Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2)=O)=CC=1.[NH2-].[Na+].N.C(I)C.[Cl-].[NH4+].Cl.[Cl:31][C:32]1[CH:53]=[CH:52][C:35]([C:36]([C:38]2[N:42]([CH3:43])[C:41]([CH:44]([CH2:50][CH3:51])[C:45]([O:47]CC)=[O:46])=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1.[OH-].[Na+]>C(O)C.CCOCC>[Cl:31][C:32]1[CH:53]=[CH:52][C:35]([C:36]([C:38]2[N:42]([CH3:43])[C:41]([CH:44]([CH2:50][CH3:51])[C:45]([OH:47])=[O:46])=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(CC)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: Cl
Agent: N
Solvent: CCI
Solvent: CCOCC
Solvent: CCO
Product: CCC(C(=O)O)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 6.5 g (0.021 mole) of ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 60 ml. of ether is added to a suspension of 1.25 g. (0.032 mole) of sodamide in 150 ml. of refluxing liquid ammonia. After 10 minutes, 4.98 g. (0.032 mole) of ethyl iodide is added. The mixture is stirred for 1.5 hours, and an additional 1.0 g. (0.0064 mole) of ethyl iodide is added. Stirring is continued for 30 minutes and ammonium chloride is then added to neutralize any anion. The mixture is allowed to warm to room temperature and the ammonia allowed to escape. Ether is added, and the mixture poured into dilute hydrochloric acid. The ether layer is separated, and the aqueous layer is washed with ether. The combined ether solutions are washed successively with sodium bisulfite solution and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give about 7.4 g. of a yellow oily residue containing ethyl 5-(p-chlorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetate, which is used as such in the following transformation to acid procedure. A 6.9 g. sample of the oily residue is dissolved in 30 ml. of ethanol and 11.4 ml. of 1N sodium hydroxide is added. The mixture is refluxed for 1 hour. The solvent is then evaporated in vacuo, and the residue partitioned between ether and water. The aqueous layer is separated and acidified with dilute hydrochloric acid. The precipitated oil, which is separated, crystallizes on scratching to give a solid, 5-(p-chlorobenzoyl)-α-ethyl-1-methylpyrrole-2-acetic acid, which is collected and dried, m.p. 108-112° C. After successive recrystallizations from ether-methylcyclohexane, benzene-hexane, methylcyclohexane and ether-hexane, the m.p. is 110-114° C. Analysis: Calcd. for C16H16ClNO3 : C, 62.84; H, 5.27; N, 4.58% Found: C, 63.01; H, 5.36; N, 4.61%
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH3:41])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH2:39][CH3:40])[N:18]=3)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([C:11]4([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.31 mmol) in DCM (10 mL) was added TFA (2 mL) and the resulting mixture allowed to stir at r.t. for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (1.1 g, quant.). LCMS (method H): RT 1.79 min, [M+H]+ 463.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:15]([O-:17])=O)=[N:13]O)[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1.[CH3:26][N:27]1[CH2:32][CH2:31]N[CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N:13]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[N:15][OH:17])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=NO)C2=Nc3ccc(Cl)cc3C(c3ccccc3F)=NC2)CC1

Procedure:
This compound was obtained by reacting 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine with N-methylpiperazine in tetrahydrofuran. The analytical sample was recrystallized from ethanol, mp 198°-200° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1O.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1cccc(Cl)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 5 °C
Yield: 62.7 %

Procedure:
A mixture of 48 g (0.2 mole) of 1-(diphenylmethyl)azetidin-3-ol and 22 g (0.22 mole) of triethylamine in 800 mL of toluene was cooled to 5° C. in an ice bath while stirring under nitrogen. The cooled reaction mixture was treated dropwise with 25.2 g (0.22 mole) of methanesulfonyl chloride in 25 mL of toluene. The reaction mixture was removed from the ice bath. After stirring for 3 hr, the reaction mixture was treated with ice water to dissolve the triethylamine hydrochloride then the aqueous phase was separated and the toluene phase washed with ice water (2×200 mL). The toluene solution was returned to the reaction flask and treated with 31.4 g (0.22 mole) of 2-chloro-6-methylphenol, 50 mg of tetrabutylammonium bromide and 26.4 g (0.66 mole) of sodium hydroxide in 100 mL of water. The reaction mixture was heated at reflux while stirring vigorously for 24 hr then stirred an additional 72 hr without heat. The mixture was transferred to a separatory funnel and the basic aqueous portion separated. The toluene portion was washed with water (3×100 mL), dried over magnesium sulfate and concentrated in vacuo to obtain 64.8 g. The crude product was purified by column chromatography using 800 g of Florisil and eluted with benzene to remove trace impurities and then eluted with an acetone gradient from 1-5%. The product came off in 5% acetone/benzene and was collected in 6 fractions which were combined and concentrated in vacuo, 55 g. The oily product which began to crystallize was triturated with ligroin to aid crystallization. Filtration yielded 45.6 g of product (62.7%). A sample recrystallized from ligroin then from 95% ethanol still showed a trace of impurity by t.l.c. (10% methanol/methylene chloride on silica gel). A sample was chromatographed on a 50 g column of Florisil. Elution with 2% acetone/benzene gave the pure product which was recrystallized from 95% ethanol yielding fine white crystals, mp. 92°-93° C.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[NH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1>O1CCCC1>[N:3]1([C:1]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=2)=[O:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1csc(NC(=O)n2ccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture comprising 25 g of carbonyldiimidazole, 30.87 g of ethyl 2-aminothiazol-4-ylglyoxylate and 300 ml of tetrahydrofuran was stirred at room temperature for 1 day. After completion of the reaction, the crystals which precipitated out were collected by filtration and washed with ethyl acetate to give crude ethyl 2-(1-imidazolylcarbonylamino)thiazol-4-ylglyoxylate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:8]=2)[N:5]=[C:4]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[CH:3]=1.[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32]>CCOC(C)=O>[Cl:36][C:35]([Cl:38])([Cl:37])[CH2:34][O:33][C:31](=[O:32])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:8]=2)[N:5]=[C:4]([C:23]([C:24]#[N:25])([CH3:27])[CH3:26])[CH:3]=1
Reactant: CC(C)(C#N)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Intermediate 20c (317 mg, 0.86 mmol) was dissolved in EtOAc (2.5 mL) and 1M NaOH solution (1.4 mL, 2.14 mmol) and cooled in an ice bath. While stirring, 2,2,2-trichloroethyl chloroformate (227 mg, μL, 1.07 mmol) was then added dropwise, and the ice bath removed. After 30 min, a further 0.65 eq. of 2,2,2-trichloroethyl chloroformate was added, and the reaction continued. After 30 min, a further 0.65 eq. of 2,2,2-trichloroethyl chloroformate was added, and the reaction continued overnight. The reaction was then partitioned between H2O and EtOAc, the organic layer was separated, and the aqueous layer extracted again with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 5-30% EtOAc in cyclohexane, to afford the title compound as a light yellow oil (375 mg, 80%). LCMS (Method 3): Rt 4.41 min, m/z 567, 569 [M+Na].
Reaction SMILES: Cl.Cl[CH:3]([CH3:15])[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][NH:5][CH2:4][CH:3]([CH3:15])[C:13]=2[CH:12]=1
Reactant: CC(Cl)CNCCc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CC1CNCCc2ccc(Cl)cc21
Temperature: 126 °C

Procedure:
1,2-Dichlorobenzene (about 1522 kg), 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride (about 530 kg, 1.97 kmol, 1.00 eq.), and aluminum chloride (about 387 kg, 2.90 kmol, 1.47 eq.) are charged to a vessel vented to a caustic scrubber. The mixture is then stirred and heated at about 126° C. under nitrogen for about 16 h. The resulting Friedel-Crafts reaction mixture is then cooled. Purified or potable water (about 1060 kg) and silica gel are charged to a second vessel. The cooled Friedel-Crafts reaction mixture is then added to the aqueous silica gel slurry stirred and cooled in the second vessel. The stirred quench mixture is filtered at about 58° C., and the silica gel filter cake is washed with purified or potable water (about 212 kg). Optionally, some or all of this water may be used to rinse the quench vessel into the filter. The mother and wash liquor filtrates are combined in a vessel and are cooled with stirring to about 22° C. Stirring is then stopped, and upon settling, three phases separate. The brown lowest phase consists mostly of 1,2-dichlorobenzene and is drained to solvent regeneration. The lower of the remaining two phases, which is the middle phase of the original three-phase mixture, contains most of the product. The topmost phase is a turbid water phase containing a smaller amount of the product. These upper two phases are partitioned between cyclohexane (about 583 kg) and enough aqueous sodium hydroxide solution, approx. 30 wt %, to achieve an aqueous phase pH of at least about 13. The cyclohexane phase is washed with purified or potable water (about 1272 kg) at about 57° C. and then distilled at reduced pressure to remove solvent and provide crude title compound, an oil, as the distillation residue.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([OH:29])=[O:28].[CH2:31]([C:38]1[S:39][C:40]([CH2:43]O)=[CH:41][N:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([O:29][CH2:43][C:40]1[S:39][C:38]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:42][CH:41]=1)=[O:28]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCSC1=O
Reactant: OCc1cnc(Cc2ccccc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2cnc(Cc3ccccc3)s2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 17 h
Yield: 48.3 %

Procedure:
0.1 g of 4-dimethylamino-pyridine and 0.94 g of dicyclohexylcarbodiimide were added to a solution of 1.1 g of (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid in 10 ml of methylene chloride and then a solution of 1 g of (2-benzyl-5-thiazolyl)-methanol in 12 ml of methylene chloride was added to the mixture. The mixture was stirred for 17 hours at 20° C. and was filtered and the organic filtrate was washed with water, dried and evaporated to dryness under reduced pressure. The residue was taken upin 8 ml of a 7-3 cyclohexane-ethyl acetate mixture and the mixture was filtered. The filtrate was chromatographed over silica gel and was eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 0.97 g of (2-benzyl -5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+38°±2° (c=0.5% in benzene).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(O)(O)=O>CC#N.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>[Cl:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15])=[N:3]2
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2c(Cl)cccc2nc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.9948 g, 8.8243 mmol), 2-(trifluoromethyl)phenylboronic acid (1.8436 g, 9.7067 mmol), tetrakis(triphenylphosphine)palladium (0.50985 g, 0.44121 mmol), and sodium carbonate anhydrous (4.6763 g, 44.121 mmol) in 88 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 5 hr, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 30 min as eluent to give 5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (1 H, s), 9.19 (1H, d, J=1.0 Hz), 8.08-8.14 (1 H, m), 7.97-8.03 (2 H, m), 7.89-7.95 (1 H, m), 7.73-7.84 (2 H, m), 7.55-7.61 (1 H, m); LC-MS (ESI) m/z 336.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:24]=[N:25][C:26]([N+:29]([O-])=O)=[CH:27][CH:28]=3)[CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CCOC(C)=O.[Pd]>[NH2:29][C:26]1[N:25]=[CH:24][C:23]([O:22][C:20]2[CH:19]=[CH:18][N:17]=[C:16]([C:13]3[CH:14]=[N:15][C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[CH:11][CH:12]=3)[CH:21]=2)=[CH:28][CH:27]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Yield: 86.9 %

Procedure:
A solution of tert-butyl methyl(4-((6-nitropyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)carbamate (0.26 g, 0.614 mmol) in EtOAc (10 mL) was treated with 10% Pd/C (50% wet, 6.53 mg, 0.061 mmol) and hydrogenated (1 atm) for 16 h. The solids were removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to dryness to afford tert-butyl (4-((6-aminopyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)(methyl)carbamate (210 mg, 87%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.7 Hz, 1H), 8.34 (dd, J=8.8, 2.5 Hz, 1H), 7.84 (d, J=2.9 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.31 (dd, J=8.9, 3.0 Hz, 1H), 6.75 (dd, J=5.7, 2.4 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 6.03 (s, 2H), 3.33 (s, 3H), 1.47 (s, 9H); MS (ESI) m/z: 394.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[CH2:20][CH2:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([F:31])[C:27](F)=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>>[Cl:23][C:24]1[CH:25]=[C:26]([F:31])[C:27]([O:1][C:2]2[CH:3]=[C:4]([CH3:22])[C:5]([CH:9]3[C:10](=[O:21])[CH:11]4[CH:16]([CH:15]5[CH2:19][CH2:20][CH:12]4[CH2:13][CH2:14]5)[C:17]3=[O:18])=[C:6]([CH3:8])[CH:7]=2)=[N:28][CH:29]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: Cc1cc(O)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ncc(Cl)cc2F)cc(C)c1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(4-hydroxy-2,6-dimethylphenyl)hexahydro-4,7-ethanoindene-1,3-dione (0.40 g, 0.0013 mol), 5-chloro-2,3-difluoropyridine (0.20 g, 0.0013 mol) and potassium carbonate (0.40 g, 0.0029 mol) is added N,N-dimethylaminopyridine (10 ml), and the reaction mixture is then heated at 140° C. for 40 minutes under microwave irradiation. After cooling to room temperature 2M aqueous hydrochloric acid is added, and the crude product is extracted with ethyl acetate. The organic phase is separated, washed with distilled water, then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is then purified by preparative reverse phase HPLC to afford 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)-2,6-dimethylphenyl]hexahydro-4,7-ethanoindene-1,3-dione as a cream solid.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13](=[O:18])[C:14]([O:16]C)=O)=[C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]=1[C:23]([O:25][CH3:26])=[O:24].[OH-].[NH4+:29].[Na+].[Cl-]>C(Cl)Cl>[F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:6]([C:13](=[O:18])[C:14]([NH2:29])=[O:16])=[C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: [NH4+]
Reactant: COC(=O)C(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)C(N)=O)c1CC(C)C
Reaction time: 2 h

Procedure:
To 16.5 g of methyl 6-(difluoromethyl)-4-(2-methylpropyl)-5-(methoxycarbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetate (prepared by example E of U.S. Pat. No. 5,298,479) in 60 ml of methylene chloride was added 25 ml of concentrated ammonium hydroxide. The reaction mixture was stirred for 2 h and the aqueous layer was saturated with NaCl and the organic was extracted into methylene chloride. The methylene chloride layer was dried (MgSO4) and concentrated in vacuo. The residue was recrystallized from 20% EtOAc-benzene to give 12.5 g of 6-(difluoromethyl) -4-(2-methylpropyl)-5-(methoxy-carbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetamide. A mixture of 2.4 g of this material, 2.0 g of phosphorus pentasulfide, 2 g of Celite and 16 ml of toluene was held at reflux for 2h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% EtOAc in hexane) to give an oil which crystallized from 3% EtOAc in hexane as a solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1>ClCCl>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: Brc1nccs1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nccs2)CC1
Temperature: 100 °C
Yield: 62.9 %

Procedure:
A mixture of 2-bromo-1,3-thiazole (522 mg, 3.18 mmol) and ethyl piperidine-4-carboxylate (1 g, 6.36 mmol) was heated to 100° C. neat overnight, then cooled to room temperature. The residue was dissolved in dichloromethane and directly purified by CombiFlash (0-40% ethyl acetate/hexanes) to provide 654 mg (2.7 2 mmol, 86% yield) of ethyl 1-(1,3-thiazol-2-yl)piperidine-4-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of ethyl 3-benzyloxy-1-phenyl-1H-pyrazole-4-carboxylate (8.06 g) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (0.95 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added sodium sulfate decahydrate (8.06 g) and the mixture was stirred at room temperature for 1 hr. After removing the precipitate by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give (3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methanol (5.91 g, yield 84%) as colorless crystals from a fraction eluted with ethyl acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 93-94° C.
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.C1(C)C(C)=CC=CC=1.NC1C=CC=CC=1S.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:39]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[CH:40]([OH:44])[C:41]([NH2:43])=[O:42]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][C@@H:39]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)[C@@H:40]([OH:44])[C:41]([NH2:43])=[O:42]
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Nc1ccccc1S
Solvent: CO
Solvent: Cc1ccccc1C
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (1.93 g) and xylene (15 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (1.38 g) and ferrous sulfate heptahydrate (0.28 mg) in methanol (0.2 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes, and cooled to room temperature. The reaction mixture is subjected to HPLC analysis to confirm the production of 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (2.69 g, (2S,3S)/-(2S,3R)=91/9). The reaction mixture is concentrated under reduced pressure to remove the solvent, and the residue is dissolved with heating in ethanol (3 ml) and water (3 ml). The mixture is gradually cooled to 0° C. with stirring to crystallization. The precipitated crystals are collected by filtration, washed with chilled 50% ethanol, and dried at 50° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (0.84 g).