Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=C(F)C=1C(Cl)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1)[NH2:29].C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:23]([NH:22][C:20](=[O:21])[C:14]2[C:13]([F:12])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[S:24])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1c(F)cccc1F
Agent: O=C(N=C=S)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(F)cccc4F)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,6-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,6-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (59 mg, yield 74%). 1H-NMR (DMSO-d6, 400 MHz): δ 3.94 (s, 3H), 3.96 (s, 3H), 6.57 (d, J=4.64 Hz, 1H), 7.11–7.51 (m, 4H), 7.62–7.64 (m, 1H), 7.80–7.83 (m, 2H), 8.08 (m, 1H), 8.52 (d, J=5.12 Hz, 1H), 12.16 (s, 1H), 12.28 (s, 1H) Mass spectrometry value (ESI-MS, m/z): 530 (M++1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A suspension of 6-bromo-4-hydroxycarbostyril (2.23g, 0.0093 mole) in glacial acetic acid (15 ml) was swirled during the addition of concentrated nitric acid (2.5 ml, d, 1.42). On heating at 100° C for several minutes a thick yellow solid separated. After cooling, ethanol (40 ml) was added and the mixture filtered and the solid washed free of nitric acid with ethanol. Drying in vacuo over P2O5 gave the title compound, m.p. 231°-4° C (d). (Found; C, 37.83; H, 1.74; N, 9.77; Br, 28.33; C9H5N2BrO4 requires; C, 37.92; H, 1.77; N, 9.83; Br, 28.03%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=2)[N:20]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:18][C:19]2[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:29][CH:28]=3)[N:20]=2)[CH:11]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cc([N+](=O)[O-])ccc3OCc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cc(N)ccc3O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.9 %

Procedure:
Into a 50 mL autoclave was charged Pd—C (0.025 g). MeOH was added under nitrogen. A solution of N4-(2-(benzyloxy)-5-nitrophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.10 g) in methanol and THF was added to the suspension. The autoclave was flushed with nitrogen and 8 kg/cm2 Hydrogen pressure was applied. The reaction mixture was stirred at room temperature for 18 h at same pressure. After completion, the reaction mixture was filtered using Celite and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure at 40° C. to give 0.08 g of 4-amino-2-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenol. Crude material was taken in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Into a 2 L three-neck flask equipped with a stirrer, a thermometer and a nitrogen-introducing tube, 240.2 g (2.50 mol) of fluorobenzene was introduced, and was cooled to 10° C. in an ice bath. Then, 134.6 g (0.50 mol) of 2,5-dichlorobenzoic acid chloride, and 86.7 g (0.65 mol) of aluminum chloride were slowly added such that the reaction temperature would not exceed 40° C. After the addition, the mixture was stirred at 40° C. for 8 hours. After the disappearance of the raw materials was confirmed by thin-layer chromatography, the mixture was dropped in iced water, and extraction using ethyl acetate was carried out. The extraction liquid was neutralized by 5% sodium bicarbonate water, and the resultant was washed with saturated saline water. The liquid washed was dried with magnesium sulfate, and then the solvent was distilled away using an evaporator. The residue was allowed to recrystallize in methanol, thereby an intermediate product, 2,5-dichloro-4′-fluorobenzophenone, was obtained. Amount obtained was 130 g, and yield percentage was 97%. Note that, the yield percentage was calculated by following formula (hereinafter, the same): yield percentage (%)=(amount of product obtained/theoretical amount of product)×100.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>>[OH:17][CH2:12][CH2:13][CH2:14][C:15]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]2)=[O:16]
Reactant: O=C1CCCO1
Reactant: O=C1CCc2ccccc2N1
Product: O=C1CCc2cc(C(=O)CCCO)ccc2N1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
14.4 Grams of 3,4-dihydrocarbostyril and 10 g of γ-butyrolacton were mixed into 120 g of polyphosphoric acid and stirred at 80°-90° C. for 10 hours. The reaction mixture was poured into 300 ml of ice-water and was allowed to stand overnight. Then the precipitates thus formed were collected by filtration and washed with water, then recrystallized from ethanol-ethyl acetate to obtain 9.5 g of 6-(4-hydroxy-1-oxobutyl)-3,4-dihydrocarbostyril, having the melting point of 175°-176° C. in colorless prism-like crystals. Next, 5 g of 6-(4-hydroxy-1-oxobutyl)-3,4-dihydrocarbostyril and 0.5 g of palladium black wre mixed in 160 ml of ethanol and the mixture was subjected to catalytic reduction under 3 kg/cm2 of hydrogen gas at 60° C. for 6 hours. The reaction mixture was then cool and was added 1 ml of concentrated hydrochloric acid thereinto. Further the reaction mixture was subjected to the catalytic reduction under 3 kg/cm2 of hydrogen gas for 6 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure. The residue was recrystallized from ligroin to obtain 3.2 g of 6-(4-hydroxybutyl)-3,4-dihydrocarboxtryril, having the melting point of 133°-134° C. Next, 3.2 g of 6-(4-hydroxybutyl)-3,4-dihydrocarbostyril and 5 ml of thionyl chloride were mixed into 50 ml of chloroform and the mixture was stirred at a room temperature for 24 hours. The reaction mixture was concentrated under a reduced pressure. The residue was then recrystallized from ligroin to obtain 1.8 g of 6 -(4-chlorobutyl)-3,4-dihydrocarbostryl, having the melting point of 119°-121° C., in colorless prism-like crystals.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 94 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.192 g, 0.39 mmol) and 2M methylamine in THF (1 mL; 5 eq) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as an off-white solid (0.174 g, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.66 (s, 1H), 7.36 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 3.59-3.51 (m, 3H), 2.90 (d, J=4.4 Hz, 1H), 2.05 (s, 3H), 1.45 (s, 9H); (ESI) m/z: 479.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.C(OO)(=[O:17])C>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[N+:5]([O-:17])=[CH:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Temperature: 23 °C
Reaction time: 50 h

Procedure:
27.6 g (0.15 mol) of 4,4'-dimethyl-2,2'-bipyridine are dissolved in 300 ml of dichloromethane. 86 ml of a 1.837-molar solution of peracetic acid in ethyl acetate are added dropwise at 23°-28° C. After stirring for 50 hours at 23° C., the mixture is concentrated in vacuo. 27.2 g (90% of theory) of 4.4'-dimethyl-2,2'-bipyridine 1-oxide crystallise from ethylbenzene/petroleum ether; melting point 80°-130° C. (over a range).
Reaction SMILES: [Br:1][C:2]#[C:3][C:4]([O:6][CH3:7])=[O:5].[N:8]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9]1>>[Br:1][C:2]1[CH:9]2[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]([CH:11]=[CH:10]2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C#CBr
Reactant: CC(C)(C)OC(=O)n1cccc1
Product: COC(=O)C1=C(Br)C2C=CC1N2C(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 30 h

Procedure:
Into a 2000-mL 3-necked round-bottom flask was placed methyl 3-bromopropiolate (120 g, 736.33 mmol, 1.00 equiv) and tert-butyl 1H-pyrrole-1-carboxylate (615.61 g, 3.68 mol, 5.00 equiv). The resulting solution was stirred for 30 hr at 95° C. in an oil bath. The reaction mixture was cooled and distilled under reduced pressure (20 mm Hg). The fraction collected at 55° C. was purified by silica gel chromatography (ethyl acetate/petroleum ether, 1:20) to afford 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a yellow liquid.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[N:30]=[C:29](Cl)[S:28][N:27]=1.C(N(CC)CC)C>ClCCl>[Cl:25][C:26]1[N:30]=[C:29]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)[S:28][N:27]=1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cl)ns2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrogen chloride salt (696 mg), 3,5-dichloro-1,2,4-thiadiazole (372 mg), and triethylamine (0.42 mL) in dichloromethane (30 mL) is stirred overnight at room temperature. More triethylamine (0.40 mL) is added and the mixture is stirred until the conversion is complete (1 h). The solvent is partly evaporated and the residue is triturated with water. The precipitate is filtered off, washed with dichloromethane and dried to yield the title compound. LC (method 5): tR=2.08 min; Mass spectrum (ESI+): m/z=430/432 (Cl) [m+H]+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([OH:39])=O)[C:30]=2[CH:40]=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>CN(C=O)C>[Cl:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:39])[C:30]=2[CH:40]=1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Reactant: CN[C@@H](CN1CCOCC1)c1ccc(-c2cccc(OC)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.2 %

Procedure:
(1R)—N-Methyl-1-[3′-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethanamine (3.3 g, 10 mmol) was dissolved in 100 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (4.3 g, 12 mmol, with 23 wt % LiCl) followed by triethylamine (2.8 mL, 20 mmol) and BOP (5.3 g, 12 mmol). The reaction mixture was maintained at room temperature for 16 h. The reaction mixture was filtered and the filtrate was added slowly to of H2O (300 mL) with vigorous stirring. The precipitate which formed was collected by filtration and further purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 80 mL/min, A: MeOH (with 10% NEt3), B: CH2Cl2, A: 1% for 20 min, 2% for 20 min, 5% for 10 min; detection at 254 nm). The combined fractions were concentrated, and the resulting residue was triturated with MeOH. The white solid was collected by filtration to give the title compound (2.7 g, 46%). MS (ES) m/e 585 [M+H]+.
Reaction SMILES: ClC1SC(C(O)[C:8]2[C:9](CC(C)C)=[C:10]([C:21]([O:23]C)=[O:22])[C:11](C(F)F)=[N:12][C:13]=2C(F)(F)F)=CN=1.C(N(CC)CC)C>[Pd].CO>[N:12]1[CH:13]=[CH:8][CH:9]=[C:10]([C:21]([OH:23])=[O:22])[CH:11]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2cnc(Cl)s2)c1CC(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1
Reaction time: 18 h

Procedure:
This example illustrates the preparation of Compounds 62, 106, 107, and 109, an example of reduction of a α-hydroxyhaloheterocyclomethyl derivative to the α-hydroxyheterocyclomethyl derivative, and oxidation of this derivative to compounds of the present invention. A mixture of methyl 5-[(2-chloro-5-thiazolyl)-hydroxymethyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (7.2 g, 16 mmol), 6 mL triethylamine, and 5% of palladium on activated carbon catalyst (5 g) in 80 mL methanol was placed in a Parr hydrogenation apparatus at 50 psi and RT for 18 h. The reaction mixture was filtered through celite. The celite was thoroughly washed with methanol. The combined filtrates was concentrated in vacuo. The residual solid was purified by flash chromatography on silica gel with 30% ethyl acetate-cyclohexane to afford 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-(hydroxy-5-thiazolylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester (5 g, 73.5%) as A light yellow solid. m.p. 140°-150° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH:13][C:14](=[O:18])[CH2:15][CH2:16]Cl)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:13]2[CH2:16][CH2:15][C:14]2=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(NC(=O)CCCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(N2CCC2=O)cc1OC
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3,4-dimethoxyphenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3,4-dimethoxyphenyl)-2-azetidinone as the residue.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][N:5]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([SH:24])=[N:23][C:19]=2[CH:18]=1>CO.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([S:24][CH2:3][C:4]3[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][N:5]=3)=[N:23][C:19]=2[CH:18]=1
Reactant: COc1ccnc(CCl)c1OC
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccnc(CSc2nc3cc(Cl)ccc3[nH]2)c1OC

Procedure:
2-chloromethyl-3,4-dimethoxypyridine hydrochloride (896 mg, 0.004 mol) was dissolved in 25 ml MeOH and treated with NaOH (390 mg, 0.008 mol) dissolved in 1.5 ml H2O. 5-chloro-2-mercapto-1H-benzimidazole (812 mg, was added and the resulting mixture allowed to react for 2h at room temperature. The solvent was evaporated and the residue partitioned between 50 ml 2.5 % NaOH and 75 ml CH2Cl2. The aqueous layer was separated and extracted twice with 25 ml CH2Cl2. The organic layers were combined, washed with 25 ml H2O, dried over MgSO° and the solvent was evaporated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([OH:21])=O)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[CH3:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([NH:30][CH2:29][C:26]2[CH:27]=[N:28][C:23]([CH3:22])=[CH:24][CH:25]=2)=[O:21])[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:11]=1
Reactant: COCCOc1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Reactant: Cc1ccc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(2-methoxyethoxy)-4′-methylbiphenyl-3-carboxylic acid (50 mg, 0.18 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (45 mg, 0.37 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC to afford the title product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])=[N:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc2ccoc2c1OCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.047 mmol), phenylboronic acid (11.5 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=5.94 (s, 2H), 6.78 (d, J=2.3 Hz, 1H), 7.52-7.60 (m, 4H), 7.94-8.00 (m, 4H), 8.32 (d, J=9.6 Hz, 1H). MS (ES+): m/z 359.04 (100) [MH+]. HPLC: tR=2.21 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][Si:21]([C:24]#[C:25][Sn](CCCC)(CCCC)CCCC)([CH3:23])[CH3:22]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: Oc1ccc(-c2cc(Br)c3cc(O)ccc3n2)cc1
Product: C[Si](C)(C)C#Cc1cc(-c2ccc(O)cc2)nc2ccc(O)cc12
Yield: 83 %

Procedure:
This compound was prepared from 6a and (trimethylsilylethynyl)tributyltin according to method J. Yellow powder; Yield: 83%; mp 210° C. (dec.); 1H-NMR (300 MHz, acetone-d6) δ 0.38 (s, 9H), 7.02 (d, J=8.7 Hz, 2H), 7.44 (dd, J=9.1, 2.7 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 8.05 (s, 1H), 8.18 (d, J=8.7 Hz, 2H), 8.70 (s, 1H), 9.15 (s, 1H); MS (ESI) m/z 332 ([M−H]−), 334 ([M+H]+); Anal. Calcd for C20H19NO2Si: C: 72.04, H: 5.74, N: 4.20. Found: C: 71.67, H: 5.79, N: 4.07.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:43](=[O:44])[C:42]4[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(F)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-fluorobenzoyl chloride (475.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.