Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])/[N:7]=[C:8](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])\[C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH:22]=[CH2:23].C1COCC1>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])([C:9]([F:10])([F:11])[F:12])[CH2:23][CH:22]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(C)OC(=O)/N=C(/c1ccccc1F)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCC(NC(=O)OC(C)(C)C)(c1ccccc1F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of [2,2,2-Trifluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-carbamic acid tert-butyl ester (16.63 g, 57.1 mmol) in 170 mL THE at −75° was added dropwise allylmagnesium chloride solution 2 mol/L in THF (31.4 ml, 62.8 mmol). The reaction temperature was not allowed to exceed −60° C. After 30 minutes, the reaction was quenched with 10% aqueous NH4Cl and extracted with TBME. The organic phase was washed with brine, dried with MgSO4.H2O and evaporated. The crude product was chromatographed on silica gel with hexane/TBME 95/5 to give 18.52 g of the title compound.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.[F:6][C:7]1[CH:8]=[C:9]2C(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:16][C:17]=1[F:18].Cl>O>[F:6][C:7]1[CH:8]=[C:9]([NH2:4])[C:10](=[CH:16][C:17]=1[F:18])[C:11]([OH:13])=[O:12]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(F)c(F)cc1C(=O)O
Yield: 95 %

Procedure:
Sodium hydroxide (7.5 g, 0.19 mol) and hydroxylamine hydrochloride (5.4 g, 0.0781 mol) were combined in 100 mL of water. 4,5-difluorophthalic anhydride (11.5 g, 0.062 mol) was added, and the reaction was heated to 90°-100° C. for 0.5 hour. The reaction was cooled, and acidified with HCl to a pH between 4 and 5. The precipitate was collected and dried to yield 10.2 g (91%) of 4,5-difluoroanthranilic acid.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[O:9]=[C:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH:8]1[NH:4][C:3](=[O:10])[CH2:2][CH2:1]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Cl[Mg]Cc1ccccc1
Solvent: ClCCl
Product: O=C(CCC1CCC(=O)N1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of tetrahydro-pyrrolizine-3,5-dione (5 g, 36 mmol) in CH2Cl2 (320 mL) at 0° C. was added benzyl magnesium chloride (1M solution in THF, 39 mL, 39 mmol) dropwise. The solution was stirred at 0° C. for 3 h and was quenched with saturated aqueous ammonium chloride. After warming to room temperature, the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2) to yield 5.9021 g of 5-(3-oxo-4-phenyl-butyl)-pyrrolidin-2-one. 1H NMR (CDCl3) δ 87.35-7.18 (m, 5H), 3.69 (s, 2H), 3.56 (m, 1H), 2.50 (t, 2H), 2.27 (m, 2H), 2.15 (m, 1H), 1.73 (m, 2H), 1.61 (m, 1H).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.C[N:28](C1C=CC=CN=1)C.[OH-].[NH4+]>O>[C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:28])=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12
Reactant: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reactant: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
To a stirred solution of 3-phthalimido-3(4-propoxyphenyl)propionic acid (1.41 g, 4.0 mmol) in 25 mL of under nitrogen was added carbonyldlimidazole (0.68 g, 4.2 mmol) followed by a catalytic amount of dimethylaminopyridine. The mixture was stirred for 45 minutes at room temperature. To the reaction mixture was then added concentrated ammonium hydroxide (0.29 mL, 4.4 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then diluted with 10 mL of water and the tetrahydrofuiran was removed in vacuo. The resulting slurry was filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 1.2 g of crude product. The crude product was purified by dissolving in 200 mL of ethyl acetate, stirring for 3h and then concentrating to an 80 mL volume. The resulting slurry was filtered and the solid was washed with ethyl acetate (2×20 mL). The solid was air-dried to afford 0.513 g (36%) of 3-phthalimido-3-(4-propoxyphenyl)propionamide as a white powder: mp 109.5-110.4° C.; 1H NMR (DMSO-d6, 250 MHz) δ7.85 (br s, 4H), 7.55 (br s, 1H), 7.33 (d, 2H, J=8 Hz), 6.75-7.00 (m, 3H), 5.69 (t, 2H, J=8 Hz), 3.88 (t, 2H J=6 Hz), 3.10-3.30 (m, 2H), 1.60-1.80 (m, 2H), 0.95 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ171.2, 167.7, 158.0, 134.5, 131.23, 131.19, 128.4, 123.1, 114.3, 68.9, 49.9, 36.9, 22.0, 20.4, 10.4; Anal. Calcd. for C20N2O40.37 H2O. Theoretical: C, 66.90; H, 5.61; N, 7.80. Found: C, 66.90; H, 5.52; N, 7.75.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][SH:5].C1(CCS)C=CC=CC=1.Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])=[O:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][S:5][C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:38])([F:40])[F:39])=[O:30])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: CC(C)CCS
Agent: SCCc1ccccc1
Product: CC(C)CCSc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure set forth above in Example 6, only making variations using 3-methylbutane-1-thiol to replace 2-phenylethanethiol to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (24.3 mg, 26.4% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.98, 6.99, 3.79, 3.56, 3.45-3.47, 3.40, 1.85-1.87, 1.52, 0.72-0.80, 0.46-0.48, 0.09-0.10.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][C:11]2=[O:22])(=[O:5])[CH3:4]>CO.C(Cl)Cl>[OH:5][CH:3]([C:6]1[CH:7]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[CH:9]=[C:10]2[C:15]=1[O:14][C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][C:11]2=[O:22])[CH3:4]
Reactant: COC(=O)c1cc(C(C)=O)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C(C)O)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
Sodium tetrahydroborate (82 mg, 2.16 mmol) was added to a solution of methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (650 mg, 1.96 mmol) in methanol (20 mL) and DCM (10 mL) at −10° C. After 15 min of stirring at −10° C., the reaction mixture was quenched with water (25 mL). The volatiles were removed and the aqueous layer extracted twice with DCM. The combined organics phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with diethylether and the solid collected by filtration to give methyl 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (500 mg, 76%) as a brown solid, which used for the next step without further purification. Mass Spectrum: M+H+ 334.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:17]/[C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Product: CCOC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from diethyl (4-chlorobenzyl)phosphonate and ethyl 3-formyl-4-methoxybenzoate obtained in step C of Example 1-2-1 in accordance with the same procedure as in the methods described in step A of Example 2-2-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([NH:38][S:39]([C:42]1[S:46][C:45](Cl)=[N:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F-].[K+].O>C1(C)C=CC=CC=1>[C:34]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[N:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Yield: 47.2 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.55 g, 0.93 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.26 g, 1.0 mmol), tetrakis(triphenyl-phosphine)palladium (0.064 g, 0.055 mmol) in toluene (10 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (10 mL), water (40 mL) was added and the water layer was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.23 g) as a light brown solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N=C=N.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH2:33][CH2:32]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Cc4ccc(C(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
To a solution of 4-isopropylphenylacetic acid (36 mg, 0.2 mmol) in anhydrous DCM (1 mL) was added PS-carbodiimide (100 mg, 0.3 mmol) and the mixture was shaken at rt for 15 min. Then, a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (27.5 mg, 0.1 mmol), as prepared in Example 1d, in anhydrous DMF (1 mL) was added to the mixture and it was shaken overnight at rt. It was then filtered and the resin was washed with THF/DCM and the combined filtrate and washings were concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to yield 13.4 mg (31%) of pure 1-[4-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-1-yl]-2-(4-isopropyl-phenyl)-ethanone. 1H-NMR (300 MHz, CDCl3): δ 9.06 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 7.23-7.19 (m, 4H), 4.82 (d, 1H), 4.17-4.00 (m, 7H), 3.76 (m, 2H), 3.57 (m, 1H), 3.23 (m, 1H), 2.96-2.80 (m, 2H), 2.06-1.80 (m, 4H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 433.2, found 434.4 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH2:14]Cl)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:11][O:13][CH3:14])[CH:3]=1
Reactant: CCOCCl
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 31.4 g (183.3 mmol) of 3-Bromo-phenol in 450 mL of dried acetonitrile a dispersion of 12 g (274.9 mmol) of sodium hydride (55% in oil) was added portionwise at 0° C. The mixture was then allowed to agitate at 0° C. for 3 hours. A solution of 25 g (210.8 mmol) of chloromethyl ethyl ether in 30 mL of acetonitrile was added dropwise, and the mixture was allowed to agitate overnight at room temperature (20-30° C.). The reaction mixture was then filtered and the filter cake was washed with a small amount of acetone. The combined filtrates were evaporated. This gave 32.3 g of 1-Bromo-3-methoxymethoxy-benzene. The resulting crude product was used in the next step without further purification.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.CC(OC)(C)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CO
Product: CCNC1(C(N)=O)CNC1

Procedure:
To a suspention of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1f; 36.1 g, 117 mmol) in methanol (560 ml) at room temperature was added concentrated aqueous HCl (19.5 ml, 234 mmol), resulting in a clear solution. To 20% Pd(OH)2 on carbon (3.75 g) was added methanol (85 ml), followed by the methanolic solution of I-2A-1f. The mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 20 hours. The reaction was then filtered through Celite® and then concentrated to low volume under reduced pressure, at which point a precipitate formed. The suspension was diluted with MTBE (500 ml), stirred for an additional hour, and the precipitate collected by vacuum filtration. The solid was washed washed with MTBE and then dried, in vacuo, to afford I-2A-1g (24.8 g, 98%) as a colorless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)C=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)C=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.72 g (3.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 178.3 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 0.954 g (4.6 mmol) of 4-trifluoromethoxy-phenylboronic acid and 3 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 426 mg.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14]Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:25]=2)=[C:19]([O:36][CH3:37])[CH:18]=1>C(#N)C>[NH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH:30]3[CH2:31][CH2:32][N:33]([CH2:14][CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[CH2:34][CH2:35]3)[N:25]=2)=[C:19]([O:36][CH3:37])[CH:18]=1
Reactant: BrCC1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1-c1nn(C2CCNCC2)c(=O)o1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(N)c(Cl)cc1-c1nn(C2CCN(CC3CCCCC3)CC2)c(=O)o1
Temperature: 70 °C
Reaction time: 48 h
Yield: 47.8 %

Procedure:
2.01 ml (13.92 mmol) of triethylamine and then 0.92 g (5.2 mmol) of cyclohexylmethyl bromide in 5 ml of acetonitrile are successively added at room temperature, under an argon atmosphere and with magnetic stirring, to a solution of 1.13 g (3.48 mmol) of 5-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one in 40 ml of acetonitrile and the mixture is stirred at 70° C. for 2 days. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform, the solution is washed a number of times with water and dried, the solvent is evaporated under reduced pressure and the residue is crystallized from acetone. 0.7 g of white solid is obtained. Melting point: 186.5-186.7° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.[CH:20]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21]1>CCO>[CH:20]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[O:3][C:4]4[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=4[N:6]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1
Reactant: C1CN(C2CC2)CCN1
Reactant: N#Cc1ccc2oc(Cl)nc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Yield: 52.6 %

Procedure:
To a solution of 2-chlorobenzooxazole-5-carbonitrile (1.69 g, 9.5 mmol) in EtOH (34 mL) was added Et3N (4.8 g, 47.5 mmol), followed by 1-cyclopropylpiperazine (1.44 g, 11.4 mmol) and the mixture was heated at reflux for 12 h. Then the volatiles were evaporated to remove EtOH and water (120 mL) was added. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 10% ethyl acetate in petroleum ether, 0.1% NH4OH added) to give 1.34 g (53%) of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:34]([NH2:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:43][C:34]([CH3:36])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35])=[O:7]
Reactant: CC(C)(N)c1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 97.2 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methylbenzoic acid (1.00 g, 5.86 mmol) was dissolved in DMF (20 mL), and the solution was treated with EDCI (2.25 g, 11.7 mmol), HOBT monohydrate (792 mg, 5.86 mmol) and cumylamine (1.69 mL, 11.7 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure. The obtained solid was purified by slurry using diisopropylether to obtain 3-chloro-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (1.64 g, yield 97%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15].[Cl-].[S:17](=[CH2:20])(=[O:19])=[O:18]>N1C(C)=CC=CC=1C.CCOCC>[CH3:20][S:17]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:13])([F:14])[C:10]1=[O:15])(=[O:19])=[O:18]
Reactant: O=C1N(c2ccccc2CO)CC1(F)F
Reactant: C=S(=O)=O
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)OCc1ccccc1N1CC(F)(F)C1=O
Temperature: 7 °C
Reaction time: 1.5 h

Procedure:
0.17 mmole of compound 4a is dissolved in 0.8 ml of 2,6-lutidine at 0° C., followed by the addition of 0.18 mmole of sulphonyl methane chloride to said solution. After stirring the reaction mixture for 90 min. at a temperature of 4 to 10° C., the solution is taken up in 1 ml of ether and then washed twice with 0.5 ml of saturated aqueous NaCl solution.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:34]([O:35]C(=O)C)[C@H:33]([O:39]C(=O)C)[C@@H:32]([CH2:43][O:44]C(=O)C)[O:31][C@H:9]1[O:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18]C(=O)C)[CH:14]=[CH:13][C:12]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=1)(=O)C>CO>[O:10]([C:11]1[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:12]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=1)[C@@H:9]1[O:31][C@H:32]([CH2:43][OH:44])[C@@H:33]([OH:39])[C@H:34]([OH:35])[C@H:8]1[OH:7]
Reactant: CCc1ccc(Cc2ccc(COC(C)=O)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2ccc(CO)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 103.3 %

Procedure:
Sodium methoxide (28% methanol solution; 0.3 mL) was added to a solution of 5-acetoxymethyl-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (1.0 g) in methanol (12 mL), and the mixture was stirred at room temperature for 40 minutes. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=7/1) to give 2-(4-ethylbenzyl)-5-hydroxymethylphenyl β-D-glucopyranoside (0.68 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.C(N(CC)CC)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1.Cl>O1CCCC1>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.1 %

Procedure:
To a solution of 100 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26 and 0.1 ml of triethylamine in 5 ml tetrahydrofuran was added 55 mg of nicotinic acid chloride hydrochloride, and the mixture was stirred at room temperature for two days. After the completion of the reaction, the reaction mixture was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 62 mg of the title compound as a colorless powder.
Reaction SMILES: C(CC[N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:8][N:7]=[N:6]1)#N.O.[OH-].[Li+]>C1COCC1.O.Cl>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:5][N:6]=[N:7]1
Reactant: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Preparation H7, Step 3: To a solution of methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate (180 mg, 0.7 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (50 mg, 2.1 mmol) in 5.0 mL of water. The reaction mixture was stirred at RT for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 100 mg (58% yield) of 3-(1H-tetrazol-5-yl)benzoic acid. MS found: (M+H)+=191.