mmol) as starting materials.
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[ClH:20]>O.CC(C)=O>[Cl:20][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cl
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(OC)cc1OC
Temperature: 25 °C

Procedure:
A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in a mixture solvent of 1.5 ml of water and 10 ml of acetone, and 1.3 ml of concentrated hydrochloric acid was added thereto, followed by dropwise addition of 0.23 g of sodium nitrite dissolved in 1 ml of water under ice-cooling and subsequent stirring for a while. Next, 0.35 g of cuprous chloride was added and the mixture was warmed up to room temperature. After completion of the reaction, insoluble matter was filtered and the resulting residue was mixed with water, extracted with ethyl acetate and then washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=500:1-40:1) to give 0.56 g of methyl 5-chloro-2,4-dimethoxybenzoate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([C:13]3[C:17]4[N:18]=[C:19](Cl)[N:20]=[CH:21][C:16]=4[S:15][CH:14]=3)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(NC(C3C4N=C(O[N:45]5[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=6[N:47]=N5)N=CC=4SC=3)=O)=CC=2OC1.N[C@@H]1CCCC[C@@H]1N>O1CCOCC1.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([C:13]3[C:17]4[N:18]=[C:19]([NH:45][C@@H:49]5[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:48]5[NH2:47])[N:20]=[CH:21][C:16]=4[S:15][CH:14]=3)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc2c(c1)OCO2)c1csc2cnc(On3nnc4ccccc43)nc12
Reactant: O=C(Nc1ccc2c(c1)OCO2)c1csc2cnc(Cl)nc12
Agent: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1Nc1ncc2scc(C(=O)Nc3ccc4c(c3)OCO4)c2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of the mixture of 80 mg of 2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid benzo[1,3]dioxol-5-ylamide and 2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid benzo[1,3]dioxol-5-ylamide (from step a) and 0.17 g (1.41 mmole) of cis-1,2-diaminocyclohexane in Dioxane (3 mL) was stirred at 60° C. for overnight. The reaction were cooled down and diluted with CH2Cl2, washed with aqueous Na2CO3, brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, 40 g, 0% to 30% MeOH (0.7 N) in CH2Cl2) to 40 mg of 2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid benzo[1,3]dioxol-5-ylamide as light yellow solid. MH+/Z=412.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=O)[CH2:4][O:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:1](=[O:8])[CH2:2][O:3][CH2:4][C:5]1=[O:7]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCO
Product: O=C1COCC(=O)N1CCCO
Yield: 99 %

Procedure:
A solution of diglycolic anhydride (2.32 g, 20 mmol) in 3-amino-1-propanol (6 ml) was refluxed at 180° C. for 3 hours. The volatiles were removed by evaporation and the residue was purified by column chromatography on silica eluting with methylene chloride/methanol (8/2) to give 4-(3-hydroxypropyl)-3,5-dioxomorpholine (3.46 g, 99%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH2:13][PH:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][PH:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=1
Reactant: CCO[PH](=O)Cc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCO[PH](=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
BBr3 (3.16 mL, 1 M solution in DCM) was added to a solution of ethyl (3-methoxyphenyl)methylphosphinate (0.169 g, 0.789 mmol) in DCM at 0° C. The reaction was stirred at rt for 15 h, then partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.35-7.40 (m, 1H), 7.19-7.26 (m, 2H), 7.05 (dd, 1H, J=8.3, 2.6 Hz), 3.85-4.05 (m, 2H), 1.69 (d, 3H, J=14.6 Hz), 1.29 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:37])([F:36])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:37])([F:35])[F:36])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)CC1
Yield: 85.2 %

Procedure:
A solution of ethyl 1-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}piperidine-4-carboxylate (0.06 g, 0.12 mmol) in 5 mL of methanol containing 1 mL of 1 N NaOH was stirred overnight at ambient temperature. The reaction mixture was neutralized with dilute HCl and partitioned with ethyl acetate and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was triturated with petroleum ether to give the title compound as an amber solid (0.049 g).