Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]2[S:19](=[O:21])(=[O:20])[NH:18][C:17](=[O:22])[CH2:16]2)=[C:13]([F:23])[C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]([CH3:34])([CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C:27]#[N:28].C(N(CC)CC)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:33]=[CH:32]\[CH2:31][CH2:30][CH2:29][C:26]([CH3:34])([CH3:25])[C:27]#[N:28])=[C:13]([F:23])[C:14]=1[N:15]1[CH2:16][C:17](=[O:22])[NH:18][S:19]1(=[O:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCC(C)(C)C#N
Reactant: O=C1CN(c2c(OCc3ccccc3)ccc(Br)c2F)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C#N)CCC/C=C\c1ccc(OCc2ccccc2)c(N2CC(=O)NS2(=O)=O)c1F
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(6-benzyloxy-3-bromo-2-fluorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.0 g, 2.4 mmol), 2,2-dimethylhept-6-enenitrile (493 mg, 3.6 mmol), Pd(OAc)2 (108 mg, 0.48 mmol), triethylamine (1.67 mL, 12 mmol) and 2-(di-t-butylphosphino)biphenyl (286 mg, 0.96 mmol) in acetonitrile (15 mL) is stirred in a microwave apparatus at 100° C. for 10 min. It is then filtered and the solvent is removed to give the title compound as a red liquid. The material is used in the next step without purification.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:10]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)=[N:9][CH:8]=1)C.COC(=O)C1C=C(C2C=CC(C(F)(F)F)=CC=2)C(CCC2C=NC=NC=2)=NC=1.Cl.O1CCOCC1>O1CCCC1.CO>[N:29]1[CH:30]=[C:25]([CH2:24][CH2:23][C:10]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[CH:8][N:9]=2)[CH:26]=[N:27][CH:28]=1
Reactant: CCOC(=O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: COC(=O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cnc(CCc2cncnc2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Aqueous 1M lithium hydroxide solution (2.25 ml, 2.25 mmol) was added to a solution of 6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester and 6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (46:54, 196 mg, 0.49 mmol) in tetrahydrofuran and methanol (6:1, 7 ml). The reaction mixture was stirred for 20 hours at room temperature then concentrated in vacuo. The residue was treated with 4M HCl in dioxane (0.56 ml, 2.25 mmol) and concentrated in vacuo to give crude 6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinic acid. This material was used in the subsequent amide coupling step without further purification. LC at 215 nm; Rt 1.72: 89%, m/z (ES+): 374 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>CO.C1(C)C=CC=CC=1.[Pt]=O>[O:1]=[C:2]1[CH2:11][CH:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)Cc1cc(=O)[nH]c2ccccc12
Agent: O=[Pt]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC1CC(=O)Nc2ccccc21
Yield: 73 %

Procedure:
50 g (0.23 mol) of methyl 2-oxo-1,2-dihydro-4-quinolinacetate dissolved in 1 l of methanol is subjected to hydrogenation in a Parr apparatus in the presence of 2 g of Adams' platinum oxide under 40 to 45 psi and at 60° C. for approximately 1 h. After the catalyst is filtered off and the solvent evaporated off, the oily residue is chromatographed on silica. Elution with a dichloromethane/acetone (95:5) mixture yields an oil, which is solubilized in 250 ml of boiling toluene. After being cooled, this solution is diluted with 250 ml of petroleum ether. The crystalline product thereby obtained is drained, washed and dried. 36.8 g (73%) of methyl (±)-2-oxo-1,2,3,4-tetrahydro-4-quinolineacetate, melting point 115°-116° C., are obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:30].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][N:7]2[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][CH2:10][CH3:11])[N:3]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:2]2=[O:1])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCCc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propyl-3,4-dihydropyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.4 g) and N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.076 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.63 g, 81%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1>S(Cl)(Cl)=O>[CH3:17][C:14]1([CH3:18])[CH2:15][O:16][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[C:2](=[O:1])[O:3][CH2:4]3)=[N:13]1
Reactant: CC(C)(CO)NC(=O)c1ccc2c(c1)COC2=O
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc3c(c2)COC3=O)=N1
Temperature: -5 °C

Procedure:
To thionyl chloride (130 ml), cooled at −10° C., 2-[[(1-oxo-1,3-dihydroiso-benzofuran-5-yl)carbonyl]amino]-2-methyl-1-propanol (85 g, 0.34 mol) is added portionwise with stirring. The temperature is maintained at −10→−5° C. for 1.5 hours whereafter the cooling is removed and the reaction is stirred overnight at ambient temperature. It is then cooled to 0° C. and tetrahydrofuran (860 mL) is added dropwise keeping the temperature below +8° C. The obtained suspension is kept under stirring for 2 hours at 5° C., and then filtered and the crystals washed with tetrahydrofuran (150 mL). The wet solid is dissolved in deionized water (400 mL) and the pH is adjusted to 9.1 by the addition of 25% aqueous ammonia. The solid is filtered, washed with deionized water and dried for 14 hours at 50° C. under reduced pressure. Yield: 62.8 g (80%) of a white product having a purity (HPLC, peak area)=94%. 1H NMR (DMSO d-6, 500 MHz): 1.31 (6H, s), 4.18 (2H, s), 5.44 (2H, s), 7.9 (1H, d, J=11.3 Hz), 8.01 (1H, d, J=11.3 Hz), 8.12 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])[CH3:2].C([Li])CCC.CN(C)CCN(C)CCN(C)C.[C:28](=[O:30])=[O:29]>C1COCC1.Cl>[CH2:1]([O:3][C:4]1[C:5]([F:10])=[C:6]([CH:7]=[CH:8][CH:9]=1)[C:28]([OH:30])=[O:29])[CH3:2]
Reactant: CCOc1ccccc1F
Reactant: O=C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C. was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed by N′-(2-dimethylaminoethyl)-N,N,N′-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 h at −78° C. before it was transferred quickly via large cannula to a mixture of crushed dry ice (freshly crushed under N2) under ether. The mixture was warmed to RT, diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30 mL), washed with 10 mL brine, and dried over MgSO4 to give 3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc. 184.1. found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4].[Li+].[OH-]>CO>[C:31]([O:30][C:28]([N:6]1[CH2:7][CH:8]([N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C:11]([O:13][CH2:14][C:15]([Cl:17])([Cl:16])[Cl:18])=[O:12])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)C1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)O
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 4-[(2,4-difluoro-benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester (8 g, 14.7 mmol) in MeOH (50 ml) cooled to 0 degree was added LiOH (2.47 g, 58.8 mmol), and the mixture was stirred overnight. After removal of methanol, the residue was acidified with 2M HCl. The aqueous layer was extracted with EA, and the organic solution was dried and concentrated. The residue was purified by chromatography (PE:EA=3:1) on silica gel to afford the title product as yellow oil (3.5 g, 6.5 mmol). MS m/e=531.2 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[C:17]([C:19](OCC)=[O:20])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O=[Si]=O>O1CCCC1>[OH:20][CH2:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[CH3:6]
Reactant: CCOC(=O)C1(C)Cc2ccccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: C1CCOC1
Product: CN1Cc2ccccc2CC1(C)CO
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
N-tert-Butyloxycarbonyl-3-ethoxycarbonyl-3-methyl-1,2,3,4-tetrahydroisoquinoline (10 g) was dissolved in 100 mL of tetrahydrofuran and lithium aluminum hydride (3.42g) was added carefully at 0° C. and the mixture was stirred for 30 min. Then, it was refluxed for 3 h and the reaction mixture was poured onto ice portion wise. The mixture was acidified to pH 1 by 2N HCl (2000 mL) and fltered over Celite 545. Volatile components in the resulting clear solution was evaporated in vacuo and after addition of 100 mL brine, it was extracted with dichloromethane (100 mL×3). Combined organic layer was dried over MgSO4, filtered and concentrated to afford the product as yellow solid (5.98 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:18]2[S:22][C:21](B(O)O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[C:12]1([C:18]2[S:22][C:21]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][C:6](=[O:11])[CH2:5]4)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: OB(O)c1ccc(-c2ccccc2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Cc2cc(-c3ccc(-c4ccccc4)s3)ccc2N1
Temperature: 120 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of 5-bromooxindole (100 mg, 0.572 mmol) in dioxane/H2O (3 ml/1 ml) was added Pd(PPh3)4 (55 mg, 0.047 mmol), 5-phenylthiophene-2-boronic acid (106 mg, 0.519 mmol) and potassium carbonate (196 mg, 1.42 mmol). The mixture was stirred at 120° C. for 1 hour under microwave irradiation. The residue was extracted with CHCl3, and the organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (CHCl3/MeOH) to give 5-(5-phenylthiophen-2-yl)indolin-2-one (44 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(OCCC3CCNCC3)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOc3ccc(OCc4ccccc4)cc3)CC2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A solution/suspension of 4-[2-[4-(benzyloxy)phenoxy]ethyl]piperidine (220 mg, 0.71 mmol), 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (277 mg, 0.78 mmol, 1.1 equiv.), sodium tert-butoxide (136 mg, 1.42 mmol, 2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (45 mg, 40 μmol, 0.06 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 50 mg, 90 μmol, 0.12 equiv.) in anhydrous toluene (20 mL) was stirred overnight at 100° C. under N2. After cooling to room temperature, the mixture was concentrated under vacuum, and the residue was taken up in 500 mL of EtOAc and washed with brine. The organic layer was dried and concentrated in vacuo, and the residue was applied onto a silica gel column, which was eluted with EtOAc/CH2Cl2 1:5 to 1:2 to provide the title compound (300 mg, 72%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.90 (s, 1H), 7.67 (s, 1H), 7.46-7.34 (m, 5H), 7.08 (s, 1H), 6.93 (d, 2H, J=9.3 Hz), 6.85 (d, 2H, J=9.3 Hz), 5.02 (s, 2H), 4.18-4.13 (m, 3H), 4.00 (t, 2H, J=5.7 Hz), 3.76 (m, 2H), 3.41 (m, 2H), 2.83 (s, 2H), 2.07-2.03 (m, 2H), 1.90-1.72 (m, 3H), 1.77 (m, 3H), 1.49 (s, 9H), 1.40-1.30 (m, 2H), 1.28-1.26 (m, 1H). LC-MS (ESI) m/z 588 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[N:7][N:8]2C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][C:3]=1[NH2:39].[C:40]([OH:43])(=O)[CH3:41]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:39][C:40](=[O:43])[CH3:41]
Reactant: CC(=O)O
Reactant: Nc1cc2c(/C=C/c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Product: CC(=O)Nc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F

Procedure:
525 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine and 80 μl of glacial acetic acid were dehydraing-condensed in accordance with Example 127, followed by deprotection in the similar method as described in Example 16, to afford 150 mg of the title compound as bright yellow crystals.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([N:18]1[CH2:17][CH:16]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19]1)=[O:23]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 105.2 %

Procedure:
Triethylamine (2.6 mL, 19.15 mmol) was added to a suspension of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.50 g, 7.66 mmol) in DCM (30 mL). The resulting mixture was stirred for 5 minutes until complete dissolution of the solids, then was cooled to 0° C., and methyl chloroformate (0.65 mL, 8.43 mmol) was added dropwise. A thick white precipitate formed. The reaction mixture was warmed to room temperature and stirred for 1 hour, then was quenched by addition of water, and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give 1.75 g of 4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester as a pale yellow oil. This crude product (7.66 mmol) was dissolved in chloroform (30 mL) and 3-chloroperoxybenzoic acid (77%, 2.22 g, 9.95 mmol) was added. The resulting solution was stirred at room temperature for 18 hours. An aqueous solution of Na2SO3 (20%, 30 mL) was added and the resulting mixture was vigorously stirred for 1 hour. The phases were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with a saturated aqueous solution of NaHCO3, dried over MgSO4, filtered and evaporated under reduced pressure to give a pale yellow oil. This crude oil was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 1.68 g (94% 2 steps yield) of 6-phenyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[CH2:36][CH2:35][O:34][CH:33]1[C:37]1[O:41][C:40]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:38]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[O:41][C:37]([CH:33]2[O:34][CH2:35][CH2:36][O:32]2)=[CH:38][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1ccc(C2OCCO2)o1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(C2OCCO2)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-(1,3-dioxolane-2-yl)furan-2-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 71 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-(1,3-dioxolane-2-yl)furan-2-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2=[C:12]([CH3:15])[N:13]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:21](=[O:22])[C:20]4[CH:31]=[CH:32][C:17]([F:16])=[CH:18][CH:19]=4)=[CH:30][CH:29]=3)[N:14]=[C:8]2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c2cnn(C(C)(C)C)c(=O)c12
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)n(C(C)(C)C)ncc2nn1Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (10 ml) was dissolved 5-t-butyl-3-methyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (516 mg) followed by addition of 4-(4-fluorobenzoyl)benzyl bromide (1.1 g) and potassium carbonate (525 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with diethyl ether and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexaneethyl acetate=1:1), washed with the following solvent, and dried. As the washing solvent, n-hexanediethyl ether was used for 5-t-butyl-1-[4-(4-fluorobenzoyl) benzyl]-3-methyl-1H-pyrazolo[3,4-d]-pyridazin-4(5H)-one and diethyl ether-ethyl acetate for 5-t-butyl-2-[4-(4-fluorobenzoyl)benzyl]-3-methyl-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1.O>C1COCC1>[CH2:23]([S:24][C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: SCc1ccccc1
Reactant: CCn1ccnc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ccnc(SCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To 250 mg (1.23 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 340.3 mg (2.46 mM) of potassium carbonate in 4 ml of THF were added 159 μl (1.35 mM) of benzylthiol. The reaction mixture was then stirred at room temperature for 16 h. Water was added and the organic phase was extracted with ethyle acetate. The combined organic layer was washed with water, dried on anhydrous sodium sulfate and the solvent was removed under vacuum, to give a solid, which was triturated in diisopropyle oxide, filtrated and dried under vacuum, to give 250 mg of 3-(benzylthio)-1-ethylpyrazin-2(1H)-one. Yield: 82%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[N:6]=[C:5]2[N:13]([NH2:19])C(OCC)=O.CN(C)[CH:22]=[O:23]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[C:22](=[O:23])[NH:19][N:13]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2ccc(F)cc12
Product: O=c1[nH]nc2c3cc(F)ccc3[nH]c(=O)n12
Temperature: 25 °C

Procedure:
3.7 g (0.014 mol) of ethyl 6-fluoro-2-hydroxy-quinazolin-4-yl-carbazate in 75 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, washed with acetone and dried in a vacuum. Yield: 1.7 g (56%) of 9-fluoro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. >350° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C1C(=O)N([Cl:20])C(=O)C1.O>C(#N)C>[Cl:1][C:2]1[C:10]([Cl:20])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O
Product: COc1cc(Cl)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 549 %

Procedure:
A mixture of 4-chloro-2-methoxybenzoic acid (10 g, 53.6 mmol) and NCS (35 g, 19.2 mmol) in acetonitrile (200 mL) was stirred at room temperature for 48 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to get the crude product (23.3 g).