Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.CN(C=O)C.[CH2:10]([C:12]1[N:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:14]=[C:15]2[C:24]=1[C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:17][C:16]2=O)[CH3:11].[Cl:32]CCl>C(#N)C>[Cl:32][C:16]1[C:15]2=[N:14][N:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]([CH2:10][CH3:11])=[C:24]2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thionyl chloride (4 mL) and DMF (4 mL) were combined and added dropwise to a mixture of 1-ethyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (1.29 g, 4.40 mmol) and dichloromethane (80 mL) at 0° C. The resulting suspension was stirred 5 minutes at 0° C. before warming to ambient temperature and stirring 50 minutes. The suspension was concentrated under reduced pressure to afford an oily solid that was stirred in acetonitrile and filtered to obtain 450 mg of 4-chloro-1-ethyl-2-phenyl-2H-pyrazolo[3,4-c]quinoline as white crystals, mp 207-209° C. MS (APCI) m/z 308 (M+H)+; Anal. calcd for C18H14ClN3: C, 70.24; H, 4.58; N, 13.65. Found: C, 69.94; H, 4.48; N, 13.54
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]([F:32])([F:31])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[F:31][C:15]([F:14])([F:32])[C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([N:1]3[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)=[O:29])[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
tert-Butyl (3S)-pyrrolidin-3-ylcarbamate (0.65 g, 3.5 mmol), 1-[3-(trifluoromethyl)phenyl]piperidine-4-carboxylic acid (0.80 g, 2.9 mmol), triethylamine (0.82 mL, 5.8 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.4 g, 3.2 mmol) were mixed in dry methylene chloride (10 mL). After being stirred overnight, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (20% EtOAc/hexanes to 40% EtOAc/hexanes) to give 0.975 g of the desired product. MS (M+H) 442.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[N:12]1([C:17](N2C=CN=C2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[O:18])[S:8][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: CN(C)C=O
Product: Cc1ccc2nc(NC(=O)n3ccnc3)sc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 6-methylbenzo[d]thiazol-2-amine (109, 328 mg, 2 mmol, Sigma-Aldrich) in DMF (5 mL) was added di(1H-imidazol-1-yl)methanone (110, 357 mg, 2.2 mmol, Sigma-Aldrich) at 0° C. Under vigorous stirring, the resulting reaction mixture was slowly allowed to warm to a temperature of about 25° C. over 14 h. A white precipitate formed. The precipitate was collected by filtration under reduced pressure, washed twice with EtOAc (10 mL for each wash), and dried under reduced pressure to provide 108 (yield >99%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH:20]1[C:28]2[C:23](=[C:24]([CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:20]1[C:28]2[C:23](=[C:24]([CH2:29][NH:30][C:2]3[CH:7]=[C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:3]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: NCc1cccc2[nH]ccc12
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(-c2nc(NCc3cccc4[nH]ccc34)cc(-c3cccnc3)n2)nc1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine (Intermediate A) (1 eq, 0.2 g), C-(1H-indol-4-yl)-methylamine (1.1 eq, 0.12 g) and K2CO3 (3 eq, 0.308 g) in NMP (6 ml) is heated using microwave radiation at 120° C. for 1 hour. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by mass directed preparative HPLC eluting with acetonitrile in water—0.1% TFA and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound [M+H]+=379.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([CH3:26])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:7]=1)[CH3:5].[OH-].[Na+]>CO.O>[CH3:26][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])[CH:7]=1)([CH3:5])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the title B compound, 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester (3.45 g, 9.45 mmol) in methanol (30 mL) is added sodium hydroxide (1.51 g, 37.81 mmol) in water (10 mL) at RT. The reaction mixture is stirred at 70° C. for 4 h. The reaction mixture is concentrated, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is dried over magnesium sulfate and concentrated to give 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]=[CH2:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: CCO
Product: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g), bis(tricyclohexylphosphine)palladium (II) dichloride (332 mg), tripotassium phosphate (11 g) and vinylboronic acid pinacol ester (3 g) were added toluene (27 mL) and water (1.4 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g). 4-(3-Methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g) was dissolved in ethanol (20 mL), 5% palladium carbon-ethylenediamine complex (600 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 8 hr at room temperature. After celite filtration, the solvent in the filtrate was evaporated to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg). 4-(5-Ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (870 mg) was dissolved in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. 1N Aqueous sodium hydroxide solution (7 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (441 mg).
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[CH:9](OCC)(OCC)[O:10]CC.CC(O)C.[ClH:23]>O>[OH2:4].[OH2:10].[ClH:23].[OH:4][C:3]1[NH:5][CH:9]=[N:1][C:2]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(N)C(N)=O
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1nc[nH]c1O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under the nitrogen atmosphere, 10 g of 2-aminomalonamide and 35.4 mL of triethyl orthoformate were added to 200 mL of 2-propanol. After heating to 80° C., the reaction mixture was stirred for 8 hours at the same temperature. Color of the reaction liquid was pale yellow when the reaction was completed. Subsequently, after cooling to 57° C., the reaction mixture was added with 10 mL of water followed by 8 mL of conc. hydrochloric acid. After cooling with water, the crystal was collected by filtration and then washed with 40 mL of acetone to give 16 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate as a pale yellow crystal.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH2:11][CH:10]([CH2:12]OS(C)(=O)=O)[O:9][N:8]=2)=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:18]([CH2:12][CH:10]1[O:9][N:8]=[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:11]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)s2)=NO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)s2)=NO1
Temperature: 75 °C
Yield: 97.6 %

Procedure:
Methanesulfonic acid 3-(5-bromo-thien-2-yl)-4,5-dihydro-isoxazol-5-ylmethyl ester (9 g, 26.4 mmol) was added to dimethyl formamide (25 ml) followed by addition of sodium azide (3.4 g, 52.8 mmol). The mixture was heated to 75° C. for five hours and then added to aqueous sodium chloride (100 ml) followed by extraction with ethyl acetate (3×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (7.4 g).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.Br[C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][N:54]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][N:54]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)nc1
Reactant: Cc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C)ccn2)nc1
Temperature: 80 °C
Reaction time: 120 h
Yield: 44.6 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (200 mg) is dissolved in 1,4-dioxane (4 ml) and thereto are added 2-bromo-4-methyl-pyridine (70 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg) and cesium carbonate (133 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. for 5 days. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→14:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85 mg). MS (m/z): 701 [M+H]+
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 243A (0.093 g, 0.20 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.152 mL, 0.30 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (m, 3 H) 4.41 (d, J=68.76 Hz, 1 H) 5.85 (m, 1 H) 7.28 (m, J=7.54, 7.54 Hz, 7 H) 7.59 (m, 4 H) 8.07 (m, 2 H) 16.30 (s, 1 H). MS (ESI−) m/z 459 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:21])(=[O:20])[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:31])[CH3:30])=[O:24].C=O.[C:34]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.O.C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:20])(=[O:21])[CH2:17][CH2:16][N:15]([CH3:34])[CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH2:27][O:28][C:29](=[O:31])[CH3:30])=[O:24]
Reactant: [BH3-]C#N
Reactant: CC(=O)OCCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)OCCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCN(C)C2
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 2-acetoxyethyl 9-(2,3-dichlorophenyl) -1,1-dioxo-2,3,4,5,6,9-hexahydro-7-methyl-pyrido[2,3-f][1,4]thiazepine-8-carboxylate (0.880 g, 1.69 mmole) from Example 19, and 1 mL of 38% aqueous formaldehyde solution in 20 mL of acetonitrile was treated with sodium cyanoborohydride (0.070 g, 1.69 mmole). After stirring for 1 hour, 0.5 mL of acetic acid was added, and the reaction was stirred for another 2 hours. After the addition of 40 mL of water and adjustment of the pH to 9 with 6N sodium hydroxide, the reaction was extracted with 3×30 mL of chloroform. The combined organic extracts were dried with sodium sulfate, the solvent was removed under reduced pressure, and the residue was chromatographed (2% methanol, 0.1% ammonia in chloroform on silica gel) to obtain the title compound (0.743 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:18][CH2:19][C:20]#[C:21][CH3:22].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11]2[N:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:12]=2[C:13](=[O:15])[CH2:14]1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2F)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a mixture of 5-(2,4-difluorophenyl)cyclohexane-1,3-dione (2.0 g), 1-amino-2-butyne hydrochloride (0.94 g), molecular sieves 4A (4 g) and tetrahydrofuran (40 ml) was added triethylamine (0.90 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 5 hours at 220° C., to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give, the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from isopropylether and hexane to give colorless crystals of 7-(2,4-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.47 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(F)ccc1F)C2
Yield: 99.6 %

Procedure:
A solution of 7-(2,5-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.2 g) and aminoguanidine hydrochloride (0.58 g) in ethanol (30 ml) was combined with concentrated hydrochloric acid (1.1 ml) and water (1.1 ml), and the mixture was heated under reflux for 14 hours. The solvent was distilled off under reduced pressure, and the resultant crystal was recrystallized from ethanol to obtain 7-(2,5-difluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound K) (1.6 g) as a colorless crystal.
Reaction SMILES: C(OC(=O)C=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19]C=N3)[CH:14]=2)[NH:9][CH:8]=1)C.C1N2CN3[CH2:31][N:25](C2)CN1C3.C(O)(=[O:34])C>>[CH:6]([C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][N:25]=[CH:31]3)[CH:14]=2)[NH:9][CH:8]=1)=[O:34]
Reactant: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cncn3)cc12
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(=O)O
Product: O=Cc1c[nH]c2cnc(-n3cnnc3)cc12
Yield: 38 %

Procedure:
A mixture of Intermediate 5 (1.62 g, 8.7 mmol) and hexamethylenetetramine (1.47 g, 10.5 mmol) was refluxed in 33% aqueous acetic acid (10 mL) for 75 min. The mixture was cooled in ice for 2 hours and the precipitate was collected by filtration to give the title compound (0.71 g, 38%) as a beige solid. The filtrate was evaporated and the residue chromatographed on silica eluting with 10% MeOH in DCM to give the title compound (0.39 g, 21%) (overall yield 59%), as a yellow solid. mp 155° C. (dec.). 1H NMR (360 MHz, d6 -DMSO) δ 8.35 (1H, s), 8.68 (1H, s), 8.83 (1H, s), 9.30 (2H, s), 10.05 (1H, s) and 12.74 (1H, br s).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])(=O)C.[K+].O1CCOCC1>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:29]3[CH2:30][CH2:31][O:26][CH2:27][CH:28]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(Oc2nccnc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
A clear 150 ml pressure tube was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (1.00 g, 2.85 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.396 g, 11.40 mmol), Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]palladium dichloride (0.101 g, 0.143 mmol), potassium acetate (0.616 g, 6.27 mmol), dioxane (9 mL) and water (1.000 mL). The reaction flask was flushed with nitrogen and capped. The reaction was heated to 100° C. for 16 hours. The reaction was then cooled down to RT and partitioned with ethyl acetate (50 ml) and water (50 ml). The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and then filtered. The volatile were reduced to a smaller volume and the solid that precipitated out was filtered off. The cake obtained was suspended in hot MeOH, filtered and dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5](P(OC)(OC)=O)[CH:6]([CH3:10])[C:7]([O-:9])=[O:8])=[O:4].[CH3:17]N(C)C(N(C)C)=N.[O:25]1[CH2:30][CH2:29]C(=O)[CH2:27][CH2:26]1>O1CCCC1>[CH3:17][O:9][C:7](=[O:8])[C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[C:10]1[CH2:29][CH2:30][O:25][CH2:26][CH2:27]1
Reactant: COC(=O)N(C(C)C(=O)[O-])P(=O)(OC)OC
Reactant: O=C1CCOCC1
Reactant: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)OC)=C1CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of N-methoxycarbonyl-2-methyl-(dimethylphosphono)glycinate (1.45 g, 5.68 mmol) in tetrahydrofuran (22 mL) was cooled to −78° C. 1,1,3,3-Tetramethylguanidine (0.680 mL, 5.42 mmol) was added and the resulting solution was stirred at −78° C. for 30 minutes. Tetrahydropyran-4-one (0.500 mL, 5.42 mmol) was added and the reaction was stirred at −78° C. for 1 hour. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. In the morning, the reaction was diluted with ethyl acetate. The organics were washed with 1N aqueous HCl and brine, dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography to yield methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester. 1H-NMR: 400 MHz, (CDCl3) δ: 5.94 (br s, 1H), 3.80-3.74 (m, 7H), 3.71 (s, 3H), 2.95-2.91 (m, 2H), 2.45-2.41 (m, 2H) ppm.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.C[N:18]([CH:20]=[O:21])C.C(Cl)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:20]([NH2:18])=[O:21])=[C:3]([CH3:9])[CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)ccc1N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(O)ccc1-c1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
4-Amino-3-methylphenol (370 mg, 3.00 mmols) was put into a 30-ml conical flask, purged with argon, and dissolved in 1.3 ml of dry DMF. Next, 0.42 ml (1 eq.) of dry triethylamine was added. Then, a dry DMF solution (3.0 ml) of benzoyl chloride (0.35 ml) was added, and stirred at room temperature for 12 hours. The resulting reaction mixture was poured into 50 ml of cold water, suction filtered, extracted with methylene chloride, and washed with water. The methylene chloride layer was dried with sodium sulfate, and methylene chloride was removed by evaporation under reduced pressure. Next, the residue was purified by column clromnatography (silica gel eluted with methylene chloride) to obtain 400 mg of the intended product, 4-hydroxy-2-methylphenylbenzamide (yield: 60%).