Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].N1C=CC([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]2)=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:26][CH:25]([CH:22]1[CH2:21][CH2:20][NH:19][CH2:24][CH2:23]1)[C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)=[O:12])([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: OCC1CCN(c2ccncc2)CC1
Solvent: ClCCl
Product: O=C(Nc1ccccc1[N+](=O)[O-])OC(c1ccncc1)C1CCNCC1
Yield: 197.1 %

Procedure:
A solution of 2-nitrophenyl isocyanate (4.25 g, 25.9 mmol) and 1-(4-pyridyl)piperidine-4-methanol (4.13 g, 21.5 mmol) in methylene chloride (100 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 5% methanol/1% triethylamine/94% chloroform) to yield 7.55 g (96%) of the title compound.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[H-].[Na+].[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>CN(C=O)C.CN1C(=O)N(C)CCC1>[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: OCC#CCO
Reactant: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)ncnc1OCC#CCO
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a solution of 11.02 g of 2-butyne-1,4-diol in 100 ml of DMF and 30 ml of DMPU was added 2.8 g sodium hydride in portions. After completion of the addition stirring was continued for 1.5 h followed by the addition of 2.78 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide. The mixture was heated to 90° C. and stirred for 65 h. The solvent was removed in vacuo, the residue was taken up in 250 ml of 10% aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. Column chromatography of the crude product on silica gel eluting with hexane:ethyl acetate 1:1 to 1:4 furnished 1.27 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)4-pyrimidinyl]-2-pyridine sulfonamide as a brown solid. Beige crystals were obtained for analytical purposes after crystallisation of a part of the isolated product from 2-propanol. LC-MS: tR=4.50 min, [M+1]+=485.27, [M−1]−=483.41.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:13]=1>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:15])=[O:16])[CH:13]=1
Reactant: CC(C)(N)CO
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Product: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Yield: 99.3 %

Procedure:
Prepared by general procedure III from 2-amino-2-methyl-1-propanol (2.23 g, 25 mmol) and commercially available 5-bromo-2-methoxybenzenesulfonyl chloride (1.43 g, 5 mmol) to give the title compound as an off-white solid (1.68 g, 99%). MS (ISN) 336.2 [(M−H)−], 338.1 [(M+2−H)−]. mp 168° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1)=[O:2].[CH2:13](I)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])=[O:2]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(C=O)ccc1O
Yield: 30 %

Procedure:
5-Formylsalicylic acid (5.0 g, 30 mmol), n-butyl iodide (3.4 mL, 30 mmol), and potassium carbonate (4.2 g, 30 mmol) were stirred in DMF (40 mL) for 27 h at room temperature. After several EtOAc/H2O extractions, the mixture was dried (MgSO4), and concentrated. Chromatography on silica gel, eluting with 5% to 30% EtOAc in hexanes, followed by solvent removal gave a white solid (2.0 g). HR-MS: Calc'd 223.0970, Found 223.0968. Anal. Calc'd for C12H14O4 : C, 64.84; H, 6.36; Found: C, 64.82; H, 6.30.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:7][C:8]([OH:10])=[O:9])=[O:6])[CH3:2].[C:11]([O:14][CH:15]1[C:16]([O:53]C(OCC)C)([CH3:52])[CH2:17][CH2:18][CH:19](O)[CH2:20][C:21]([O:23][CH:24](/[C:29](/[CH3:50])=[CH:30]/[CH:31]=[CH:32]/[CH:33]([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([O:41]C(OCC)C)[CH2:39][CH3:40])[CH:25]([CH3:28])[CH:26]=[CH:27]1)=[O:22])(=[O:13])[CH3:12]>>[C:11]([O:14][CH:15]1[C:16]([OH:53])([CH3:52])[CH2:17][CH2:18][CH:19]([O:9][C:8](=[O:10])[CH2:7][C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])[CH2:20][C:21]([O:23][CH:24](/[C:29](/[CH3:50])=[CH:30]/[CH:31]=[CH:32]/[CH:33]([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([OH:41])[CH2:39][CH3:40])[CH:25]([CH3:28])[CH:26]=[CH:27]1)=[O:22])(=[O:13])[CH3:12]
Reactant: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Reactant: CCOCC(=O)CC(=O)O
Agent: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: CCOCC(=O)CC(=O)OC1CCC(C)(O)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(O)CC)OC(=O)C1
Product: CCOCC(=O)CC(=O)OC1CCC(C)(O)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(O)CC)OC(=O)C1

Procedure:
Ethoxyacetylacetic acid was esterified with (8E,12E,14E)-7-acetoxy-6,21-bis(1-ethoxyethoxy)-3-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide through the similar synthetic route as Example B24, to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH3:12][Mg]Cl.CO.Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: C[Mg]Cl
Reactant: O=Cc1c(F)ccc(F)c1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1c(F)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent) was dissolved in THF (0.2 M) and stirred at 0° C. for 5 min. The corresponding methylmagnesium chloride solution (1.1 molar equivalent) was added. The reaction was warmed up gradually to ambient temperature and stirred for 2 hr. Methanol, and 1 N HCl was added to the mixture and diluted with ethyl acetate. The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated to give 1-(2-chloro-3,6-difluoro-phenyl)-ethanol as oil. 1H NMR (400 MHz, DMSO-d6) δ 1.42 (d, 3H), 5.21 (m, 1H), 5.42 (m, 1H), 7.09 (m, 1H), 7.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])#[N:26].O1CCOCC1.C([O-])(O)=O.[Na+]>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.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[C:28]([F:36])[CH:29]=2)[N:3]=1
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(Cl)nc(N)n2)C1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To N-[(3R,5R)-1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-3-piperidinyl]-N,3,3-trimethylbutanamide (80 mg, 0.23 mmol) and (4-cyano-3-fluorophenyl)boronic acid (49 mg, 0.29 mmol) were added 1,4-dioxane (4 mL) and sat. aq. NaHCO3 (2 mL), and the resulting mixture was purged (“degassed”) with N2 into a sealable tube. Pd(Ph3P)4 (26 mg, 0.023 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The reaction was allowed to cool down to room temperature and poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 75% EtOAc/Hexanes) afforded the title compound (84 mg) as a solid. LC-MS (ES) m/z=439 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][C:7]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:6][NH:5]1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.Cl>CN(C)C=O>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:5]2[C:4](=[O:3])[CH2:8][C:7]3([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH2:6]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)CC2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, to an N,N-dimethylformamide (2 mL) solution of sodium hydride (60%, 94 mg), an N,N-dimethylformamide (4 mL) solution of tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (514 mg) was added at 0° C. The reaction solution was stirred at 50° C. for one hour. The solution was cooled to 0° C. and then an N,N-dimethylformamide (2 mL) solution of methyl 4-(bromomethyl)benzoate (442 mg) was added. The reaction solution was stirred at 0° C. for 30 minutes. To the reaction solution, 0.5N-hydrochloric acid (20 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The aqueous layer was combined with the organic layer, washed in turn with water and saturated brine, and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→1:2) to obtain the title compound (553 mg) having the following physical properties.
Reaction SMILES: Cl[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:4][C:5]2[CH:6]=[C:7]3[CH2:14][CH2:13][CH2:12][C:8]3=[CH:9][C:10]=2[N:11]=1.[CH3:21][N:22]([CH3:30])[CH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:30])[CH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:4][C:5]3[CH:6]=[C:7]4[CH2:14][CH2:13][CH2:12][C:8]4=[CH:9][C:10]=3[N:11]=2)[CH2:25][CH2:24]1
Reactant: Clc1nc2cc3c(cc2nc1-c1ccccn1)CCC3
Reactant: CN(C)C1CCC(N)CC1
Solvent: Cc1ccccc1
Product: CN(C)C1CCC(Nc2nc3cc4c(cc3nc2-c2ccccn2)CCC4)CC1
Yield: 43.6 %

Procedure:
A solution of 2-chloro-3-pyridin-2-yl-7,8-dihydro-6H-cyclopenta[g]quinoxaline (0.5 g) and N,N-dimethyl-cyclohexane-1,4-diamine (0.51 g) in toluene (30 mL) was refluxed under nitrogen atmosphere for 16 hours. The reaction was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:19 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as yellow crystals ( 0.3 g); mp 158-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=S)(=[O:14])=[O:13].C(N(CC)CC)C.C(Cl)(Cl)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:19]([NH:18][C:16]1[NH:1][C:2]2[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=2[S:12](=[O:14])(=[O:13])[N:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)NC(=S)NS(=O)(=O)c1ccc(S(C)(=O)=O)cc1N
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)NC1=NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of N-(2-amino-4-(methanesulfonyl)benzenesulfonyl)-N′-isopropylthiourea (3.0 g) and triethylamine (1.7 g) in 30 ml of dry THF at 0° C. was added 5.2 ml of a 20% solution of phosgene in toluene during 5 min. The mixture was stirred at 0° C. for 1 h and then evaporated in vacuo. The white, solid residue was triturated with 50 ml of water for 45 min. and then the product was isolated by filtration. The filter cake was rinsed on the filter with water and dried to give the title compound as white crystals; m.p. >300° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 71.7 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 227 mg, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.755 mL, 4.36 mmol) in DMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. The mixture was part-purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (360 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.12-3.19 (1H, m), 3.74-3.78 (2H, m), 3.95 (3H, s), 4.04-4.09 (2H, m), 6.29 (1H, s), 7.08 (1H, td), 7.28 (1H, d), 7.36-7.41 (1H, m), 8.26 (1H, s), 8.35 (1H, d), 8.45-8.49 (2H, m), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 461.33.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)(O)[O-].[Na+].O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([F:39])([F:38])[F:27])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccccc3C(F)(F)F)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (100 mg, 0.24 mmol) and [2-(trifluoromethyl)phenyl]boronic acid (68.3 mg, 0.36 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (9.78 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added and the insoluble mixture was heated in a microwave at 110° C. for 15 min. Water was added and the solids that precipitated were filtered off. DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (87 mg, 74%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 11.52 (s, 1H) 8.53 (t, J=4.80 Hz, 1H) 8.43 (s, 1H) 7.88 (d, J=7.83 Hz, 1H) 7.81 (s, 1H) 7.77 (t, J=7.45 Hz, 1H) 7.66 (t, J=7.71 Hz, 1H) 7.53-7.57 (m, 2H) 5.87 (s, 1H) 5.05 (dt, J=13.14, 6.57 Hz, 1H) 4.35 (d, J=4.80 Hz, 2H) 2.19 (s, 3H) 2.10 (s, 3H) 1.48 (s, 3H) 1.47 (s, 3H). MS(ES) [M+H]+ 483.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11]>>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CNc1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CNc1cccc(-c2ccc(C=O)cc2)c1
Yield: 59.2 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 4.3 g (23.2 mmol) of (3-bromophenyl)-methylamine with 5.2 g (34.8 mmol) of 4-formylbenzene-boronic acid, 2.9 g (60%) of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:29]([CH2:45][CH:46]=[C:47]([CH3:49])[CH3:48])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CC(C)=CCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CC=C(C)C)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 7.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 1-chloro-3-methylbut-2-ene to give the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[OH-].[K+].I[CH3:32]>CS(C)=O>[CH3:32][O:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]2[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)[N:16]3[N:17]=2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(CO)cc4)nn23)c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1ccc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)cc1
Reaction time: 3 h
Yield: 12 %

Procedure:
To the solution of (4-(5-(3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)phenyl)methanol (200 mg, 0.51 mmol) in dimethyl sulfoxide (2 mL) was sequentially added potassium hydroxide (28 mg, 0.51 mmol) and iodomethane. After 3 hr, the reaction mixture was partitioned between water and dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative thin layer chromatography afforded the desired product (45 mg, 12%). LCMS (ESI) m/z: 409.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH3:25]>CN1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH3:25]
Reactant: CCI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 39.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 153 mg, 0.5 mmol) and iodoethane (0.21 mL, 2.6 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube for 17 h. The reaction mixture was purified by preparative HPLC to give a brown semi-solid which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (66 mg, 39%) as a pale yellow foam. ES(+)-MS (M+H) 333.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([NH:14]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>[Ni].O1CCOCC1.CO>[NH2:14][C:6]1[C:7](=[O:13])[N:8]([CH3:12])[C:9]2[C:4]([C:5]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: Cn1c(=O)c(NC(=O)OCc2ccc([N+](=O)[O-])cc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1c(=O)c(N)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A mixture of 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-3-(4-nitrobenzyloxycarbonylamino)-2-oxoquinoline (1.9 g, 3.8 mmol) and Raney nickel (1.9 g, 50% slurry in water) in 75 ml dioxane and 75 ml methanol was shaken under hydrogen (50 psi) in a Parr hydrogenation apparatus for 3 h. The catalyst was filtered and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in 100 ml ethyl acetate and the solution was washed with 60 ml brine. The ethyl acetate solution was then dried (sodium sulfate) and concentrated in vacuo to a solid (1.2 g) which was purified by column chromatography on silica gel (150 g), eluting with 7:3 hexane/ethyl acetate to yield the title compound as an off-white solid (950 mg, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][N:18]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:19][CH2:20][OH:21].COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[OH:15][CH2:16][CH2:17][N:18]([CH2:19][CH2:20][OH:21])[C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=3)[N:1]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c(=O)c2cc1OC
Yield: 24 %

Procedure:
2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,5-dimethoxy-benzamide and 4-(N,N-bis(2-hydroxyethyl)amino)benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one (72 mg, 24%) was isolated as a yellow solid. Selected data: MS (m/z): 386.15; MP 268-270° C.