Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14].[I:22]I>C1COCC1.C(OCC)(=O)C>[F:21][C:20]1[C:15]([C:13]#[N:14])=[N:16][CH:17]=[CH:18][C:19]=1[I:22]
Reactant: N#Cc1ncccc1F
Reactant: II
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1nccc(I)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
Diisopropylamine (50.9 mL, 360 mmol) was added to THF (1600 mL), and the mixture was cooled to 0° C. in an ice bath and then n-butyllithium (137.6 ml, 2.5 M in hexane) was added drop wise at 0° C., and stirred for another 30 minutes. The mixture was then cooled to −78° C., and a solution of 2-cyano-3-fluoropyridine (40 g, 328 mmol) in 300 mL of THF was added. After 25 minutes, a solution of I2 (83.2 g, 328 mmol) in THF (80 mL) was added and the reaction was stirred for 40 minutes at −78° C. The reaction was removed from the cooling bath and quenched with 400 mL sodium thiosulfate solution (10% aq.) followed by water (400 mL). The reaction mixture was diluted with ether (400 mL), and the layers were separated. The organic layer were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown solid. The solid was purified with silica column chromatography eluted with 95:5 hexanes:ethyl acetate to give 3-fluoro-4-iodopicolinonitrile (25.6 g, 31.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.25-8.26 (m, 1H) 8.35 (t, J=5.05 Hz, 1H). MS [M+H] found 249.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O.CCOC(C)=O>[N+:12]([C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 48.4 %

Procedure:
To a solution of 5-(trifluoromethyl)pyridine-2-amine (1.1 g, 6.79 mmol) dissolved in sulfuric acid (20 mL) at room temperature was added nitric acid (0.475 g, 6.79 mmol). After heating to 70° C. for 1 hr, the reaction mixture was cooled to room temperature and diluted with EtOAc and ice. The organic layer was separated, washed with sat. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM) to give the title compound (680 mg). LC/MS: m/z 208(M+H). 1H-NMR (500 MHz, CD3OD): δ 8.60 (d, 1H), 8.67 (d, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN
Product: CNc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 1, the title compound was synthesized from 4-fluorobenzonitrile and 40% aqueous methylamine solution.
Reaction SMILES: CC(CC(C)C)=O.[CH2:8]([C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:34]=[N:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].[OH-].[K+:58].C>CO>[CH3:11][CH2:10][CH2:9][CH2:8][C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]=[N:36][N-:35][N:34]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1.[K+:58]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Under nitrogen, in a 500 ml flask a mixture of 175 ml of dry methanol, 20 g (0.026 mol) of 2-n-butyl-4-chloro 1-[(2′-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1′biphenyl-4-yl)-me thyl]-1H-imidazol-5-methanol methyl-isobutyl ketone solvate and 1.46 g (0.026 mol) of potassium hydroxide in 25 ml of methanol was warmed to reflux temperature over a period of 30 min. After refluxing for 4 h, the reaction was cooled to room temperature, treated with 0.6 g of charcoal and filtered. The filtrate was concentrated to a volume of 30-35 ml under diminished pressure, and after addition of 85 ml of acetonitrile again to a volume of 30-35 ml. After addition of further 85 ml of acetonitrile the solution is concentrated to a volume of 60-65 ml. The suspension was stirred at 0−(+)2° C. for 2 h, the precipitated crystals were filtered, washed three times with 30 ml of cold acetonitrile and dried at 70° C. to give 11.5 g (94%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C)(=O)=O)[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:22]=[N+:23]=[N-:24])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Yield: 86.3 %

Procedure:
Heat a mixture of (2S,4R)-4-methanesulfonyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.60 mol, 185 g) and sodium azide (1.20 mol, 78 g,) in N,N-dimethylformamide (1 L) to 80° C. for 16 h. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with 0.5 N hydrochloric acid, saturated sodium bicarbonate solution, and brine. Dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (140 g, 88%) as a thick, yellow oil. ES-MS m/z 271.2 [M+1]+, 171.0 [M−Boc]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:10][CH:11]=1
Reactant: CCO
Reactant: NCc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CN)cc1

Procedure:
A mixture of 4-aminomethylbenzoic acid (25 g) and concentrated sulphuric acid (25 ml) in ethanol (250 ml) was heated at reflux for 18 hours. The volume of solvent was reduced to a third by evaporation. The residue poured onto ice (500 g) and basified with concentrated aqueous ammonia. The product was extracted with ethyl acetate (3×200 ml) and the extracts dried and evaporated to give ethyl 4-aminomethylbenzoate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[O:11][CH2:10]1)(=[O:3])[CH3:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])([OH:11])[CH2:10][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (24.0 g, 0.07 mol) in DMF (250 ml), 1,2,4-triazole (16.6 g, 0.24 mol) and potassium carbonate (33.2 g, 0.24 mol) were added, followed by stirring at room temperature for 12 hours and then at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ethyl ether and an insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. The residue so obtained was recrystallized from isopropyl ether-ethyl acetate, whereby 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (12.2 g, yield: 37.8%) was obtained as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.O.[OH-].[Na+]>C1COCC1>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccncc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccncc2)c1CO
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of 5-methyl-3-pyridin-4-yl-isoxazole-4-carboxylic acid ethyl ester (7.06 g, 17.3 mmol) in THF (350 mL) was added at 5° C. lithiumaluminumhydride (635 mg, 16.7 mmol). After stirring for 2 h at this temperature further lithiumaluminumhydride (318 mg, 8.4 mmol) was added and stirred for 1 h at 5° C. Water (1.9 mL) was added carefully follwed by aqueous sodium hydroxide (15%,1.9 mL) and water (0.540 mL). The resulting suspension was stirred for 15 min at ambient temperature and filtered over Hyflo®. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (2.15 g, 65%) as a light yellow solid. MS: m/e=191.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(C1CCN(C(OCC2C=CC=CC=2)=O)CC1)=O.Cl.[NH2:40][CH2:41][C:42]1[C:47]([Cl:48])=[N:46][CH:45]=[CH:44][N:43]=1>>[Cl:48][C:47]1[C:42]([CH2:41][NH:40][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[N:43][CH:44]=[CH:45][N:46]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 83.4 %

Procedure:
Using the procedures described in example 16 step 16a 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (2.5 g) was transformed into 2.75 g of crude benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate and the latter compound was coupled with 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 2.28 g) to give benzyl 4-((3-chloropyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (3.08 g) after purification by column chromatography (silica gel, dichloromethane/methanol gradient 100/0 to 90/10).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:25][CH2:24][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO>[ClH:1].[ClH:1].[N:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:25][CH2:24][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)CC2
Agent: Cl
Solvent: CO
Product: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reaction time: 0.5 h

Procedure:
Hydrogen chloride in methanol (1.25 mol/l, 6.3 ml) was added to tert-butyl 9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.52 g, 1.569 mmol) and the mixture was refluxed for 1 h. The solvent was removed in vacuo, the residue taken up in ethanol (3 ml) and the mixture cooled. Acetone (80 ml) was added and the mixture was stirred in an ice bath for 30 min. The precipitate was filtered out with suction, washed with diethyl ether and dried in vacuo.
Reaction SMILES: [OH:1][C@@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@@H:2]([O:1][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C[C@H](C)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Methyl (S)-(+)-3-hydroxybutyrate (0.48 g, 4.04 mmol) (Aldrich) was dissolved in dichloromethane (6 mL, dried over molecular sieves). Imidazole (0.39 g, 5.65 mmol) (Aldrich) was added. When all had dissolved, tert-butyldiphenylsilyl chloride (1.05 mL, 4.04 mmol) was added dropwise and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with additional dichloromethane, washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 5:95 ethyl acetate-hexanes) gave (S)-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester. (Yield 1.33 g, 92.4%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:5][C:6]1([CH3:18])[CH2:7][CH2:8][C:9]([CH3:17])([CH3:16])[C:10]2[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][C:15]1=2
Reactant: CC(=O)Cl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 2 h

Procedure:
A suspension of 3.45 g (25.9 mmol) aluminum chloride in 15 ml methylene chloride was cooled under argon in an ice-salt bath and treated with stirring with a mixture of 4 g (21.2 mmol) 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene and 1.94 g (24.7 mmol) acetyl chloride via a dropping funnel over a period of thirty minutes. The cooling bath was removed and the mixture stirred for 2 hours, then quenched with ice. The organic layer was separated and the aqueous layer extracted with 2×50 ml methylene chloride. Organic extracts were combined and washed with water and saturated NaHCO3 solution and then dried (MgSO4). Solvent was removed in-vacuo and the residue distilled by the kugelrohr method (90° C.; 0.45 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.32 (6H, s), 1.33 (6H, s), 1.72 (4H, s), 2.60 (3H, s), 7.41 (1H, d, J~8.9 Hz), 7.71 (1H, dd, J~8.8, 2.6 Hz) 7.96 (1H, d, J~2.6 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(=O)c2cc(C(=O)O)ccc21
Reaction time: 16 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and TBF (10 mL) was added sodiumhydroxide 9 mL (1M solution). The solution was stirred for 16 h and thereafter acidified with 10% HCl. The mixture was extracted with ethyl acetate, the combined organic layer was washed with water and brine, and dried over MgSO4. The solvent was distilled off under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:16]#[N:17])[N+:13]([O-])=[CH:14][C:8]=3[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:5]=[CH:4][CH:3]=1.ClC1C=CC2C3C=C(C#N)[N+]([O-])=CC=3N(COCC[Si](C)(C)C)C=2N=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:16]#[N:17])[N:13]=[CH:14][C:8]=3[N:7]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2c(Cl)ccnc21
Agent: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2ccc(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21

Procedure:
A solution of 4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide with 2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide (6.5:1, 220 mg, 0.59 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (17 mg, 0.02 mmol), and triethylamine (0.24 mL, 1.8 mmol) in acetonitrile (3.1 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 40 g, ISCO, 5-85% ethyl acetate in heptane) to afford the title compound as a 6.5:1 mixture of the title compound with 2-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile as an off-white solid (180 mg, 80%). The mixture was used in subsequent steps without any further purification. 1H NMR (CDCl3, 400 MHz): 9.20 (d, J=0.9 Hz, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.39 (d, J=5.3 Hz, 1H), 6.02 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.94 (t, J=8.0 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid [prepared according to the procedure of Braish et al., Syn. Comm., 3067-3074 (1992)] in 75 mL of tetrahydrofuran was added 2.43 g (15 mmol) of carbonyldiimidazole. The solution was heated under reflux for 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodium borohydride in 15 mL of water was added. The reaction was stirred for 10 min and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was washed twice with warm water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To a solution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30 mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbon tetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue stirred with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo, and purified by flash chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford 2.9 g of 2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromide which was used without further purification. Using the procedures outlined for the preparation of Intermediates 2-4, the benzyl bromide derivative was converted to the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:15])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:16].O1CCOCC1>C(Cl)Cl>[ClH:16].[CH3:14][C:11]1([OH:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.08 g, 4.87 mmol) in DCM (25 mL) is added 4M HCl in 1,4-dioxane (20 mL, 80 mmol) and the reaction stirred at about 25° C. for 18 hours. The reaction is concentrated, suspended in Et2O and heptane, and filtered to afford the title compound (R) as a white powder.
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:17]O>>[F:2][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:17])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(F)c1

Procedure:
A commercial product, 3-fluoro-4-hydroxybenzoic acid hydrate (1.1 g) was dissolved in methanol (11 mL), and in an ice bath, thionyl chloride (0.77 mL) was added thereto, and heated under reflux for 2 hours. After the reaction, the reaction liquid was entirely concentrated to obtain the entitled compound (1.1 g).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:22]=[CH:21][C:15]2[O:16][C:17]([F:20])([F:19])[O:18][C:14]=2[CH:13]=1.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.[OH-].[Na+].Cl>C(OCC)C>[F:19][C:17]1([F:20])[O:16][C:15]2[CH:21]=[CH:22][C:12]([B:27]([OH:28])[OH:26])=[CH:13][C:14]=2[O:18]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Product: OB(O)c1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 1.5M tert-butyllithium in pentane (130 mL, 195 mmol) in diethyl ether (500 mL) at −78° C. was treated with 5-bromo-2,2-difluoro-1,3-benzodioxole (18 g, 76 mmol) in diethyl ether (80 mL), stirred for 1 hour, treated with triisopropylborate (37 mL, 160 mmol), warmed to room temperature over 1 hour, poured into 4M NaOH (700 mL), stirred for 15 minutes, cooled, adjusted to pH 1 with concentrated HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated to provide 14.7 g (95%) of the desired product. 1H NMR (DMSO-d6) δ 7.75 (m, 1H), 7.66 (m, 1H), 7.51 (m, 1H), 7.39 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C>O1CCCC1>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([B:22]([OH:23])[OH:21])=[CH:3][C:4]=2[O:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reaction time: 5 h
Yield: 117.9 %

Procedure:
A solution of the title compound of Step A (15 g, 63 mmol) in tetrahydrofuran (approximately 200 mL) was cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium (40 mL of a 1.6M solution in hexanes) was added dropwise while maintaining the reaction temperature below -55° C. The reaction mixture was stirred at -78° C. for 20 min before a solution of triisopropylborate (29.4 mL, 127 mmol) in tetrahydrofuran (approximately 50 mL) was added dropwise over 30 min. The reaction was allowed to come to room temperature while stirring for 5 h. The reaction mixture was then partitioned between diethyl ether and 1M hydrochloric acid solution. The organic layer was separated, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step B as a brown oil (15 g) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:25]=[O:26])C.Cl>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:25]=[O:26])[C:9]=1[F:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (−78° C.) solution of (2,4-difluoro-phenyl)-carbamic acid tert-butyl ester (5 g) in THF (50 ml) under an argon atmosphere was added dropwise a 1.6 M solution of BuLi in hexanes (28.6 ml) for 20 min (temperature below −68° C. during the addition). When addition was complete, the mixture (turning to orange, then to light red) was stirred at −78° C. for 1 h 30. DMF (7.55 ml) was then added for 10 min (temperature below −70° C.) and stirring at −78° C. was continued for 15 min. As the mixture had turned to a compact mas (no more stirring), it was allowed to warm to room temperature. Water (50 ml) was added and the pH was set to 3 by the dropwise addition of 3 N HCl. EtOAc (50 ml) was added. The organic phase was washed with water and brine dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 85:15) to give (2,4-difluoro-3-formyl-phenyl)-carbamic acid tert-butyl ester (1.75 g) as an off-white solid.