Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1cccc(B(O)O)c1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Yield: 67.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (180 mg, 0.4337 mmols), [3-(hydroxymethyl)phenyl]boronic acid (264 mg, 1.74 mmols), cesium carbonate (282 mg, 0.868 mmol), and Pd(PPh3)4 (22 mg, 0.021 mmol) in dioxane/water (2 mL/0.7 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (130 mg, 68%)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(Cl)c(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dichloro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3]1.C(OC(=O)C)(=O)C>[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1
Reactant: CCOC(=O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1CC(=O)c2ccccc2O1
Temperature: 60 °C

Procedure:
A hydrogenator was charged by adding 6 g of ethyl 4-oxochromene-2-carboxylate, 3.5 mL of acetic anhydride, 1 g of 10% palladium on carbon, 4.0 g of dried 3A molecular sieves (powered), and 30 mL of glacial acetic acid. After purging several times with nitrogen, the hydrogenator was purged several times with hydrogen. While maintaining stirring the reaction mixture was pressurized to about 30 psi of hydrogen, heated to about 60° C. and maintained under those conditions for about 10-12 hours. HPLC monitoring of the reaction was used to determine when the reaction was essentially complete, e.g., when the area ratio by HPLC between the chromen-4-one and the chroman-4-one was not more than 3%. The mixture was then cooled to room temperature and filtered through a celite bed. The catalyst and sieves were washed with 10 mL aliquots of glacial acetic acid and the washes were combined with the filtrate. The combined mixture was concentrated under mild distillation conditions to an oil, which was dissolved with ethyl acetate and extracted with saturated NaHCO3. After the extraction, the aqueous layer was washed with ethyl acetate and the mixture neutralized to a low pH with concentrated HCl. The mixtures was extracted several times with ethyl acetate, the extracts were combined, concentrated to a solid, washed with acetonitrile and then filtered. Upon drying, about 3.5-4.0 grams of ethyl 4-oxo-chromane-2-carboxylate were obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([NH:15][NH2:16])=[O:14])=[CH:7][CH:6]=2.[N:17]#[C:18]Br>CO.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[O:14][C:18]([NH2:17])=[N:16][N:15]=1)=[CH:7][CH:6]=2
Reactant: NNC(=O)Cc1ccc2ncc(Br)cc2c1
Reactant: N#CBr
Solvent: CO
Solvent: O
Product: Nc1nnc(Cc2ccc3ncc(Br)cc3c2)o1

Procedure:
A mixture of (3-bromo-quinolin-6-yl)-acetic acid hydrazide (prepared according to procedure described herein) (4.12 g, 14.7 mmol), cyanogen bromide (1.1 eq., 16.2 mmol, 1.7 g) and KHCO3 (1.25 eq., 18.3 mmol, 1.83 g) was stirred in methanol (30 mL) at ambient temperature for 18 hours. The was then diluted with water (40 mL) and the solid was collected via filtration and washed with cold methanol and dried to return the title compound as an off white solid (4.02 g, 13.2 mmol, 90%). 1H NMR (DMSO-d6): δ 4.27 (2H, s), 6.94 (s, 2H), 7.71 (dd, 1H), 7.86 (d, 1H), 8.02 (d, 1H), 8.73 (d, 1H); 8.93 (d, 1H); MS (m/z) 305 [M+H+]+.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1>>[CH3:14][C:12]1([CH3:15])[N:13]=[C:9](/[CH:8]=[CH:1]/[C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[O:10][CH2:11]1
Reactant: CC1=NC(C)(C)CO1
Reactant: O=Cc1ccco1
Product: CC1(C)COC(/C=C/c2ccco2)=N1

Procedure:
4,4-Dimethyl-2(2-α-furylethenyl)-2-oxazoline (P-1906) was prepared by reacting furfural with 2,4,4-trimethyl-2-oxazoline. The product had a boiling point of 87° at 0.14 mm and the nmr spectrum and infra-red absorption spectrum were consistent with the proposed structure. The oral LD0 by adminstration to mice was 50 mg/kg; the LD50 was 212 and the LD100 was 300 mg/kg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-])=O.[H][H]>C(O)C.[Pd]>[N:11]1([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[NH2:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccncc1N1CCCCC1
Reaction time: 15 h
Yield: 73 %

Procedure:
To a solution of 4-nitro-3-(piperidin-1-yl)pyridine 1-oxide (1.0 equiv.) in ethanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time LC/MS analysis indicated that the nitro was reduced to the amine, but the N-oxide was remaining. More 10% palladium on carbon (0.2 eq.) was added and the mixture was resubmitted to a balloon atmosphere of hydrogen. After stirring for 24 hours, more 10% palladium on carbon (0.2 eq.) was added and the mixture was resubmitted to a balloon atmosphere of hydrogen. After stirring for an additional 3 days the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding 3-(piperidin-1-yl)pyridin-4-amine (73%). LCMS (m/z): 178.0 (MH+); LC Rt=1.66 min.
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:31])[CH:11]=[C:12]([C:29]#[N:30])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)=[CH:16][CH:15]=1)=[O:8])[CH3:5].[H][H]>[Pd].C(OCC)(=O)C>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH3:31])[CH:11]=[C:12]([C:29]#[N:30])[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])=[CH:18][CH:19]=1)=[O:8])[CH3:5]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3[N+](=O)[O-])cc2)c(C#N)cn1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3N)cc2)c(C#N)cn1C
Reaction time: 18 h

Procedure:
Add a 1:1 ethanol:ethyl acetate mixture to palladium on carbon (catalytic, 0.30 g) followed by 3(2′-nitro-biphenyl-4-yl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (3.00 g, 8.30 mmol, prepared in example E-9) with stirring. Subject the reaction to an atmosphere of hydrogen gas. After 18 hours, filter and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 332.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.[CH3:36][S:37][C:38](SC)=[N:39][C:40]#[N:41]>CC(O)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH:16]1[C:15]([C:31]([O:33][CH3:34])=[O:32])=[C:14]([CH3:35])[NH:13][C:12]([CH2:11][O:10][CH2:9][C:6]2[N:7]=[N:8][N:4]([CH2:3][CH2:2][NH:1][C:38](=[N:39][C:40]#[N:41])[S:37][CH3:36])[N:5]=2)=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CSC(=NC#N)SC
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCc2nnn(CCNC(=NC#N)SC)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 60.8 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (1.04 g) and dimethyl N-cyanoimidodithiocarbonate (0.30 g) in propan-2-ol (10 ml) was heated under reflux for 16 hours and then evaporated. The residual oil was triturated with hexane containing a small amount of methanol and the resulting solid was collected washed with hexane and dried to give 5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2-[2-(3-cyano-2-methyl-1-isothioureido)ethyl]tetrazole (0.75 g), m.p. 78°-80° C. Found: C,48.53; H,4.93; N,17.60. C25H28Cl2N8O5S requires C,48.23; H,4.34; N,18.00%.
Reaction SMILES: Cl.[O:2]=[C:3]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:6](=[O:8])[CH2:5][CH2:4][C:3](=[O:2])[C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)CCC(=O)c1cccs1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1cccs1
Yield: 32.3 %

Procedure:
Proceeding as in Example 1, but substituting 4-oxo-4-(thien-2-yl)butanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 91, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(4-oxo-4-(thien-2-yl)butanoyl)pyrrolidine-2-carboxamide (10.8 mg, 32.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.84 (s, 1H), 7.95 (m, 2H), 7.53 (m, 2H), 7.29 (m, 2H), 7.24-7.14 (m, 8H), 6.91 (m, 2H), 4.43 (t, 1H), 3.69 (m, 1H), 3.24 (m, 1H), 3.05 (m, 2H), 2.67-2.59 (m, 5H), 1.91 (m, 2H). MS (EI) for C32H29FN2O4S. found 557.7 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH:16]([N:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: OCCc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc(CCO)n1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
To a solution of 1.0 gm (9.0 mMol) 2-(3-pyrazolyl)-1-ethanol in 36 mL dimethylformamide were added 2.38 gm (22.5 mMol) sodium carbonate followed by the dropwise addition of a solution of 0.89 mL (9.0 mMol) 2-iodopropane in 8 mL dimethylformamide. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was then cooled to ambient and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic phase was then washed with water followed by saturated aqueous sodium chloride and was then dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 0.36 gm (26.0%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]=[C:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[N:6][CH:7]=1.O(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:16](=[O:18])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1cncc(Br)c1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)c1c[nH]c2cc(Br)cnc2c1=O
Temperature: 25 °C

Procedure:
In a RBF fitted with a reflux condenser a mixture of diethyl 2-((5-bromopyridin-3-ylamino)methylene)malonate (1 g, 3 mmol) and 1-phenoxybenzene (10 mL, 63 mmol) was heated to reflux for 1 h. The reaction mixture was allowed to cool to RT and CH3CN was added. The resulting solids were filtered and dried to provide the desired product as a light brown solid.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:14]([CH3:27])=[C:13]([CH3:28])[N:12]=1.O>O1CCCC1>[CH3:28][C:13]1[C:14]([CH3:27])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Under a nitrogen atmosphere, tetrahydrofuran (THF) (150 mL) was cooled to 0° C. Sodium hydride (9.30 g, 233 mmol), available as a 60% dispersion in mineral oil, was added with stirring. A solution of phenol (21.1 g, 225 mmol) in THF (80 mL) was added dropwise over a period of one hour. A solution of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol (44.5 g, 155 mmol) in THF (80 mL) was then added dropwise over a period of 40 minutes. The reaction was allowed to warm to room temperature and heated at reflux overnight. An analysis by thin layer chromatography (TLC) indicated that the reaction was incomplete. Additional reagent was prepared as described above by adding phenol (7.1 g, 75 mmol) to sodium hydride (3.2 g, 80 mmol) in THF (50 mL), and the reagent was added to the reaction solution at room temperature. The reaction was heated at reflux overnight and then allowed to cool to room temperature. Water (50 mL) was added, and the solvent was removed under reduced pressure. The aqueous solution was extracted with ethyl acetate. The organic solution was washed with water (3×) and brine (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The crude product was purified twice by column chromatography on silica gel (eluting sequentially with 50:50 hexane:ethyl acetate and 25:75 hexane:ethyl acetate) to provide 40.24 g of 5-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-ylamino)pentan-1-ol as a yellow oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:31]=[C:32]([N:47]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:48](=[O:51])[O:49][CH3:50])[CH:33]=[C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]3[CH2:46][O:45][CH2:44]3)[CH2:39][CH2:38]2)[C:35]=1[F:36].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:14]([C:13]1[N:9]2[C:10]([C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:6][C:7]([NH:29][C:30]3[CH:31]=[C:32]([N:47]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([O:59][CH3:60])=[CH:57][CH:58]=4)[C:48](=[O:51])[O:49][CH3:50])[CH:33]=[C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH:43]5[CH2:46][O:45][CH2:44]5)[CH2:41][CH2:42]4)[C:35]=3[F:36])=[N:8]2)=[N:11][CH:12]=1)#[N:15]
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C3COC3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Nc2nc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)c(F)c(N2CCN(C3COC3)CC2)c1
Temperature: 45 °C
Reaction time: 16 h
Yield: 179.8 %

Procedure:
4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 3) (58.4 mg, 0.146 mmol), methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (62 mg, 0.098 mmol) and Cs2CO3 (95 mg, 0.293 mmol) in DMF (1 ml) were heated at 70° C. for 80 minutes. Additional 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (58.4 mg, 0.146 mmol) and Cs2CO3 (95 mg, 0.293 mmol) were added and the mixture stirred at 45° C. for 16 hours. The mixture was partitioned between EtOAc and dilutes aq. NH4Cl solution. The organic layer was washed twice with dilute NaHCO3 solution, once with brine, then dried over MgSO4, filtered and evaporated to dryness to give methyl (3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4 methoxybenzyl)carbamate (134.4 mg). The material was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21]([O:23]C)=O)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CO>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][C:21]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)OC
Reactant: C1CCNC1
Solvent: CO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)N1CCCC1
Yield: 72.2 %

Procedure:
A solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxy-2-oxoethoxy)benzamide (1.07 g, 3 mmoles) (prepared in Example 15) in methanol (10 ml) and pyrrolidine (0.952 g, 23 mmoles) was refluxed overnight. The solvent was evaporated and the residue was chromatographed over deactivated silica using methylene chloride (100), methanol (2.5), ammonia (0.5) solvent system. The appropriate fractions were combined, the solvent evaporated and the residue crystallized from 2-propanol and recrystallized from methanol-ether to yield 0.86 g (72%) of the title compound, mp. 160°-162° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>C1COCC1>[CH3:10][NH:11][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(C#N)n1
Reaction time: 8 h

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (14.1 g, 101 mmol, prepared according to the procedure of Daves et. al J. Het. Chem. 1964, 1, 130-132) in 100 ml THF was cooled to 0° C. Reaction progress was monitored as aliquots of methylamine solution (in THF, 2.0 M, Aldrich) were added dropwise over the course of 1 h (58 ml+15 ml+15 ml). The mixture was stirred overnight. Additional methylamine solution (15 ml) was added very slowly, and the reaction was stirred 10 min. After concentration, the residue was extracted with EtOAc (400 ml) and saturated aqueous NaHCO3 (15 ml), and the organic layer was washed with 100 ml brine. The combined aqueous layers were extracted with EtOAc again (200 ml), and this organic layer was washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The orange solid was packed into a filtration apparatus, and submerged in just enough MeOH to cover the material (15 ml). Orange liquid was allowed to drain by gravity, then under high vacuum. The solid was washed in the same manner with t-BuOMe (15 ml). 2-Methylamino-pyrimidine-4-carbonitrile was obtained as peach-colored “fly-away” crystals. MS: 135.0 (M+1); Calc'd. for C6H6N4—134.14.
Reaction SMILES: I.C[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11]C)[CH:5]=1>>[CH3:10][C:8]1[CH:7]=[C:6]([OH:11])[CH:5]=[C:4]([CH:9]=1)[OH:3]
Reactant: COc1cc(C)cc(OC)c1
Agent: I
Product: Cc1cc(O)cc(O)c1
Reaction time: 3 h

Procedure:
Methylmagnesium bromide (35 g) was added to 1,3-dimethoxy-5-benzoyl chloride (100 g) to obtain 1,3-dimethoxy-methylphenone in a yield of 45%. Then, the reduction was conducted by adding water (300 cc), concentrated hydrochloric acid (300 cc) and 1,3-dimethoxy-methylphenone (100 g) to zinc amalgam obtained from zinc (400 g) and mercuric chloride (20 g). Further, concentrated hydrochloric acid (10 to 15 cc) was added every one hour. After the completion of the reaction, the reaction solution was cooled and saturated with sodium chloride, and then extracted with ether to obtain 40 g of 1,3-dimethoxy-5-methylbenzene. Hydrogen iodide was added to the resulting 1,3-dimethoxy-5-methylbenzene and stirred at 115° to 125° C. for 3 hours under nitrogen atmosphere. After cooling, the product was extracted with methylene chloride to obtain 30 g of 5-methylresorcinol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH:5]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:23][CH:24]=[O:25])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cncn2)c(F)c1
Product: O=CC=Cc1ccc(-n2cncn2)c(F)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (prepared as described in Reference Example 7) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 218 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([OH:28])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1.O>CN(C)C=O>[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([O:28][CH2:7][CH3:8])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1
Reactant: CCI
Reactant: Cn1nc(O)c(CSC2=NOC(C)(C)C2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(C)c(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
0.20 g (1.3 mmoles) of anhydrous potassium carbonate and 0.20 g (1.5 mmoles) of ethyl iodide were added to a solution of 0.30 g (1.0 mmoles) of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting-organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.30 g (yield: 92.0%) of intended 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.