Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6]1([S:12]([CH2:15][CH2:16][S:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:25]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCCCCC>O1CCOCC1>[C:6]1([S:12]([CH2:15][CH2:16][S:17][C:18]2[C:23]([NH:24][C:32](=[O:33])[CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)CC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C(CC1CCCCC1)Nc1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
336 mg (4.0 mmol) NaHCO3 were added to a solution of 294 mg (1.0 mmol) [2-[2-(benzenesulfonyl)-ethylsulfanyl]-pyridin-3-yl]amine (VPF-002) in dioxane (10 ml) and the mixture was stirred for 10 min at RT. Then 321 mg (2.0 mmol) 2-cyclohexylacetylchloride were added at 5° C. and the mixture was stirred for a further 16 h at RT. Then it was diluted with EE and filtered through kieselguhr. The filtrate was washed with a saturated aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:1) of the residue yielded 368 mg (0.9 mmol, 88%) N-[2-[2-(benzenesulfonyl)-ethyl-sulfanyl]-pyridin-3-yl]-2-cyclohexyl acetamide. MS: m/z 419.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:30]2[CH2:29][CH2:28][NH:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[N:21]1[C:30]2[CH2:29][CH2:28][N:27]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: c1cnc2c(c1)CNCC2
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ncccc4C3)n2)c1

Procedure:
B38 was prepared following the general procedure reported for B10 using A1 and 5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride. The title compound (B38) was purified by reverse phase RP-HPLC (column: C18), using H2O (0.1% TFA) and MeOH (0.1% TFA) as eluents; yield: 67.6 mg (17%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.98 (bs, 2H), 4.12 (t, J=6.0 Hz, 2H), 4.26 (bs, 2H), 4.95 (s, 2H), 6.86 (bs, 2H), 7.02 (d, J=7.9 Hz, 1H), 7.25 (dd, J=7.8 Hz, J=4.7 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.47-7.80 (bm, 2H), 7.83-8.10 (bm, 1H), 8.39 (dd, J=4.8 Hz, J=1.6 Hz, 1H), 8.30 (s, 1H), 9.77 (s, 1H). MS (ES) C18H19N7O2S requires: 397. found: 398 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: CCNCC(=O)O
Reactant: Cc1cccc(Cl)c1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(C)cccc2Cl)C1=S
Yield: 40.6 %

Procedure:
A mixture of the crude N-ethyl glycine (9.2 g), 2-chloro-6-methylphenyl-isothiocyanate (9.1 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3.5 hours. The solvent was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (5.4 g) as a creamy solid, m.p. 124°-126° C. Anal. Calcd. for. C12H13Cl N2 O S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (EI, M.+) m/z 268/270.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:7]23[CH2:15][CH2:14][O:13][CH2:12][C@H:11]2[CH2:10][O:9][NH:8]3)[S:5][CH:6]=1>C(O)(=O)C.[Zn]>[NH2:8][C@@:7]1([C:4]2[S:5][CH:6]=[C:2]([Br:1])[CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][C@H:11]1[CH2:10][OH:9]
Reactant: Brc1csc([C@]23CCOC[C@H]2CON3)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2cc(Br)cs2)CCOC[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Zinc (374 mg) was added to a solution of (±)-(3aS*,7aS*)-7a-(4-bromo-thiophen-2-yl)-hexahydro-pyrano[4,3-c]isoxazole (166 mg) in acetic acid (5 mL), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure. Ice was added to the residue, followed by neutralization with a 2 N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (147 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:26]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:14]3[C:9]([O:8][C@H:5]4[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]4)=[N:10][CH:11]=[CH:12][CH:13]=3)[C:17]=2[C:24]=1[CH3:25])=[O:27]
Reactant: CN(C)CCCN
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.083 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 26 μl N,N-dimethyl-1,3-propanediamine in THF using TBTU instead of HATU.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O-:10].[Na+]>CS(C)=O>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)ccn1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccnc(N)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of 4-chloropyridin-2-amine (3 g, 23.2 mmol) in DMSO (60 mL) was added sodium methoxide (12.6 g, 232 mmol) and the mixture was then stirred at 150° C. for 3 hours then poured into ice-water. The product was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography using a solvent system of 50% petroleum ether/EtOAc to give 4-methoxypyridin-2-amine (460 mg, 16%) as a yellow solid MS ESI calcd for C6H8N2O [M+H]+ 125, found 125.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[N+:27]([O-:29])=[O:28]>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[C:3]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[CH:4]=2)[NH:8][CH:7]=1)[CH2:26][N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])/C=C/c1ccccc1F
Reactant: Cc1cc2[nH]ccc2cc1Oc1cncnc1
Solvent: ClCCl
Product: Cc1cc2[nH]cc(C(C[N+](=O)[O-])c3ccccc3F)c2cc1Oc1cncnc1
Temperature: 130 °C
Yield: 52.9 %

Procedure:
6-Methyl-5-(pyrimidin-5-yloxy)-1H-indole (0.1783 g, 0.792 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.159 g, 0.950 mmol) were dissolved in CH2Cl2, and the solution was concentrated in vacuo. The residue was heated at 130° C. for 4 hr, and the crude product was purified by flash chromatography using an ISCO 40 g column eluting with 0-5% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.1644 g, 0.419 mmol, 52.9% yield) as a tan foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[OH:13].[CH3:14][C:15](OC(C)=O)=[O:16]>C(Cl)(Cl)Cl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15](=[O:16])[CH3:14])=[C:3]([OH:13])[CH:4]=1)(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(=O)c1ccc(N)c(O)c1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)c1ccc(NC(C)=O)c(O)c1
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
To a solution of 1-(4-amino-3-hydroxyphenyl)butan-1-one (0.71 g, 4.0 mmol) in CHCl3 (8 mL) was added Ac2O (0.4 mL, 4.2 mmol, 1.06 eq) at 0° C. After 5 min, reaction was quenched with H2O then extracted with CH2Cl2 (3×30 mL). Solvent was removed under reduced pressure to afford N-(4-butyryl-2-hydroxyphenyl)acetamide (0.81 g, 3.7 mmol, 93%) with ca. 80% purity which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[CH2:6][C:5]1=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C>[CH3:3][C:4]1([CH3:11])[CH2:8][CH:7]([Cl:9])[C:6](=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:5]1=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1(C)CC(Cl)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(Cl)C(=Cc2ccc(F)cc2)C1=O
Reaction time: 0.5 h
Yield: 69 %

Procedure:
10% strength aqueous sodium hydroxide solution (50 cc) is added to a mixture of 2,2-dimethyl-4-chloro-1-cyclopentanone (10 g) and 4-fluorobenzaldehyde (8.4 g) in ethanol (100 cc) at 0° C. After 30 minutes, a thick slurry is filtered and the solid washed and then dried. 2,2-Dimethyl-4-chloro-5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g), m.p. 69° C., is obtained. Sodium hydride (3.1 g; 80% strength dispersion in mineral oil) in anhydrous DMSO (50 cc) is heated to 80° C. until the solid is dissolved completely. The solution is then diluted with THF (100 cc) and thereafter cooled to -10° C. A solution of trimethylsulphonium iodide (11.5 g) in dimethyl sulphoxide (80 cc) is added to the mixture in the course of 10 minutes and the mixture is stirred for 15 minutes at -10° C. A solution of 2,2-dimethyl-4-chloro-5-(4-fluorobenzylidene)-1-cyclopentanone (11.8 g) is then added in THF (100 cc). The mixture thereby produced is left at room temperature, then poured into water and extracted with ether, washed with water, dried and distilled. 7-(4-Fluorobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]hept-5-ene, used directly for the next step, is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]2[O:12][CH2:13][C:14](=O)[NH:15][C:16]=2[N:17]=1>C1COCC1>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]2[O:12][CH2:13][CH2:14][NH:15][C:16]=2[N:17]=1
Reactant: Cc1ccc2c(n1)NC(=O)CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)NCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A flask was charged with lithium aluminum hydride (607 mg, 16.0 mmol) was placed in an ice-water bath under an argon atmosphere. THF (13 mL) was added slowly. To this suspension was added slowly a solution of 6-methyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.05 g, 6.40 mmol) in THF (13 mL). After the addition was completed, additional THF (9 mL) was added, d and the reaction was stirred in the ice-water bath for 30 minutes. Ice-water bath was removed, the mixture was stirred at ambient temperature for 3 h. The mixture was cooled with an ice-water bath, and H2O (0.86 mL) was added slowly, followed by cooled aqueous NaOH solution (0.64 mL, 10%). The ice-water bath was removed, additional H2O (1.8 mL) was added. After stirring for 30 minutes, Celite and Na2SO4 were added. The mixture was filtered through Celite, and the Celite was washed with EtOAc. The filtrate and the washing were combined, dried over Na2SO4, and concentrated to give the title compound (0.96 g, quantitative yield) as a while solid. 1H NMR(CDCl3) δ 6.85 (d, 1H, J=8.0 Hz), 6.35 (d, 1H, J=8.0 Hz), 6.08 (bs, 1H), 4.19–4.16 (m, 2H), 3.54–3.52 (m, 2H), 2.31 (s, 3H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][NH:11][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1
Reactant: NCC(O)c1cccc(O)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: Oc1cccc(C2CNC3(CCCCC3)O2)c1

Procedure:
A suspension of 20 g. of 1-(3'-hydroxyphenyl)-2-amino-ethanol hydrochloride in 100 ml. of cyclohexanone is heated, while stirring vigorously, in a three-necked flask equipped with a dropping funnel, water separator, and thermometer. Above a temperature of 80°C., up to 100 ml. of benzene are added dropwise in such a manner so that the water of reaction formed together with the benzene is distilled of azeotropically. The temperature of the flask contents is, at the finish, about 130°C. After cooling, the crystalline reaction product is separated off, digested with benzene, and collected on a frit. There is obtained 20.3 g. (71.5% of theory) of 2-(3'-hydroxyphenyl)-1-oxa-4-azospiro[4,5]decane hydrochloride. After recrystallization from isopropanol/ethyl acetate, the product is obtained in the form of colorless crystals with a melting point of 138°-139°C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:42](Cl)(=O)[C:43](C)([CH3:45])[CH3:44]>ClCCl>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:43]([CH3:45])([CH3:44])[CH3:42])[CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=12
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
1-{4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2,2-dimethyl-propan-1-one was prepared according to General Procedure J by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid in dichloromethane followed by reaction with pivaloyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 9H), 1.98-2.03 (m, 4H), 3.06-3.12 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.40-4.46 (m, 2H), 4.99-5.03 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.92 (m, 1H), 8.21-8.25 (m, 1H), 8.30-8.43 (m, 2H), 10.38 (s, 1H). Mass spectrum MH+=475.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:17][C:18]1[CH:36]=[CH:35][C:21]([C:22]([O:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)=O)=O)=[CH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([NH2:40])(=O)C>C(Cl)Cl>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[N:40]=[C:22]([C:21]3[CH:35]=[CH:36][C:18]([O:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=3)[O:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(N)=O
Reactant: CCCCCCCOc1ccc(C(=O)OCC(=O)c2ccc(Br)cc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)co2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To boron trifluoride etherate (0.322 mL, 2.5 mmol) was added 2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate (1.0 g, 2.3 mmol) and acetamide (4.91 g, 83.0 mmol) in DCM (10 mL). The reaction mixture was heated to 50° C. then 140° C. for 16 h, DCM was distilled off. The reaction mixture was cooled, diluted with acetonitrile and stirred at RT for 1 h. The precipitate was isolated by filtration to afford 273 mg (23%) of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole as a brown solid. LCMS-ESI (m/z) calculated for C22H24BrNO2: 414.3. found 414.0 [M+H]+, tR=3.00 min. (Method 4).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:44][C:43]([CH3:46])([CH3:45])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]3)=[CH:34][N:33]=2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH:39]4[CH2:44][C:43]([CH3:45])([CH3:46])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]4)=[CH:34][N:33]=3)=[CH:26][CH:25]=2)[N:7]([CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(N)cc3)nc2)CC1(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4C)cc3)nc2)CC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 6 %

Procedure:
A mixture of 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate from Step 1 of this example (65 mg, 0.24 mmol), N-(4-aminophenyl)-5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide dihydrochloride from Example 49 (90 mg, 0.20 mmol), triethylamine (92 μL, 0.66 mmol), and N,N-dimethylpyridin-4-amine (2 mg, 0.02 mmol) in THF (3 mL) was stirred at rt for 2 d. The solvent was removed under reduced pressure. The crude residue was purified by silica gel flash chromatography, eluting with 9% MeOH/1% NH3 in DCM. The resulting compound was then purified by reverse phase HPLC to afford N-(4-(3-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)ureido)phenyl)-5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamide (7 mg, 6% yield). LCMS (ESI) m/z 562 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.76 (br s, 1H), 9.47 (br s, 1H), 8.35-8.34 (d, 1H), 8.11-8.08 (d, 1H), 7.78-7.75 (d, 2H), 7.63-7.59 (d, 1H), 7.47-7.44 (d, 2H), 6.02 (s, 1H), 4.87 (t, 1H), 3.6 (s, 3H), 2.2 (s, 3H), 2.04-1.99 (d, 2H), 1.49-1.42 (t, 2H), 1.21 (s, 9H), 1.13-1.12 (m, 12H).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28].[C:29]([O-:32])(=[O:31])[CH3:30].[K+]>O>[C:29]([O:32][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28])(=[O:31])[CH3:30]
Reactant: CC(=O)[O-]
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To N,N-dimethylformamide (200 ml) are added 5-(4-bromomethyl-3-chlorophenyl)-3(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (24.3 g) and potassium acetate (29.0 g), which are stirred at 130° C. for 3 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 11.8 g of desired compound.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][CH:12]([CH3:16])[C:13]([NH2:15])=O.N1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C>>[C:13]([CH:12]([NH:11][C:5](=[O:7])[C:4]1[CH:3]=[CH:2][N:10]=[CH:9][CH:8]=1)[CH3:16])#[N:15]
Reactant: CC(N)C(N)=O
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C#N)NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a mixture of 2-methylisonicotinic acid (2.00 g, 15 mmol) and 2-aminopropanamide (3.7 g, 29 mmol) in pyridine (15 ml, 15 mmol) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.6 g, 29 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated, to the residue was added 10% methanol/DCM (80 mL). The white precipitate was collected and the residue was purified by CombiFlash using 0-10% methanol/DCM as the eluent to give 2.14 g of N-(1-cyanoethyl)isonicotinamide 22B. LCMS (ES+) m/z 208.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[C:7]3[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=[N:5][C:6]=3[N:11]2[N:12]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1N1CCN(C)CC1

Procedure:
3.04 g. of 6-chloro-2,5-dimethylpyrazolo[1,5-a]-pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester (0.01 mol.) and 10 ml. of N-methylpiperazine are heated at reflux temperature for 5 minutes. The excess N-methyl piperazine is removed in vacuo and the residue is treated with water. The product, 2,5-dimethyl-6-(4-methyl-1-piperazinyl)pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester, crystallizes and is filtered off, yield 3.1 g. (85%), m.p. 158°-159°.
Reaction SMILES: C[O-].[Na+:3].[C:4]([CH2:6][N:7]([CH3:12])[C:8](=[O:11])[O:9][CH3:10])#[N:5].[CH:13](OCC)=[O:14]>O1CCCC1>[C:4](/[C:6](/[N:7]([C:8]([O:9][CH3:10])=[O:11])[CH3:12])=[CH:13]\[O-:14])#[N:5].[Na+:3]
Reactant: CCOC=O
Reactant: COC(=O)N(C)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C)/C(C#N)=C/[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.46 g (0.01 mmol) of sodium methoxide is added under argon to tetrahydrofuran (solution A). Then 1.00 g (0.01 mmol) of methyl cyanomethyl(methyl)carbamate from Example 9A is added to 1.73 g (0.02 mmol) of ethyl formate. Solution A is slowly added dropwise to this mixture. The mixture is stirred at RT overnight. The solvent is concentrated in vacuo in a rotary evaporator, and diethyl ether is added to the residue. The crystals which have separated out are filtered off with suction and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([OH:17])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:42][O:43][CH2:44][CH2:45]Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH2:45][CH2:44][O:43][CH3:42])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1
Reactant: COCCBr
Reactant: CN1CCN(Cc2csc(C(=O)Nc3c(O)cc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Yield: 60.2 %

Procedure:
E, In a manner similar to that described in Paragraph B above, N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide (7.0 g, 13 mmol) reacted with cesium carbonate (29 g, 89 mmol) and 2-bromoethyl methyl ether (2.6 g, 19 mmol) in DMF (100 mL) at 60° C. Purification by flash chromatography on silica gel afforded 4.8 g (62% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6 /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1 (d, 2), 7.9 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.2 (s, 2), 4.2 (br, 2), 3.6 (s, 2), 3.8-3.0 (br, 8), 3.2 (s, 3), 2.9 (s, 3) ppm.