Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[OH:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[O:11][CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])=[O:5])[CH3:2]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1c(CC)n[nH]c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)n[nH]c1OC(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-ethyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (1.5 g, 8.14 mmol) in DMF (10 ml) is added K2CO3 (1.15 g, 8.14 mmol). The mixture is heated to 50° C. and treated with a solution of 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (2.53 g, 8.96 mmol) in DMF (10 ml). Stirring continues at 50° C. for 1 hour and after cooling to RT, the reaction mixture is poured into water (300 ml, pre-cooled to 10-15° C.) which is subsequently allowed to reach ambient temperature over 3 h (with stirring). The resulting suspension is filtered, washed with water and the solid dried in vacuo overnight. The resultant crude product is triturated in diethyl ether (approx. 15 ml) for 20 mins. then dried in vacuo to yield 5-[2-(2,4-dichloro-phenyl)-1-methyl-2-oxo-ethoxy]-3-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester: yield: MS: m/z 385.13 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:22]1[CH:30]=[CH:29][C:25]2[CH2:26][CH2:27][O:28][C:24]=2[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8]1=[O:21])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:22]1[CH:30]=[CH:29][C:25]2[CH2:26][CH2:27][O:28][C:24]=2[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8]1=[O:21])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC(C)=O)C1=O

Procedure:
A solution of 4-1 (600 mg, 1.4 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 4-2 as a colorless oil.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 23 °C
Yield: 86 %

Procedure:
A mixture of thiobenzamide (13.7 g, 0.10 mol), 1,3-dichloroacetone (12.7 g, 0.10 mol), sodium bicarbonate (8.4 g, 0.10 mol) and dichloroethane (200 mL) is refluxed for 6 hours. The reaction mixture is cooled to 23° C. and the solid by-products are removed by filtration. The filtrate is concentrated under reduced pressure to give the crude product (19.0 g). This material is recrystallized from hexane and the title product is obtained as a light yellow solid (18.2 g) in 86.0% yield, m.p. 44°-48° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][O:45][CH3:46])[NH2:38].COCCOC>Cl.CCOC(C)=O.O>[Cl:34][C:35]1[CH:36]=[C:37]([NH:38][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH2:44][O:45][CH3:46]
Reactant: COCCOc1ccc(N)cc1Cl
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COCCOc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1Cl
Temperature: 160 °C
Yield: 40.2 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (0.1 g, 0.218 mmol) and 3-chloro-4-{[2-(methyloxy)ethyl]oxy}aniline (0.057 g, 0.283 mmol) were combined in a microwave safe reaction vessel. Ethylene glycol dimethyl ether (1.5 mL) and HCl (˜½ drop) were then added and the resulting mixture was heated in a microwave to 160° C. for 8 min. The reaction was then cooled to rt diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo onto silica gel. This was then purified via silica gel chromatography (EtOAc/Hexanes) to provide 55 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.53 (s, 1H), 8.83 (d, 1H), 8.42 (br m, 1H), 8.25 (d, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.80 (d, 1H), 7.62-7.42 (m, 4H), 7.33 (d, 1H), 7.24 (m, 2H), 7.12 (m, 1H), 7.03 (d, 1H), 6.52 (d, 1H), 4.11 (m, 2H), 3.65 (m, 2H), 3.30 (s, 3H); HRMS: calc. C33H26N6O3F2 (M+H)+ 627.1723 found 627.1732.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:22]([O-])=O)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.CCOC(C)=O.CC(O)=O>CO.[Zn]>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:22]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c([N+](=O)[O-])c(C)cc(C)c32)cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,7-dimethyl-4-nitro-1-tosyl-1H-indole (17 g, 49.4 mmol) in MeOH (50 mL)/EtOAc (300 mL) was added Zn (16.1 g, 247 mmol). The suspension was cooled down to 0° C. To the suspension was added dropwise AcOH (30 mL) over 30 min, and then the mixture was stirred at 0° C. for 0.5 h. The flask was removed from the ice bath, and the mixture left stirring at room temperature for 18.5 h. The reaction mixture was poured into a mixture of Celite®/5% aq. NaHCO3/EtOAc, and then the basic mixture was vigorously stirred for 0.5 h. The mixture was filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phase was washed with 5% aq. NaHCO3, H2O, and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, without need of further purification. MS (ESI+) m/z 315.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[CH:13]=O.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH3:1][N:2]1[C:3]([CH3:13])=[CH:4][CH:5]=[C:6]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cn1c(C=O)ccc1-c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: Cc1ccc(-c2cccnc2)n1C
Temperature: 175 °C
Reaction time: 1.25 h

Procedure:
A mixture of 1-methyl-5-(3-pyridyl) pyrrole-2-carboxaldehyde (8.0 g, 43 mmoles), hydrazine hydrate (8.0 g, 160 mmoles) and potassium hydroxide (10.6 g of 85% pellets) in 80 ml triethyleneglycol is stirred at 125° L C for 75 min. during which time vigorous evolution of gas is observed. The temperature is then increased to 175° C and stirring continued until evolution of gas ceases. After cooling, the reaction mixture is extracted with 3 × 50 ml portions of diethyl ether. The combined ether layers are dried (anhydrous magnesium sulfate) and removed under vacuum. Fractional vacuum distillation of the residue provides the pure product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:17].[CH3:24][CH2:25][O:26][C:27](C)=[O:28]>>[O:28]1[C:24]2[CH:22]=[CH:23][C:18]([CH2:16][NH:15][C:19]3[C:18]([C:16]([NH:15][C:3]4[CH:4]=[CH:5][C:6]([O:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:7][CH:2]=4)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:19][C:25]=2[O:26][CH2:27]1
Reactant: CCOC(C)=O
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1Cl)c1cccnc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1NCc1ccc2c(c1)OCO2
Temperature: 110 °C

Procedure:
2-Chloro-(3-pyridyl)-N-(4-phenoxyphenyl)-carboxamide (0.500 g, 1.5 mmol) and 2H-benzo[d]1,3-dioxolan-5-ylmethylamine (0.680 g, 4.5 mmol) were combined and heated neat at 110° C. for 18 h. After cooling to RT, the resulting residue was dissolved in EtOAc and washed with saturated NaACO3 solution and brine, respectively. The organics were dried over Na2SO4 and evaporated. The crude material was purified by column chromatography with EtOAc/hexanes (1:2) as eluant to leave the desired compound as an off-white solid. MS: (ES+) 440 (M +1)+; (ES−): 438 (M−1)−. Calc'd. for C26H21N3O4-439.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:62]([O:64][C:65]([C:67]1[C:72](Cl)=[C:71]([CH3:74])[C:70](=[O:75])[N:69]([CH3:76])[C:68]=1[CH3:77])=[O:66])[CH3:63]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:62]([O:64][C:65]([C:67]1[C:72]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])=[C:71]([CH3:74])[C:70](=[O:75])[N:69]([CH3:76])[C:68]=1[CH3:77])=[O:66])[CH3:63]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C
Agent: [Pd+2]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
2-Fluoro-4-methylphenylamine (0.259 g, 2.07 mmol), palladium (II) acetate (0.046 g, 0.205 mmol), rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.192 g, 0.308 mmol), and cesium carbonate (1.00 g, 3.08 mmol) were added to a solution of 4-chloro-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.50 g, 2.05 mmol) in toluene (7 mL) in a sealed vial. After stirring 10 minutes, the mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The resulting precipitate was filtered and washed with EtOAc. The filtrate was diluted with EtOAc and washed with water. The aqueous layer was reextracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography (20:1 methylene chloride/MeOH) gave 0.048 g (71%) desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.C(O)(=O)C>CO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Yield: 71 %

Procedure:
A mixture of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (0.5 g, 1.62 mmol), iron powder (0.35 g, 6.26 mmol), acetic acid (0.72 mL, 11.34 mmol) in methanol (6 mL) is heated at 66 C for 1 h. After it is evaporated to dryness, ethyl acetate is added, and then the mixture is filtered through a pad of Celite. The filtrate is evaporated to yield 0.32 g (72%) of the title compound as an orange gum. NMR (CDCl3) spectrum of the product showed it is pure.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]3[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:12]4[N:13]=[CH:14][C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:20][CH3:21])=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CSc1cc(Oc2ccnc3[nH]c(=O)cnc23)ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 92 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[3,2-b]pyrazin-3(4H)-one and 4-chloro-3-trifluoromethylphenyl isocyanate, the title compound (48 mg, 92%) was obtained as a pale white powder.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:3]([CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:1][CH3:2])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: CCNCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a 100 mL round bottom flask containing tert-butyl 4-((ethylamino)methyl)-4-hydroxypiperidine-1-carboxylate (2.4 g) was added dichloromethane (30 mL) and triethylamine (3 mL, 21.52 mmol). An addition funnel was attached to the flask. The vessel was placed under nitrogen and the solution was cooled to 0° C. with an ice bath. In a separate vial, chloroacetyl chloride (1 mL, 12.48 mmol) was diluted with dichloromethane (20 mL) and transferred to the addition funnel. This mixture was added dropwise to the cold starting material over 10 min. The reaction mixture was then allowed to stir under nitrogen for 3 h while slowly allowing the ice bath to warm to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and was washed with water (2×50 mL) and brine (1×50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (3.23 g) which was carried forward without further purification. MS(ES)+ m/e 335.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2[nH]ncc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flame dried round bottom flask under N2 was added 4-chloropyrazolo[3,4-d]pyrimidine (J. Am. Chem. Soc. 1956, 78, 784) (1.80 g, 11.65 mmol), t-butyl 4-hydroxy-1-piperidinecarboxylate (2.46 g, 12.23 mol), and PS—PPh3 (9.21 g, 1.77 mmol/g) in anhydrous tetrahydrofuran (200 mL). The mixture was cooled to 0° C. and diethyl azodicarboxylate (DEAD) (2.20 mL, 13.98 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was then filtered and taken up in methylene chloride. The insoluble material was filtered off. The filtrate was concentrated, taken up in methylene chloride, and put in the freezer for 5 hr. The crystals that formed were filtered off and the filtrate was purified by silica gel chromatography (0-2% methanol/methylene chloride) to give pure tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate. 1H-NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.16 (s, 1H), 4.92-5.02 (m, 1H), 4.32 (br s, 2H), 2.97 (br s, 2H), 2.20-2.31 (m, 2H), 1.96-2.05 (m, 2H). LRMS m/z (M+H) Calcd: 337.13, found: 338.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3OCC[O:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(C)C=CC=CC=1>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2ccc(C3OCCO3)cc2)cc1F
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(F)c(F)c2)cc1
Yield: 95.7 %

Procedure:
A mixture of 5.4 g of 2-(3',4'-difluoro-4-biphenylyl)dioxolane; 100 ml of toluene and 20 ml of formic acid was stirred for 16 hours. The formic acid phase was separated and the toluene phase was washed neutral with two 50 ml portions of saturated sodium hydrogen carbonate solution and three 75 ml portions of water, dried over sodium sulphate and concentrated. There were obtained 4.3 g of p-(3,4-difluorophenyl)benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.O.O[CH2:10][S:11]([O-:14])(=[O:13])=[O:12].[Na+:15]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:3]=1.[Na+:15]
Reactant: Nc1cccnc1
Reactant: O=S(=O)([O-])CO
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CNc1cccnc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 58.9 %

Procedure:
A mixture of 3-aminopyridine (2.82 g) and sodium hydroxymethanesulfonate monohydrate (9.12 g) in water (40 ml) was stirred for 1.5 hours at 80° C. The solution was concentrated to yield a precipitate and stood for several hours. The resulting precipitate was filtered, washed with ethanol and dried to give sodium 3-pyridylaminomethanesulfonate (3.71 g), mp 211° to 220° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8].Cl[C:39]1[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=1>CO>[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][N:28]([C:39]5[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=5)[CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCNCCO4)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCN(c5nccc(C(F)(F)F)n5)CCO4)cc3)oc12
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a mixture of 48 mg of potassium carbonate in methanol (3 ml) was added 37 mg of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(7S)-1,4-oxazepan-7-ylmethyl]benzamide (INTERMEDIATE 20) followed by 2-chloro-4-(trifluoromethyl)pyrimidine (16 mg). The mixture was heated via microwave at 120° C. for 35 min, and then cooled and added directly to a 40M samplet for purification via column chromatography on a Biotage Horizon 40M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate, to provide the title compound (37 mg, 76%). Mass spectrum (ESI) 565.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.52 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.95 (s, 1H), 7.54 (s, 1H), 6.81 (d, J=4.8 Hz, 1H), 6.65 (bs, 1H), 4.26 (m, 2H), 3.98 (m, 3H), 3.70 (s, 2H), 3.69 (m, 2H), 3.48 (sept, J=7.0 Hz, 1H), 3.25 (m, 1H), 2.19 (m, 1H), 1.83 (m, 1H), 1.48 (d, J=7.1 Hz, 6H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: C[O-]
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccccn1

Procedure:
2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Freshly prepared sodium methoxide (5 g., 0.22 mole of sodium dissolved in 150 ml. of methanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then fitted. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[NH2:9][NH2:10]>C(O)CCC>[Br:1][C:2]1[N:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: NN
Solvent: CCCCO
Product: NNc1cccc(Br)n1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 2,6-dibromopyridine (1.44 g, 6.1 mmol) and hydrazine (1.65 mL, 32.2 mmol) in butanol (100 mL) was stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between an aqueous saturated solution of sodium bicarbonate and EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated to give (6-Bromopyridin-2-yl)hydrazine as a white solid (1.0 g, 92%). 1H NMR (400 MHz, CHCl3-d): δ 7.36-7.28 (m, 1 H); 6.82 (d, J=7.70 Hz, 1 H); 6.67 (d, J=7.7 Hz, 1 H); 5.97 (s, 1 H); 3.80 (s, 2 H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[CH3:36][O:35][CH2:34][CH2:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:37][CH2:38][CH2:39][O:40][CH3:41])[N:25]=[CH:24][N:23]=[C:22]2[S:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCOC
Temperature: 90 °C

Procedure:
As described in Example 50, a mixture of the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.117 g, 0.4 mmol), 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (0.125 g, 0.4 mmol) from Example 12A, and Cs2CO3 (0.20 g, 0.6 mmol) in isopropanol (5 mL) was heated at 90° C. overnight, to afford 1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butylisoxazol-3-yl)urea. as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.99 (s, 1H), 8.68 (s, 1H), 7.84 (m, 1H), 7.51 (m, 1H), 7.46 (t, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.28 (dd 1H), 6.49 (s, 1H), 4.34 (m 4H), 3.78 (m, 4H), 3.37 (s, 3H), 3.35 (s, 3H), 1.28 (s, 9H).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH3:23][C:24](C)([CH3:28])[CH2:25]CN.C1COCC1>C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:24]([CH3:28])([CH3:25])[CH3:23])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: CC(C)(C)CCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(COC(=O)NCCC(C)(C)C)ccc1OC(C)=O
Reaction time: 2 h

Procedure:
This compound was prepared from VII (288.5 mg, 0.845 mmol), 3,3-dimethylbutylamine (85.5 mg, 114 μL, 0.845 mmol) and anhydrous THF (4.2 mL) as described for 13. The reaction was complete within 2 hours. The reaction solution was diluted with CH2Cl2 and extracted with in 1N HCl and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (7:3, v/v) to render 95.8 mg (35%) of 16 as an oil; 1HNMR (CDCl3) δ 6.99 (d, 3J=7.95 Hz, 1H), 6.95 (s, 1H), 6.92 (d, 3J=7.95 Hz, 1H), 5.04 (s, 2H), 4.60 (bs, 1H), 3.82 (s, 3H), 3.21-3.17 (m, 2H), 2.29 (s, 3H), 1.42-1.38 (m, 2H) and 0.91-0.90 (m, 9H). Exact mass (ESI) calculated for C17H26NO5 [M+H]=324.1805. found 324.1814.