Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([C:42]([F:45])([F:44])[F:43])([C:38]([F:41])([F:40])[F:39])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[C:23]([CH3:36])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:37])(C)(C)C.[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[N:55][C:56](Br)=[N:57][CH:58]=1)[CH3:49].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[N:55][C:56]([C:24]2[CH:25]=[CH:26][C:21]([C:16]([CH2:19][CH3:20])([C:13]3[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:7]([OH:6])([C:42]([F:44])([F:45])[F:43])[C:38]([F:41])([F:40])[F:39])=[C:11]([CH3:37])[CH:12]=3)[CH2:17][CH3:18])=[CH:22][C:23]=2[CH3:36])=[N:57][CH:58]=1)[CH3:49]
Reactant: CCC(CC)(c1ccc(/C=C/C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 95.5 °C
Reaction time: 10 h
Yield: 40.8 %

Procedure:
Degassed N,N-dimethylformamide (0.32 mL) was added to 2-[4-(1-{4-[(E)-3-(t-butyl-dimethyl-silanyloxy)-4,4,4-trifluoro-3-trifluoromethyl-1-butenyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 77-(1); 35.8 mg, 0.0523 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 37.3 mg, 0.152 mmol), tetrakis(triphenylphosphine)palladium (0) (29.8 mg, 0.0258 mmol) and potassium phosphate (48.7 mg, 0.229 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 91 to 100° C. for 10 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (13 mg, 41%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].I[CH3:19]>CN(C=O)C>[CH3:19][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.1 %

Procedure:
A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g, 1.395 mmol) in DMF (2.5 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) in anhydrous DMF (2.5 mL) at 0 C. The reaction mixture was stirred at 0 C for 10 min followed by dropwise addition of iodomethane (86 μL, 1.395 mmol). The mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was re-treated with sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) and iodomethane (86 μL, 1.395 mmol) and was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure, dissolved in DCM and washed with a saturated aqueous solution of sodium bicarbonate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by FCC (EtOAc: heptane, 1:1) to afford the title compound (0.074 g, 23%). Method B HPLC-MS: MH+ requires m/z=229 Found: m/z=174 (MH+-tBu) Rt=1.98 min (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:21]2[C:25]([NH2:26])=[CH:24][N:23]([CH3:27])[N:22]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:26][C:25]3[C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=4)=[N:22][N:23]([CH3:27])[CH:24]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cn1cc(N)c(-c2cccc(Cl)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cccc(Cl)c2)n1
Reaction time: 1 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.166 g, 0.768 mmol) in dichloromethane (8 mL) was added 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine (73.6 mg, 0.354 mmol) and triethylamine (0.20 mL, 1.4 mmol) at room temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to yield 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which is carried forward without purification. LCMS (ESI) m+H=387.1.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:10][C:1]1[CH:6]=[C:5]2[C:4]([CH2:7][CH2:8][NH:9][CH:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(c1ccccc1)NCC2
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 82 %

Procedure:
A mixture of 12.0 g (89 mmol) of 2-p-tolylethylamine and 11.21 ml (111 mmol) of benzaldehyde in PPA (300 g) was heated at 100° C. for 5 days. After cooling to RT it was poured into a saturated aqueous K2CO3 solution (1200 ml). Following the addition of DCM (300 ml) it was stirred for 50 min at RT. Then the phases were separated and the aqueous phase was extracted with DCM (2×500 ml). The organic phases were combined, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 16.3 g of 7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline were obtained as the crude product, which was reacted further with no additional purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])=[CH:3][CH:2]=1.[C:16](=[O:19])([O-:18])N>>[C:16]([NH:11][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:13]([F:14])[CH:12]=1)([O:18][CH2:4][C:7]1[CH:13]=[CH:12][CH:10]=[CH:9][CH:8]=1)=[O:19]
Reactant: Nc1cc(F)c(-c2ccncc2)c(F)c1
Reactant: NC(=O)[O-]
Product: O=C(Nc1cc(F)c(-c2ccncc2)c(F)c1)OCc1ccccc1

Procedure:
Following the general procedure of PREPARATION 3 and making non-critical variations 4-(4-pyridyl)-3,5-difluoroaniline (PREPARATION 8, 236 mg, 1.15 mmol) is converted to the carbamate derivative. The crude product is purified by silica gel chromatography (100 g of SG, eluted with a 3-5% acetonitrile/chloroform gradient), the title compound is recovered as a solid, mp 185°-186°; FTIR (neat) cm-1 1743, 1642, 1605, 1254, 1072; HRMS calc'd for C19H14F2N2O2 =340.1023, found=340.1029; MS (EI, m/z) 340, 232, 108, 91, 79, 43; NMR (CDCl3) δ 8.67, 7.43-7.38, 7.15, 5.23.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[C:6]2[C:4]([OH:3])=[O:5])=[CH:26][CH:25]=1)(=[O:33])=[O:32]
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(Cn2c(C(=O)O)c(-c3cccs3)c3ccccc32)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and methanesulfonyl chloride followed the procedure of Example 3 Step 2 as a light yellow solid: 1H NMR (DMSO-d6) δ 2.94 (s, 3H), 5.76 (s, 2H), 7.08-7.24 (m, 7H), 7.34 (td, J=8.4, 1.2 Hz, 1H), 7.60-7.70 (m, 3H), 9.69 (br s, 1H), 13.25 (br s, 1H); MS (ESI) m/z 427 (MH+); MS (ESI) m/z 425 ([M−H]−); HRMS calcd for C21H19N2O4S2: 427.0784; found (ESI+): 427.0779.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S([O:16][CH2:17][C:18](F)([F:28])[CH2:19]OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:28][CH:18]1[CH2:17][O:16][C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:19]1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(OCC(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCC(F)CO2
Temperature: 50 °C

Procedure:
A mixture of 2 g of 3,5-dihydroxybenzaldehyde, 2.6 g of 2,2-difluoropropane-1,3-diyl bis(trifluoromethanesulfonate) and 10 g of cesium carbonate in 100 mL of anhydrous acetonitrile was heated under nitrogen to 50° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 250 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-25% ethyl acetate in hexanes) gave the product as white crystalline solid. MS (m+1)=197.1; 1H NMR (400 MHz, CDCl3) 9.82 (s, 1H), 7.45 (m, 2H), 7.05 (d, 1H), 5.1 (doublet of mutliplets, JHF=58 Hz, 1H), 4.5 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33]Cl>>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1O
Reactant: CN(C)CCCl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OCCN(C)C
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 37, 6-hydroxy-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-dimethylaminoethyl chloride to give 6-(2-dimethylaminoethoxy)-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 47% yield, m.p. 125°-126° C.;
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:17]2[NH:16][C:15](=[O:27])[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:20][CH2:19][C:18]=2[CH:21]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2

Procedure:
A mixture of 21.6 g (59.2 mmol) 3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.5 g palladium on charcoal (10%) in 300 mL methanol was hydrogenated in a 3 bar hydrogen atmosphere at 50° C. until the reaction was complete. The catalyst was removed by suction filtering and the mother liquor concentrated by rotary evaporation. The residue was triturated with 150 mL DIPE, suction filtered, washed with 100 mL DIPE and dried.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:16]([C:18]4[S:22][C:21]([C:23]([O:25]C)=[O:24])=[CH:20][CH:19]=4)=[O:17])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:16]([C:18]4[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=4)=[O:17])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4(C)CCC3)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCCc3cc(NC(=O)c4ccc(C(=O)O)s4)cc(c31)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of methyl 5-[(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)carbamoyl]thiophene-2-carboxylate (0.123 g) in ethanol (10 ml) was added with 2 N aqueous sodium hydroxide (1 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the title compound (0.107 g, yield: 91%) as pale yellow powdery crystals (melting point: 271-272° C.).
Reaction SMILES: C(O)=O.[C:4]1([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([CH2:26][CH2:27][NH:28][C:29](=O)OC(C)(C)C)=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Si]([O:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH:64]2C[O:65]2)=[CH:58][CH:57]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:65][C@@H:64]([CH2:29][NH:28][CH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[S:13][CH:14]=[C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:11]=3)[CH2:16][CH2:17]2)=[CH:37][CH:36]=1)[CH2:63][O:62][C:59]1[CH:60]=[CH:61][C:56]([OH:55])=[CH:57][CH:58]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Solvent: O=CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)cc1
Yield: 30.7 %

Procedure:
tert-Butyl 4-{[1-(4-phenyl-1,3-thiazol-2-yl)-4-piperidinyl]amino}phenethylcarbamate formate (0.40 g 1.04 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.42 g, 1.04 mmol) according to Procedure G to give the title compound (0.25 g, 0.319 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:9]=[C:10]([C:11]#[N:12])[C:3]=12
Reactant: N#Cc1n[nH]c2ncnc(N)c12
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1nc(C#N)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 22 h
Yield: 62.5 %

Procedure:
To a mixture of 4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (76.6 g, 0.476 mol) and potassium carbonate (197 g, 1.427 mmol) in DMF (680 mL) at 0° C. was added tert-butyl chloroacetate (68.1 mL, 0.476 mol) dropwise while maintaining the internal temperature below 20° C. The resulting mixture was stirred for 22 h, filtered and washed with EtOAc (100 mL×2). The solid obtained was suspended in ice water (1.5 L), filtered, washed with ice water (500 mL) and ether (100 mL×2), then dried in vacuo to afford tert-butyl 2-(4-amino-3-cyano-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (81.6 g, 62.3% yield). MS (ES) m/z 275.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH2:12](O)[C:13]1C=CC=[CH:15][CH:14]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)(Cl)(Cl)Cl>[F:11][C:2]([F:10])([F:1])[S:3]([O:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:9]=1)(=[O:4])=[O:5]
Reactant: OCc1ccccc1
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(OCc1ccccc1)C(F)(F)F

Procedure:
Benzyl trifluoromethanesulfonate was prepared in carbon tetrachloride solution and used as a dried solution in Examples 53 through 55, in the same way the 2-propen-1-yl trifluoromethanesulfonate was prepared and used in Examples 41 through 44, starting with benzyl alcohol and trifluoromethanesulfonic anhydride.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)=[CH2:2].C(=O)([O-])[OH:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:12][CH2:10]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: O=C([O-])O
Reactant: C=Cc1ccc(C=C)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C2CO2)cc1
Yield: 231.5 %

Procedure:
Into a 1-liter reactor provided with a stirrer, and a thermometer, were added 25 g of p-divinylbenzene, 40 g of sodium hydrogencarbonate, and 400 ml of toluene. To the mixture, while being kept at 5° C. and stirred, was added dropwise a solution of 100 g (40% by weight) of m-chloroperbenzoic acid in toluene. The resulting mixture was stirred at 5° C. for 10 hours. After completion of the reaction, the reaction mixture was washed with aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The mixture was filtered from the drying agent, then stripped of the toluene under reduced pressure, and purified by distillation to yield 65 g of 4-vinylstyrene oxide (1 Torr., 74° C.). In a similar manner, 3-vinylstyrene oxide was obtained from m-divinylbenzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[N:5]=[C:4]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([C:22](=[O:27])[NH:23][NH:24]3)=[CH:20][CH:19]=2)[N:3]=1.Cl.[CH3:29][O-:30].[Na+]>CO>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([O:30][CH3:29])[N:3]=[C:4]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22](=[O:27])[NH:23][NH:24]5)=[CH:20][CH:19]=4)[N:5]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Cl)nc(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Nc2ccc3c(=O)[nH][nH]c3c2)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.8 %

Procedure:
(6-[4-Chloro-6-(5-cyclopropyl-2H-pyrazol-3-ylamino)-[1,3,5]triazin-2-ylamino]-1,2-dihydro-indazol-3-one (70 mg, 0.14 mmol) was dissolved in 6 ml of 0.5 M solution of sodium methoxide in methanol and stirred at room temperature for 3 hours. The reaction was neutralized to pH 6-7 with 0.5 N hydrogen chloride. The cloudy solution was concentrated in vacuo. The resulting yellow solid was suspended in water, filtered, then purified by prep HPLC to afford 7.5 mg of the desired product as a white solid (10.8% yield). H-NMR (DMSO-d6, 500 mHz) δ 10.96 (s br, 1H), 9.76 (s br, 1H), 7.90 (s br, 1H), 7.44 (d, 1H), 7.18 (m, 1H), 6.02 (s br, 1H) 3.85 (s, 3H), 1.80 (s br, 1H), 0.84 (m, 2H), 0.61 (s br, 2H). MS (ES+): m/e=380.1 (M+H), 378.1 (M-H); LC/Method A/3.543 min, 90.0% purity by area %.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:8][N:9]1[C:13](=[O:14])[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:19])[CH3:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of ethyl bromoacetate (2.05 g, 12.3 mmol) in dimethylformamide (15 ml), N-hydroxyphthalimide (3.04 g, 18.4 mmol) and Hunig base (N,N-diisopropylethylamine, 4.24 mL) were added at room temperature, and the mixture was stirred at 80° C. overnight. The reaction solution was poured into saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated brine (2×30 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate=2:1) to give (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid ethyl ester (1.83 g, 60%) as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][O:10][C:11]1[CH:37]=[CH:36][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:31])=[O:32])=[O:21])=[CH:36][CH:37]=1
Reactant: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
In a stream of nitrogen and at 0° C., 0.15 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-(4-methoxybenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 6 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 490 mg (yield: 98.8%) of the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[N:30]2[N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)(C)C>C1COCC1.C(#N)C>[C:24]([C:25]1[N:30]2[N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:38][CH2:39]3)=[O:36])[N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cccc2nc(NC(=O)C3CC3)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: C#Cc1cccc2nc(NC(=O)C3CC3)nn12
Temperature: 25 °C
Yield: 96.7 %

Procedure:
TBAF (0.4 mmol) 1M solution in THF is added to a solution of cyclopropanecarboxylic acid(5-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.32 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture is stirred at room temperature until all the starting material disappears by LCMS. The solvent of the reaction is removed under vacuum, and the mixture is redissolved in ethyl acetate. The organic phase is washed with water. The organic layer is dried over MgSO4, filtered and the solvent is removed under vacuum to afford the pure product (70 mg, 97% yield). No further purification is carried out on the product.
Reaction SMILES: Br[CH2:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]1=[O:17].[CH2:18]([SH:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:18]([S:20][CH2:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]1=[O:17])[CH3:19]
Reactant: CCS
Reactant: COC(=O)c1cc2cccnc2n(CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCn1c(=O)c(C(=O)OC)cc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
3.00 g (10.1 mmol) of methyl 1-(bromomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in N,N-dimethylformamide (40 mL), and 0.94 g (15.1 mmol) of ethanethiol and 2.09 g (15.1 mmol) of potassium carbonate were added to the solution. The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated. Thus, 2.85 g (yield: quantitative) of the title compound was obtained as pale yellow crystals.