Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of ethyl 2-chloroacetoacetate (50 g, 0.30 mol, Aldrich) and thiourea (45.6 g, 0.60 mol) in 400 mL of absolute ethanol was heated to reflux. After refluxing overnight the reaction mixture was allowed to cool to room temperature and then concentrated to half the original volume in vacuo. The remaining ethanol solution was poured into H2O (1L) and made basic (pH 10) with 2N NaOH. An off-white solid precipitated immediately. The mixture was stirred for ~10 minutes and then the solid was removed by vacuum filtration and dried to give 54.75 g (98% yield) of the desired product as a white solid: 1H NMR (CDCl3) 67 5.5 (bs, 2H), 4.25 (q, 2H), 2.5 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N:6][CH:7]=1.[OH:19]O>C(Cl)Cl.C[Re](=O)(=O)=O.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH:5]=[N+:6]([O-:19])[CH:7]=1
Reactant: Clc1cccc(Cl)c1-n1cc2cncc(Cl)c2n1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To a solution of 7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (2.7 g, 9.0 mmol) and methyltrioxorhenium (31 mg, 0.09 mmol) in DCM (6 mL) was added hydrogen peroxide (30% aq., 1.75 mL, 18.0 mmol) and the resulting mixture stirred at room temperature for 18 hours. A catalytic amount of MnO2 was added to the mixture and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was triturated in toluene to afford the title compound as a beige solid (2.5 g, 89% yield). LCMS (Method D): RT=2.57 min, m/z: 314 [M+H+].
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].C(OC(N1CCC[C@H](C)[C@@H]1C(O)=O)=O)C1C=CC=CC=1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: C[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Product: C[C@H]1CCCN[C@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1 instead using (2R,3S)-1-((benzyloxy)carbonyl)-3-methylpiperidine-2-carboxylic acid. MS (ESI) 259 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([CH:15]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:25](=[O:37])[C:24]2=[O:38])[CH2:16][CH2:17][CH:18]([F:20])[F:19])=[O:14])[CH3:11]>O1CCCC1>[C:33]([O:32][C:30]([NH:26][C:27]1[CH:28]=[CH:29][C:21]([CH:15]([CH2:16][CH2:17][CH:18]([F:19])[F:20])[C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:22][C:23]=1[C:24](=[O:38])[C:25]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:37])=[O:31])([CH3:35])([CH3:34])[CH3:36]
Reactant: CCOC(=O)C(CCC(F)F)c1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(F)F)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
1.53 g of isoindoline are added to 5.29 g of 5-(1-ethoxycarbonyl-4,4-difluorobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline in 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 1.7 g (25%) of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-5,5-difluoropentanoate; LC-MS retention time: 2.62 min (“nonpolar” gradient).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][C:4]2=[O:11])([O-:14])=[O:13]
Reactant: O=C1CCOc2ccccc21
Reactant: O=[N+]([O-])O
Product: O=C1CCOc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (200 ml) was cooled to from -30° to -35° C. and 4-chromanone (29.0 g) was added with stirring over 30 minutes. The mixture was further stirred for 30 minutes at the intact temperature and successively poured into ice water. The resulting mixture was extracted with ethyl acetate (2,500 ml). The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the crude product as a yellow solid. The crude product was washed with a solvent mixture, n-hexane:ethyl acetate=1:1, to obtain 6-nitro-4-chromanone (27.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:29][CH3:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][C:16]=2[O:17][CH2:18][C:19](O)=[O:20])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Cl-].[NH4+].O.O[N:35]1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:29][CH3:30])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][C:16]=2[O:17][CH2:18][C:19]([NH2:35])=[O:20])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1OCC(N)=O
Temperature: 25 °C
Reaction time: 27 h
Yield: 89.8 %

Procedure:
A mixture of 0.169 g of [2-[2-(5-cyano-2-methoxybenzene-sulfonylamino)ethyl]-5-isopropylphenoxy]acetic acid, 41.8 mg of ammonium chloride, 79.2 mg of 1-hydroxybenzotriazole monohydrate, 0.272 mL of N,N-diisopropylethylamine and 0.112 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was stirred at room temperature for 27 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane-ethyl acetate) to give 151.4 mg of 2-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:17]#[N:18])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(C#N)cc2c1
Reaction time: 3.5 h

Procedure:
To a suspension of 4-chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester [CAS Reg. No 403841-76-9] (5 g) in ethanol (30 ml) were added triethylamine (3.90 g) and Pd (5% on charcoal, 200 mg). The mixture was stirred under a hydrogen atmosphere for 3.5 h using a balloon. The catalyst was filtered off and the filtrate was concentrated. Since the reaction was not finished, the hydrogenation was repeated using the same conditions. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (2.1 g) as a colorless solid. MS (m/e)=227.2 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:14][CH:13]=2)[CH:23]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: CCOc1cccc(-c2cccs2)c1
Product: CCOc1cccc(-c2ccc(Cc3cc(Br)ccc3Cl)s2)c1

Procedure:
The above 2-(3-ethoxyphenyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-1-(5-(3-ethoxyphenyl)-2-thienylmethyl)benzene as colorless oil. APCI-Mass m/Z 407/409 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[C:23]([CH3:25])=[CH:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Cc1csc(N)n1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Solvent: CCO
Product: COc1cc(-c2cn3c(C)csc3n2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (300 mg, 0.98 mmol) and 2-amino-4-methylthiazole (112 mg, 0.98 mmol) in ethanol (5 mL) was heated to reflux for 2 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with a solution of saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)-3-methylimidazo[2,1-b][1,3]thiazole. 1H NMR (CD3OD, 500 MHz) δ 8.91 (d, 1H), 8.85 (s, 1H), 8.74 (t, 1H), 8.47 (d, 1H), 8.11 (t, 1H), 7.94 (d, 1H), 7.78 (s, 1H), 7.73 (d, 1H), 7.33 (s, 1H), 4.13 (s, 3H), 2.68 (s, 3H) ppm. MS (ESI) 322 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[C:3]=1[C:32](=[O:34])[NH2:33].Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>C(O)(=O)C.CN(C)C=O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:4]3[N:5]=[C:6]([S:8][CH3:9])[N:7]4[CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:1]=[C:2]4[C:3]=3[C:32](=[O:34])[NH2:33])=[C:12]([O:30][CH3:31])[CH:13]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(SC)nc(N)c1C(N)=O
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(SC)nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3OC)c(C(N)=O)c2n1
Temperature: 60 °C

Procedure:
A mixture of the product of Example 13D (1 g, 2.0 mmol), ethyl 3-bromo-2-oxopropanoate (796 mg, 4.1 mmol) and acetic acid (2 drops) in dimethylformamide (20 mL) was heated at 60° C. for 16 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with dichloromethane (2×100 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS: 586 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][N:15]([C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:25]3[CH2:26][CH2:27][C@@H:23]([N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:24]3)=[O:13])[S:10][C:3]=12
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 37 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.05 g, 4.94 mmole), SOCl2 (10 ml), tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate 34b (0.989 g, 4.94 mmole) and Et3N (0.689 ml, 4.94 mmole) in a manner as previously described for example 9d to give a brown oil (0.723 g, 0.30%). 1H NMR (300 MHz, CDCl3) δ8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.82 (1H, m), 3.93 (3H, m), 3.63 (1H, m), 2.82 (3H, s), 2.12 (2H, m), 1.47 (9H, s); ESIMS (MH+): 396.05.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])C1C=CC=CC=1>>[OH:15][C:16]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cc(-c2cccnc2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(-c2cccnc2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (6.0 mL) was added to 2-(benzyloxy)-5-(pyridin-3-yl)benzoic acid (0.31 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the obtained residue. The solid substance was collected by filtration to obtain 2-hydroxy-5-(pyridin-3-yl)benzoic acid as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:15]([O:17][C:18](=[O:26])/[CH:19]=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:26])[C@H:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH3:16]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CCO[Si](CCCN)(OCC)OCC
Product: CCOC(=O)C[C@H](NCCC[Si](OCC)(OCC)OCC)C(=O)OCC
Temperature: 30 °C
Reaction time: 8 h

Procedure:
221.0 g (1.0 mol) of 3-aminopropyltriethoxysilane were introduced into a standard stirrer apparatus. 172.0 g (1.0 mol) of maleic acid diethyl ester were added dropwise at room temperature over a period of about 4 hours. The exothermic reaction was maintained at about 30° C. by cooling the apparatus in a water bath. Stirring was then continued for a further 8 hours at room temperature. A clear, colorless liquid having a viscosity of about 30 mPa.s (23° C.) was obtained. Base titration showed almost complete conversion. The amine equivalent weight was about 398 g (theory: 393 g).
Reaction SMILES: [CH2:1]([C:3]1([CH2:36]C)[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:23]#[C:24][C:25]3[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=3)[CH:6]=[CH:5][C:4]1=2)C.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:3]1([CH3:36])[CH2:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:23]#[C:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:34][CH:35]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(CC)CC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(C(F)(F)F)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5 diethyl-8-(4-trifluoromethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 9) 70.0 mg (0.148 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH3:21][N:22]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[N:6]1[C:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([C:21]#[N:22])[C:3]=2[CH:4]=[N:5]1
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)c1cc(Br)c2cnn(C3CCCCO3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(C(F)(F)F)cc2c1cnn2C1CCCCO1
Temperature: 85 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A sealed-cap vial was charged with 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (1.03 g, 2.95 mmol), Zn(CN)2 (0.38 g, 3.24 mmol), Pd(PPh3)4 (0.24 g, 0.21 mmol), and NMP (8 mL). The mixture was degassed for 5 min under nitrogen and the mixture then stirred under nitrogen at 85° C. for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The crude mixture was purified by SiO2 chromatography to afford 1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole-4-carbonitrile as a solid (0.69 g, 79%). MS (ESI) m/z: 296.3 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[CH3:12][O-:13].[Na+]>C1(C)C(C)=CC=CC=1.CO>[CH3:12][O:13][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
(S M:Ross, L. O.; Goodman, L.; Baker, B. R. J. Am. Chem. Soc. 1959, 81, 3108) 5.3 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute methanol. Then 5.4 gram for sodium methoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 4.8 gram (98% yield). Mp: 133.8˜134.9° C.; MS: 166.2.0 (M+H)
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)#[N:23]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(C#N)cc3)sc2Cc2ccccc2)cc1
Yield: 39.5 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and p-cyanobenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of petroleum ether and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 39.5%, mp: 194-196 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.69 (2H, d, J=8.68 Hz, ArH), 7.23˜7.32 (5H, m, ArH), 7.36 (2H, d, J=8.68 Hz, ArH), 7.48 (2H, d, J=8.16 Hz, ArH), 7.72 (2H, d, J=8.16 Hz, ArH); EI-MS m/e (%): 425.2 (M+, 100), 130.0 (40); HREI-MS Calcd. for C25H19N3O2S: 425.1198. found: 425.1191. Anal. Calcd. for C25H19N3O2S: C, 70.57; H, 4.50; N, 9.88. found: C, 70.50; H, 4.39; N, 9.99.
Reaction SMILES: [CH3:1]C1C=CC(C)=CC=1C(O)=O.F[C:13]1[CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[CH3:1][C:14]1[CH:13]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1
Reactant: Cc1ccc(C)c(C(=O)O)c1
Product: Cc1ccc(C(=O)O)cc1C(=O)O

Procedure:
4-methylisophthalic acid was synthesized from 2,5-dimethylbenzoic acid following a similar procedure to that described for 5-fluoroisophthalic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[CH:15][C:8]=23)[C:4]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[N:3]1.[N:42]1([CH2:48][CH2:49][OH:50])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:20][N:45]5[CH2:46][CH2:47][N:42]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:44]5)=[CH:22][CH:23]=4)=[CH:15][C:8]=23)[C:4]([C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[N:3]1
Reactant: OCCN1CCNCC1
Reactant: Cn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: Cn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCN(CCO)CC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and 2-(1-piperazinyl)ethanol provided the title compound. ESMS [M+H]+: 678.4.
Reaction SMILES: C(N1C(C(OCC)=O)=NNN1)C1C=CC=CC=1.[CH2:18]([N:25]1[N:29]=[N:28][C:27]([C:30]([O:32]CC)=[O:31])=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S1(CCCC1)(=O)=O.[OH-].[K+:43]>C(O)C.O>[CH2:18]([N:25]1[N:29]=[N:28][C:27]([C:30]([O-:32])=[O:31])=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[K+:43]
Reactant: CCOC(=O)c1nnn(Cc2ccccc2)n1
Agent: CCOC(=O)C1=NNNN1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C([O-])c1nnn(Cc2ccccc2)n1

Procedure:
A mixture of ethyl 1-benzyl-2H-tetrazole-5-carboxylate and ethyl 2-benzyl-2H-tetrazole-5-carboxylate (7 g; prepared as described below and still containing a little sulpholane) was dissolved in hot ethanol (100 ml) and the hot solution was treated with a solution of potassium hydroxide (2.7 g) in water (8 ml). The white solid which separated was filtered off from the hot solution and washed with ethanol to give potassium 2-benzyl-2H-tetrazole-5-carboxylate (4.64 g), m.p. 264°-267° C. [The pure salt, obtained as a hemihydrate after recrystallisation from water, had a melting point of 272°-273° C.]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[O:18]([CH2:25][C:26](O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: O=C(O)COc1ccccc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(COc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 62.4 %

Procedure:
Example 21 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.028 g) and phenoxyacetic acid (0.017 g) to give the title compound (0.026 g).