Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@:4]1(/[CH:29]=[CH:30]/[P:31](=[O:38])([O:35]CC)[O:32]CC)[C@@H:8]([OH:9])[C@@H:7]([OH:10])[C@H:6]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][CH:14]=[N:15][C:16]=3[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:5]1)=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[Si](I)(C)(C)C>CC#N>[N:1]([C@@:4]1(/[CH:29]=[CH:30]/[P:31](=[O:32])([OH:35])[OH:38])[C@@H:8]([OH:9])[C@@H:7]([OH:10])[C@H:6]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][CH:14]=[N:15][C:16]=3[NH:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:5]1)=[N+:2]=[N-:3]
Reactant: CCOP(=O)(/C=C/[C@@]1(N=[N+]=[N-])O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: [N-]=[N+]=N[C@]1(/C=C/P(=O)(O)O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 36.5 (261 mg, 0.48 mmol) was dissovled in CH3CN (9.6 mL), treated with 2,6-lutidine (0.55 mL, 4.2 mmol) and TMSI (0.34 mL, 2.39 mmol). The mixture was stirred at r.t. for 30 min and concentrated under reduced pressure. Saturated NaHCO3 was added to the residue and the mixture was stirred for 5 min. The solvent was then removed under redued pressure and CH3CN was added, the mixture was filtered and concentrated under reduced pressure. The residue was used for the next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][NH2:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][C:23]4[CH:22]=[C:21]5[C:26](=[CH:25][CH:24]=4)[N:18]([CH3:17])[CH:19]=[CH:20]5)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cn1ccc2cc(CN)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1ccc2cc(CNc3nccc(Nc4cc(C5CC5)[nH]n4)n3)ccc21
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (160 mg, 0.68 mmol), 296 (800 mg, 5.59 mmol), DIPEA (1 ml), and IPA (5.0 mL), sealed and heated at 120° C. for 18 h. It was concentrated and purified by SiO2 chromatography, and then preparative HPLC to afford 30 mg (12%) of I-33 as white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:20]=[C:19]([NH2:21])[N:18]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][CH:26]=[N:27]3)[N:17]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][C:19]2[N:18]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:17]=[C:16]([CH3:15])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OC(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 8.2 %

Procedure:
A stirred mixture of 4-isopropoxybenzene-1-sulfonyl chloride (0.10 g, 0.52 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.10 g, 0.44 mmol) in pyridine (2 mL) was heated at 80° C. for 1 h. After cooling to room temperature, aqueous saturated sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.036 mmol, 8%). 1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J=2.0, 4.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.61 (dd, J=7.6, 8.4 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.14 (dd, J=0.8, 7.2 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.25 (s, 1H), 4.57 (hept, J=6.0 Hz, 1H), 2.33 (s, 3H), 1.39 (d, J=6.4 Hz, 6H); MS: (ES) m/z calculated for C23H23N4O3S [M+H]+ 423.2. found 423.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1nc(-c2ccc(N)cc2)oc1C
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2)nc1Cl
Yield: 55.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.17 g, 1 mmol), thionyl chloride (5 mL), methyl 2-(4-aminophenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (97d) (0.15 g, 0.65 mmol) and pyridine (5 mL), to obtain 0.14 g of the title compound as a light pink solid (56%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[O:32][CH:33]=[CH:34][N:35]=1>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[O:32][CH:33]=[CH:34][N:35]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Fc1ccccc1-c1ncco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Temperature: 0 °C
Yield: 37.3 %

Procedure:
A mixture of N-benzylpiperazine (3.56 g, 20.2 mmol) and THF (25 mL) was cooled to 0° C. and n-butyllithium (2.5M in hexanes, 7.6 mL, 19 mmol) was added. The mixture was cooled 30 minutes with stirring at 0° C., stirred 1 hour at 25° C., then cooled to 0° C. and 2-fluoro-1-oxazol-2-ylbenzene (1.1 g, 6.75 mmol) was added slowly. The reaction mixture was allowed to warm to 25° C., then stirred 90 minutes and diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (9:1) to give 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.805 g, 2.52 mmol).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:25][OH:26])[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]([CH3:23])=[CH2:22])[C:13]1=[O:24].COCCOC>O>[O:26]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21]([CH3:23])=[CH2:22])[C:13]2=[O:24])=[N:25]1
Reactant: C=C(C)n1c(=O)n(CC(=NO)c2ccccc2F)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Temperature: 85 °C
Yield: 56.8 %

Procedure:
A 25 ml pear-shaped flask was charged with sodium hydride (60% oil dispersion, 68 mg, 1.7 mmol) which was washed with hexanes and then diluted with DME (3 ml). The 1-{2-(2-fluoro-phenyl)-2-[hydroxyimino]-ethyl}-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (0.5 g, 1.5 mmol) was introduced as a DME (3 ml) solution in a dropwise manner. The resulting mixture was warmed to 85° C. for 20 h and cooled to ambient temperature. The reaction was diluted with water and the product was extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 40% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give 0.26 g (55%) of the desired product.
Reaction SMILES: [CH2:1]1[C@@H:6]2[CH2:7][NH:8][C@H:9]([CH2:11][OH:12])[CH2:10][N:5]2[CH2:4][CH2:3][O:2]1.CCN(CC)CC.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH3:24][C:23]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][C@@H:9]1[CH2:10][N:5]2[C@H:6]([CH2:1][O:2][CH2:3][CH2:4]2)[CH2:7][NH:8]1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1CN2CCOC[C@@H]2CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Temperature: 25 °C

Procedure:
(7S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-7-ylmethanol (D50, 680 mg, 3.95 mmol) was almost dissolved in dry DCM (12 mL) before adding Et3N (1.10 mL, 7.90 mmol), followed by TBDMS-Chloride (894 mg, 5.93 mmol). The resulting reaction mixture was stirred over the weekend at R.T., under argon. Left stirring for 2 more hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:13]([CH:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(OCC)(SCC)=[S:38].C(O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:13]([CH:15]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28](=[S:38])[NH2:29])=[CH:26][CH:27]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP([O-])(=S)SCC
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1C(Nc1ccc(C#N)cc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1C(Nc1ccc(C(N)=S)cc1)C(=O)OCC

Procedure:
1.7 g of ethyl (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy-phenyl)-(4-cyano-phenylamino)-acetate, 1.13 ml of diethyl dithiophosphate and 4 ml of ethanol were heated for 2 hrs. to 60° C. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried and evaporated in a vacuum. Chromatography on silica gel gave 1.6 g of ethyl (RS)-(5-benzyloxy-2-ethoxycarbonylmethoxy-phenyl)-(4-thiocarbamoyl-phenylamino)-acetate, m.p. 166° C., MS: 523 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C(O)(=O)C>O>[OH:17][C:12]1[CH:13]=[C:14]([CH3:16])[N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.1 %

Procedure:
S-Methylisothiourea (22.26 g, 160 mmol) was added to a solution of sodium carbonate (16.9 g, 160 mmol) in water (50 mL) and stirred at room temperature until complete dissolution of the S-methylisothiourea. Ethyl acetoacetate (10.41 g, 80 mmol) was added to the mixture in one portion. After stirring for 60 hours at room temperature, the reaction was neutralized with acetic acid precipitating a white solid. The solid was collected, washed with water, and dried in vacuo to give 4-hydroxy-6-methyl-2-(methylthio)pyrimidine (9.38 g, 75%), m.p. 218°-221° C.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](O)=[O:23])=[N:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][N:14]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1n[nH]c2ccccc12

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1H-indazole-3-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.23-7.32 (m, 1H), 7.40-7.48 (m, 1H), 7.57-7.63 (m, 1H), 8.20 (d, J=8.1 Hz, 1H). MS (DCI/NH3) m/z 297.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:12][O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)c1cc(Br)oc1C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OC)nc2)oc1C
Yield: 80.5 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.2 g), 2-methoxy-5-pyridineboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.0 g, 81%) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>O1CCOCC1>[C:21]([NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[OH:14])(=[O:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(O)c(CN)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)NCc1cc(C(C)(C)C)ccc1O
Temperature: 0 °C

Procedure:
43 g (0.2 mole) of 2-aminomethyl-4-(1,1-dimethylethyl)-phenol hydrochloride are suspended in 400 ml of 1,4-dioxane, and 40 ml of pyridine are added. 40 ml (0.55 mole) of acetyl chloride are added dropwise while stirring and cooling with ice. The mixture is then stirred for 2.5 hours at 90° and poured into ice water, and the precipitate which has crystallized out is filtered off with suction.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:12]([O-:17])(=[O:16])[C:13]([CH3:15])=O.[Na+].Cl.Cl.N1C=CC=CC=1>C(O)(=O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:13]([CH3:15])[C:12]([OH:17])=[O:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)C(=O)[O-]
Reactant: CC(C)CC1CCCC(=O)C1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
The process according to claim 1, wherein 3-isobutyl-cyclohexanone and sodium pyruvate are heated in a HCl and acetic acid solution to give a mixture of condensation products and said condensation products are heated for 4 to 5 hours with pyridine hydrochloride to give p-isobutylhydratropic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:38]>O1CCCC1>[Cl:38][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[N:22]=3)=[C:11]2[CH:12]=[CH:13][C:14]=1[C:16]([F:19])([F:17])[F:18]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)c(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 59 %

Procedure:
To a cold (−78° C.) solution of 2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (86 mg, 0.20 mmol) in tetrahydrofuran (5 mL) was added n-butyllithium (0.30 mL, 1.6 M in hexane, 0.48 mmol) dropwise. The dark solution was stirred for 3 minutes, and then carbon tetrachloride (1 mL) was added. After 15 minutes, the bath was removed and the solution allowed to warm to room temperature and stirred an additional 15 minutes. Water was added then ether. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (4:1 hexanes-ethyl acetate) to give 7-chloro-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (55 mg, 59%) as a solid. 1H NMR (CDCl3): δ 8.50 (d, 1 H), 8.11 (d, 1 H), 7.62 (dd, 2 H), 7.50 (d, 1 H), 7.11 (t, 2 H), 6.22 (d, 1 H), 3.62 (m, 4 H), 2.01 (m, 4 H); MS m/z 462 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[N:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)c(-c2ncc(O)cc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 47 %

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-ol (300 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (257 mg) and triphenylphosphine (554 mg) in THF (5.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (943 μL) at room temperature, and the mixture was stirred for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (253 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]([C:16]1[NH:17][C:18]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([Cl:28])=[C:25]([OH:27])[CH:26]=2)[N:20]=1)([CH3:15])[CH3:14]>ClCCl.CO>[Cl:28][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:16]([C:13]([CH3:14])([CH3:15])[CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[NH:17][C:18]=2[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)=[CH:26][C:25]=1[OH:27]
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CNC(=O)Nc1ccc(Cl)cc1)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A solution of 4-chlorophenylisocyanate (46 mg, 0.3 mmol) in dichloromethane (5 ml) was treated with a solution of Example 3 (103 mg, 0.3 mmol) in methanol (1 ml). After stirring at room temperature for 30 min the solution was concentrated under reduced pressure and the residue chromatographed on silica gel eluting with dichloromethane/methanol (10:1) to the give the title compound (72 mg, 48%) as a pale yellow solid; MS(ES+) m/e 496/498/500 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:16]#[N:17]>>[C:16]([C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(F)c(F)c(Br)c1F
Product: COC(=O)c1cc(F)c(F)c(C#N)c1F
Yield: 61.8 %

Procedure:
A mixture of 269 g of methyl 3-bromo-2,4,5-trifluorobenzoate, 108 g of copper(I) cyanide and 400 ml of dimethylformainide is heated under reflux for 5 hours. All volatile components are distilled off in vacuo. Fractional distillation of the resulting mixture gives 133 g of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([N:32]([C:40]1[CH:45]=[C:44]([CH3:46])[C:43](CO)=[CH:42][N:41]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Br:24][CH2:20][C:43]1[C:44]([CH3:46])=[CH:45][C:40]([N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:41][CH:42]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CBr
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Triphenylphosphine (4.69 g, 17.9 mmol) and CBr4 (4.89 g, 14.8 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-4-methylpyridin (5.00 g, 22.0 mmol) in dichloromethane (130 mL) at 0° C. The reaction mixture was stirred for 3 h and was then diluted with dichloromethane. The organic phase was washed with water, dried and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-4-methylpyridin (5.35 g, 90%).
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: Cc1ccc(SSN(C)C(=O)F)cc1
Reactant: CC1OCSC1=NO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(SSN(C)C(=O)ON=C2SCOC2C)cc1

Procedure:
4-[[O-[N-Methyl-N-(4-methylphenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 4.0 g (0.03 m) of 5-methyl-4-oximino-1,3-oxathiolane, 6.95 g (0.03 m) of N-methyl-N-(4-methylphenylthiosulfenyl) carbamoyl fluoride and 3.07 g (0.03 m) of triethylamine in 50 ml of dioxane. The crude residual oil (7.3 g) was purified by dry column chromatography using silica gel.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=[N:20]O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].CC(O)=O>CCOC(C)=O.[Zn]>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH:11]([NH:20][C:22](=[O:24])[CH3:23])[C:12](=[O:13])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC(C(=O)c1ccccc1)c1ccc(=O)n(C(C)C)n1
Reaction time: 4 h

Procedure:
Zinc dust (1.57 g) was added in portions to a suspension of 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime (856 mg) in a mixture acetic anhydride (1.7 ml) and AcOH (10 ml) under ambient temperature and the mixture was stirred at the same temperature for 4 hours. An insoluble material was filtered off and a filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc, washed with sat. aq. NaHCO3 solution, dried over MgSO4 and subjected to column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give N-[1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-2-phenylethyl]acetamide as a solid (724 mg).