Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH:8]=1.Cl[C:19]1[N:20]=[C:21]2[CH:29]=[CH:28][N:27]=[CH:26][C:22]2=[N:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:17])=[C:7]([C:9]([CH:11]2[CH2:12][CH2:13][N:14]([C:19]3[N:20]=[C:21]4[CH:29]=[CH:28][N:27]=[CH:26][C:22]4=[N:23][C:24]=3[Cl:25])[CH2:15][CH2:16]2)=[O:10])[CH:8]=1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: O=C(c1cc(Cl)ccc1F)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cl)ccc1F)C1CCN(c2nc3ccncc3nc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
A mixture of (5-chloro-2-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (153 mg, 0.550 mmol), 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol) and DIPEA (261 μL, 1.500 mmol) in DCM (1.67 mL) was stirred at rt for 30 min. The mixture was partitioned between aqueous NH4Cl and EtOAc. The organic layer was filtered through a pad of silica, washing with EtOAc, and the filtrate was concentrated under reduced pressure to give (5-chloro-2-fluorophenyl)(1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)methanone (205.5 mg) as an orange solid. ESI-MS m/z [M+H]+ 405.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=O.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cccc(F)c1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 3-fluorobenzoate (2.0 g, 11.9 mmol) and 4-methylpyridine (1.1 mL, 1.0 g, 10.8 mmol) in THF (9 mL) at 0° C. under nitrogen atmosphere was added dropwise lithium bis(trimethylsilyl)amide (23.8 mL, 1.0M in hexane, 23.8 mmol) During the addition a precipitate was formed and the suspension was stirred at room temperature overnight. The reaction was diluted with hexane (40 mL) and filtered. The solid was partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow solid (2.09 g, 82%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][S:24][C:23]=2[CH:33]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:33][C:23]=5[S:24][CH:25]=4)[CH2:28][CH2:29]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(CCCl)c2C)C1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(CCN3CCC(c4csc5cc(F)ccc45)CC3)c2C)C1

Procedure:
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21](=[O:23])[CH3:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([C:24](=[O:26])[CH3:25])[CH:13]=2.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.O1CCOCC1.C(Cl)(Cl)Cl.CO>[CH:2]([NH:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21](=[O:23])[CH3:22])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([C:24](=[O:26])[CH3:25])[CH:13]=2)([CH3:4])[CH3:1]
Reactant: CC(=O)c1ccc2c(c1)c1cc(C(C)=O)ccc1n2CCN
Reactant: CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)c1ccc2c(c1)c1cc(C(C)=O)ccc1n2CCNC(C)C

Procedure:
Acetone (5 mL, 68.10 mmol) was added to a solution of compound 53 (1.25 g, 4.25 mmol) in CH2Cl2 (50 mL). Then STAB (3.0 g, 14.15 mmol) was added. The mixture obtained was stirred at room temperature for 4.5 h (TLC monitoring, eluent: CHCl3-MeOH, 9:1) and then poured into an aqueous solution of NaHCO3. The organic layer was separated. The aqueous layer was extracted with CH2Cl2. The product was dried over Na2SO4 and evaporated. The residue was purified on a column, eluent: CHCl3-MeOH 99:1→90:10. Example 7 (1.04 g, 73%) was isolated as a rapidly crystallizing oil. For the preparation of its hydrochloride, the base was dissolved in CH2Cl2. Then, a solution of HCl in dioxane was added. The mixture was evaporated to dryness. The product was washed with ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]#[N:20])=[C:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:49][O:50][C:51](=[O:62])[C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58](=[NH:61])[NH:59]O)[CH:53]=1>ClCCCl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([C:19]#[N:20])=[C:9]1[C:21]1[O:22][N:61]=[C:58]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([C:51]([O:50][CH3:49])=[O:62])[CH:53]=2)[N:59]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cccc(C(=N)NO)c1
Reactant: COc1ccc2c(C#N)c(C(=O)O)n(C(=O)OC(C)(C)C)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cccc(-c2noc(-c3c(C#N)c4ccc(OC)cc4n3C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), is added DCC (310 mg, 1.5 mmol), followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture is stirred at room temperature for 2 h and filtered. The filtrate is collected and the solvent is replaced with chlorobenzene, followed by the heating at 150° C. for 48 h. After cooling to room temperature, the solvent is removed in vacuo and the residue is chromatographed (silica gel, CH2Cl2/EtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylic acid tert-butyl ester, which is treated with 50% TFA in DCM (10.0 mL) at room temperature for 1 h. After removal of the volatiles in vacuo, the residue is suspended in water and neutralized with K2CO3 to provide the desired product, methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate, compound 226 (350 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:61]1[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=1.C([O-])([O-])=O.[Na+].[Na+].C>O1CCOCC1.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:22][C:19]1[O:20][CH2:21][C:17]2([C:13]3([CH2:14][O:15][CH2:16]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:61]2[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=2)=[CH:7][CH:6]=3)[N:18]=1
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: N#Cc1ncccc1-c1ccc2c(c1)C1(COC(N)=N1)C1(COC1)C1(CCC1)O2
Temperature: 100 °C
Reaction time: 7 h
Yield: 68.4 %

Procedure:
A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (300 mg, 0.531 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (150 mg, 0.584 mmol), potassium acetate (91.1 mg, 0.928 mmol) and bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) in dioxane (2.4 mL) was stirred for 7 hours at 100° C. To the mixture was added 3-bromo-2-cyanopyridine (243 mg, 1.33 mmol), Na2CO3 (225 mg, 2.12 mmol) and water (0.60 mL), and the mixture was stirred for 2 hours at 100° C. The mixture was treated with charcoal, and filtered off. The filtrate was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated to give a pale brown oil. The oil was dissolved in toluene (3.0 mL) and to the mixture was added silica gel (neutral; 900 mg). The mixture was refluxed for 1 hour. The solvent was evaporated off. Silica gel column chromatography (CHCl3-EtOH, a linear gradient of EtOH from 0 to 10%) afforded a solid. The solid was triturated in Et2O, collected by filtration, washed with Et2O and dried at reduced pressure at 70° C. to give 3-(2″-aminotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-6′-yl)pyridine-2-carbonitrile (141 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(Cl)=CC(C(F)(F)[F:30])=CN=1.ClC1C(OC)=CC(B(O)O)=C(F)C=1>>[Cl:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([Cl:18])=[CH:16][C:17]=2[F:30])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: COc1cc(B(O)O)c(F)cc1Cl
Product: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Yield: 19 %

Procedure:
In a preparation similar to that described above for 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine, reaction of 8.9 g (41 mmol) of 2,3-dichloro-5-trifluoromethylpyridine and 7.9 g (41 mmol) of 4-chloro-2-fluoro-5-methoxybenzeneboronic acid and subsequent purification of the crude product by chromatography on silica gel (methylene chloride as eluent) resulted in 2.6 g of colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=1[O:24][CH3:25])([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([CH:14]([CH3:16])[CH3:15])[N:22]=2)[CH:7]=1
Reactant: COc1ccc(N)nc1C(C)C
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(OC)c(C(C)C)n1
Temperature: 80 °C
Yield: 37 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (747 mg, 3.38 mmol) in acetonitrile (11.3 mL) was added 6-isopropyl-5-methoxypyridin-2-amine (562 mg, 3.38 mmol) and heated to 80° C. for 20 h. The mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 10 to 50% ethyl acetate in hexanes) gave ethyl 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (438 mg, 1.25 mmol, 37%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.61 (s, 1H), 9.15 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.57 (q, J=7.6 Hz, 2H), 3.88 (s, 3H), 3.53 (m, 1H), 1.53 (t, J=7.0 Hz, 3H), 1.31 (d, J=6.7 Hz, 6H); MS (EI/CI) m/z: 351.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O.ClC1C=CC2N(C(CC3C=C4C(=CC=3F)N(C)N=C4)=CN=2)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)ccc21
Agent: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Agent: II
Agent: O=[PH2]O
Product: CC(c1ccc2c(cnn2C)c1)c1cnc2ccc(Cl)nn12
Yield: 95.5 %

Procedure:
The title compound (390.0 mg, 91%) was synthesized from 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(1-methyl-1H-indazol-5-yl)-ethanol (430.0 mg, 1.31 mmol), I2 (832.0 mg, 3.28 mmol) and H3PO2 (0.72 mL, 6.56 mmol) using the same procedure as described in the synthesis of compound 69.2. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.18 (d, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.55 (m, 2H), 7.36 (d, 1H), 7.28 (d, 1H), 4.70 (q, 1H), 3.99 (s, 3H), 1.74 (d, 3H). LCMS (method A): [MH]+=312, tR=5.49 min.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][N:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:14][CH2:18][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)[N:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]n1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)n1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 44A for the product of Example 1E and substituting 6-methyl-3(2H)-pyridazinone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=2.15 Hz, 1H) 8.01 (d, J=8.90 Hz, 1H) 7.67 (dd, J=8.90, 2.15 Hz, 1H) 7.16 (d, J=9.51 Hz, 1H) 7.00 (d, J=9.51 Hz, 1H) 3.52-3.64 (m, 1H) 2.72-2.86 (m, 1H) 2.53-2.73 (m, 2H) 2.40 (s, 3H) 2.24-2.38 (m, 4H) 1.65-1.75 (m, 2H) 1.54-1.65 (m, 4H) 1.46 (d, J=4.91 Hz, 2H). MS: (M+H)+=381.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([CH3:29])[CH:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: Cc1cc2ncc3c(n2n1)CC1CCCC3N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-5-methylpyrazole.
Reaction SMILES: [C:1](C=P(CCCC)(CCCC)CCCC)#N.C1(C)C=CC=CC=1.[CH2:24]([C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[N:29][NH:30]2)[CH3:25]>C1(C)C=CC=CC=1>[CH:24]([C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[N:29][NH:30]2)([CH3:1])[CH3:25]
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: CCc1c(O)ccc2[nH]ncc12
Solvent: Cc1ccccc1
Product: CC(C)c1c(O)ccc2[nH]ncc12

Procedure:
A cyanomethylenetributylphosphorane/toluene solution (1.2 g, 4.53 mmol) was added to a solution prepared by dissolving the 4-ethyl-1H-indazol-5-ol (359 mg, 1.46 mmol) obtained in Example 682 and the cis-2-(4-hydroxycyclohexyl)-1H-isoinzole-1,3(2H)-dione (854 mg, 3.48 mmol) obtained in Example 323, (c) in toluene (15 ml), and the resulting mixture was stirred at 120° C. for 3 hours. The reaction solution was concentrated, and to the resulting residue were added chloroform and a 1N-aqueous sodium hydroxide solution to effect partition, followed by extraction with chloroform (twice). The extract solution was dried over anhydrous magnesium sulfate. The residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/1) to obtain trans-2-{4-[(4-ethyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (681.1 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[S:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:7])[N:32]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:34][CH:33]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Yield: 71 %

Procedure:
The title compound (3.64 g, 71%) was synthesized by a method similar to that in Example 331 and using 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid and 4-sulfamoylbenzylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1.CN(C=O)C.CCN(CC)CC.C(O)=O>C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CCCc1cc(C(=O)OC)cc(OC)c1OS(=O)(=O)C(F)(F)F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCCc1cc(OC)cc(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a mixture of 3-methoxy-5-propyl-4-trifluoromethanesulfonyloxybenzoic acid methyl ester (1.0 g, 2.8 mmol), Pd(OAc)2 (31 mg, 0.138 mmol) and 1,1′-bis-(diphenylphosphino)ferrocene (155 mg, 0.28 mmol) at room temperature was added DMF (20 mL), then Et3N (1.17 mL, 8.4 mmol) followed by formic acid (0.21 mL, 5.6 mmol). The resulting mixture was stirred at 60° C. for 2 h and cooled to room temperature. The reaction mixture was diluted with aqueous NaHCO3 solution (150 mL) and then extracted with EtOAc (3×70 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by column chromatography to afford 3-methoxy-5-propylbenzoic acid methyl ester (0.56 g).
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH2:12][O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)(=O)=O)=CC=1.[F-:35].C([N+](CCCC)(CCCC)CCCC)CCC>O>[F:35][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[CH2:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(S(=O)(=O)OC(COc2ncnc3ccccc23)c2ccc(C(C)(C)C)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(C)(C)c1ccc(C(F)COc2ncnc3ccccc23)cc1

Procedure:
A 15 ml round bottom flask is charged with 4-(2-p-toluenesulfonyloxy-2-(4-tert-butylphenyl) ethoxy) quinazoline (0.3 g, 0.84 mmol). Tetrabutylammonium fluoride solution (1M in THF, 4.2 ml, 4.2 mmol) is then added to it and the solution is heated at reflux for 60 minutes. The mixture is then cooled and water is added to it. It is then extracted with dichloromethane, washed with water and dried. The crude obtained after concentration is purified by silica gel flash chromatography (ethyl acetate/hexanes) to obtain the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)cc(CC(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)cc(Cl)c1
Yield: 85 %

Procedure:
A solution of 3-chloro-5-methylphenylacetic acid (5.0 g; 27.09 mmol; from step (iii) above) and H2SO4 (conc.; 0.1 mL) in EtOH (25 mL) was refluxed overnight. The solution was concentrated, and the resultant mixture digerated in Na2CO3 solution (75 mL). After extraction with ether (2×75 mL) the combined organic phases were washed with brine, dried (Na2SO4), and evaporated to yield 4.92 g (85%) of the sub-title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[N:13][CH:14]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)c1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)c1cncc(N)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of methyl 5-tert-butoxycarbonylamino-3-pyridinecarboxylate (5.7 g) and conc. hydrochloric acid (11.4 ml) in methanol (57 ml) was stirred for 1 hour at 40° C. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml) under stirring, and adjusted to pH 9.0 with 10% potassium carbonate aqueous solution. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diethyl ether-methanol to afford methyl 5-amino-3-pyridinecarboxylate (2.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:17][C:14]2([CH3:16])[CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+:19]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:17][C:14]2([CH3:15])[CH3:16])[C:9]([O-:11])=[O:10])=[CH:6][CH:7]=1.[Na+:19]
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC1(C(=O)[O-])c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of ethyl 2-(4-chlorophenyl)-2,3-epoxy-3-methylbutanoate (3.05 g, 12 mmol), prepared in Example 1d, and sodium hydroxide (0.48 g, 12 mmol) in absolute ethanol (40 ml) was refluxed for 11/2 hours. After cooling to room temperature, the precipitate was filtered off and the filtrate was evaporated in vacuo to give a residue. The precipitate and the residue from evaporation were combined and washed with isopropyl ether to give the product (2.40 g, 80%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([O:30][CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.[CH2:38](I)[CH3:39]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:38][CH3:39])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[C:9]([O:30][CH3:31])=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: COc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(C4CCNCC4)C3=O)cc12
Reactant: CCI
Product: CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(c3)c(OC)nn4Cc3ccc(Cl)cc3C(F)(F)F)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-methoxy-1H-indazol-5-yl}methylidene)-3-(1-ethylpiperidin-4-yl)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-3-methoxy-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 29) and ethyl iodide following General Procedure S.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CCN(C(C)C)C(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:4][CH2:3][CH2:1][OH:2])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: NCCO
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CNCCO)cc1

Procedure:
A solution of ethanolamine (10.05 mL, 166.6 mmol), DIPEA (5.08 mL, 29.2 mmol) and 4-nitrobenzyl bromide (6.00 g, 27.8 mmol) in DCM (50 mL) was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the resulting residue partitioned between water and EtOAc. The aqueous phase was separated and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound A68 as a light yellow solid (3.34 g, 61%); 1H NMR (300 MHz, d6-DMSO) δ 8.18 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 4.49 (t, J=5.4 Hz, 1H), 3.84 (s, 2H), 3.47 (q, J=5.6 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.28 (s, 1H).