Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([N:11]=[C:21]=[O:23])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(N=C=O)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
1.46 g (7 mmol) of N1,N1-dimethylbenzene-1,3-diamine dihydrochloride, followed by 9.9 cm3 (71.64 mmol) of triethylamine, are added, at a temperature in the region of 5° C., under an argon atmosphere, to 2.82 g (9.5 mmol) of triphosgene in solution in 150 cm3 of dichloromethane. After stirring for 20 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give a residue which is triturated in 50 cm3 of tetrahydrofuran. After filtration, a solution of 3-dimethylaminophenyl isocyanate in approximately 0.14 N tetrahydrofuran is obtained, which solution is used directly in the subsequent step.
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)(=[O:23])=[O:22])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
LiOH (20.29 mg, 0.847 mmol) was added to a stirred solution of methyl 2-[(phenylmethyl)oxy]-5-(1-piperidinylsulfonyl)benzoate (may be prepared as described in Description 68; 330 mg, 0.85 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h, and then diluted with ethyl acetate (50 ml). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 220 mg.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:19]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3[nH]2)cc1
Temperature: 170 °C

Procedure:
2-Chloro-1H-benzo[d]imidazole (1 g) was added to a neat solution of dibenzylamine (7 mL) and heated to 170° C. for 1.5 hours in a Biotage microwave synthesizer. The reaction mixture was concentrated to dryness and purified via flash column chromatography to afford 0.6 g of N,N-dibenzyl-1H-benzo[d]imidazol-2-amine.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][CH:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31].C(Cl)(Cl)Cl.ClCCl>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][CH:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(c2ccccc2)=NO1
Reactant: N
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1CC(c2ccccc2)=NO1

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[(3-phenyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.50 g, 3.56 mmol) was treated with a solution of 7 M ammonia in methanol (30 mL) at 140° C. for 15 hours according to the method described in Part F of Example 1. Chloroform was used in the work-up procedure instead of dichloromethane. The crude product was purified by flash chromatography (silica gel, elution with 97:3 dichloromethane/methanol) to afford 2-(ethoxymethyl)-1-[(3-phenyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.17 g) as a yellow solid. Recrystallization afforded white needles, mp 235-237° C.
Reaction SMILES: C([Li])(C)(C)C.CCCCCC.I[C:13](=[CH2:22])[CH2:14][C@H:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.[S:23](Cl)([Cl:26])(=[O:25])=[O:24]>C(OCC)C>[CH3:20][C:17]1([CH3:21])[O:16][C@@H:15]([CH2:14][C:13]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH2:22])[CH2:19][O:18]1
Reactant: C=C(I)C[C@H]1COC(C)(C)O1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl lithium in hexane (1.7M, 2 eq) is added dropwise to a solution of (S)-4-(2-iodoallyl)-2,2-dimethyl-1,3-dioxolane (1 eq) in diethyl ether at −78° C., and the reaction stirred at −78° C. for 30 min. Sulfuryl dichloride (1 eq) is added, the mixture warmed to room temperature and the solvents removed under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:19]([N:15]([CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH3:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCN(C)CCO
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Reaction time: 3 h
Yield: 887.5 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55. 5 mmol), N-methyl-N-dodecylethanolamine (13.5 g, 55.5 mmol) and triphenylphosphine (16.0 g, 61.0 mmol) in dry tetrahydrofuran (200 ml) was treated at 22° C. with diisopropyl azodicarboxylate (12.3 g, 61.0 mmol) added dropwise over 50 min. After 3 h at 22° C., the reaction mixture was evaporated under reduced pressure and the residue was triturated with hexane. The solid formed was filtered, washed with hexane and the combined filtrate was chromatographed on silica gel using a gradient of ethyl acetate in hexane (20%-60%) as eluent. Distillation under vacuum then gave 18.0 g (75%) of 3-{4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl} propanoic acid, methyl ester as a clear oil: b.p. 180-183° C./0.02 torr (bulb to bulb distillation, air bath temperature).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([CH3:9])([CH3:8])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C1C(C)=CC=CC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCCCC
Product: CCOC(=O)C1=C(C)C=CCC1(C)C

Procedure:
A mixture of 2.0 g of 2,6,6-trimethyl-1-ethoxycarbonyl-2,4-cylohexadiene [prepared according to the process indicated in Example 1], 100 mg of p-toluenesulphonic acid and 25 ml of anhydrous benzene were refluxed for 4 hours in a nitrogen atmosphere. The resulting solution was diluted with pentane, washed with a 5 % solution of sodium bicarbonate, then with water, and then dried over Na2SO4 and concentrated.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:16][NH:15][S:14]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:26][C:27]([NH:29][C:30]1[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=1[CH:39]([CH3:41])[CH3:40])=[O:28].O>CN(C)C=O>[CH:39]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([CH:36]([CH3:37])[CH3:38])[C:30]=1[NH:29][C:27](=[O:28])[CH2:26][N:15]1[CH2:16][C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:14]1(=[O:23])=[O:24])([CH3:40])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: O=S1(=O)NCC2(CCCCC2)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CC2(CCCCC2)N(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
75 mg (0.54 mmol) of potassium carbonate are added to a solution of 130 mg (0.49 mmol) of 1-phenyl-2-thia-1,3-diazaspiro[4.5]decane-2,2-dioxide and 136 mg (0.54 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)-acetamide in 30 ml of dimethylformamide. The reaction medium is stirred at room temperature for one night and then it is heated to reflux for 6 hours and at room temperature for 48 h. The medium is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane/ethyl acetate 90/10). 125 mg of N-(2,6-diisopropylphenyl)-2-(2,2-dioxo-1-phenyl-2-thia-1,3-diazaspiro[4.5]dec-3-yl]acetamide are obtained in the form of a yellow oil. The product is triturated in dichloromethane and plenty of heptane. A solid is obtained. M.p. 140-2° C., yield=53%.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.CNN>>[NH2:3][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(ON2C(=O)c3ccccc3C2=O)C1
Agent: CNN
Product: CC(C)(C)OC(=O)N1CCCC(ON)C1
Yield: 73 %

Procedure:
Deprotection of tert-butyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidine-1-carboxylate with methylhydrazine following the procedure described for the preparation of Reference Example 9 gave tert-butyl 3-(aminooxy)piperidine-1-carboxylate (1.0 g, 73%) as an off-white, waxy solid: 1H NMR (500 MHz, CDCl3) δ 1.34-1.39 (1H, m), 1.47 (9H, s), 1.69-1.76 (3H, m), 3.12-3.26 (1.5H, m), 3.45-3.60 (3H, m), 3.77-3.83 (0.5H, m), 3.37-5.47 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH3:10][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC#Cc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-4-ethynyl-benzene (500 mg, 2.8 mmol) in tetrahydrofuran (20 mL) at −30° C. was slowly added sodium bis(trimethylsilyl)amide in tetrahydrofuran solution (1M, 4.2 mL). After stirring 15 min, methyl iodide (1.1 g, 8.4 mmol) was added at −20° C. The resulting reaction mixture was stirred at RT for 50 min before it was added to water. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude product 1-bromo-4-prop-1-ynyl-benzene was obtained as a volatile liquid (450 mg, 82.8% yield) which was put to next step directly without further purification. 1H NMR (400 MHz, MeOD) δ ppm 7.34 (d, J=8.3 Hz, 10H), 7.14 (d, J=8.3 Hz, 10H), 1.91 (s, 3H); GCMS, (M+1)=195.1, Molecular Formula=C9H7Br.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7].N1C=CN=C1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O>[Si:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCCCO)c1cccnc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCC(=O)c1cccnc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 4.59 g (0.0256 mole) of 5-hydroxy-1-(3-pyridyl)pentan-1-one, 3.82 g (0.0561 mole) of imidazole 7.76 g (0.0282 mole) of tert-butyldiphenylsilylchloride in 10 ml of dimethylformamide is stirred at room temperature for 15 h, diluted with 75 ml of water and extracted with ethyl acetate (2×50 ml). The extracts are washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using methylene chloride-ethyl acetate (4:1) as eluent to give 5-(t-butyldiphenylsilyloxy)-1-(3-pyridyl)pentan-1-one as an oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([CH2:10]O)=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6]1.[Cl-].[Li+].C(N(CC)CC)C.CS([Cl:35])(=O)=O>C(OCC)(=O)C.C1COCC1>[Cl:35][CH2:10][C:9]1[N:5]([CH2:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[F:1])[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2ccccn2)nn1Cc1ccccc1F
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)cc1CCl
Temperature: 0 °C
Yield: 44.6 %

Procedure:
To a cold solution of intermediate 2 (385 mg) in THF (6.0 ml) at 0° C. and under argon, was added a solution of lithium aluminum hydride (880 μl, 2.0 M in THF). The mixture was removed from the ice bath and stirred at room temperature for 2 h. Upon completion of the reaction, the mixture was cooled to 0° C. and sequentially treated with water (70 μl), 15% sodium hydroxide solution in water (130 μL), and water (70 μl). The resulting precipitate was removed by filtration. The filtrate was concentrated under vacuum to give (1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-yl)methanol as white solid. In a separate flask, (1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-yl)methanol (113 mg), lithium chloride (33.8 mg), triethylamine (0.1 ml), and THF were combined (2.0 ml) and cooled to 0° C. To this mixture, was added methanesulfonyl chloride (120 μl). The mixture was gradually warmed to ambient temperature over the course of 16 h. The mixture was diluted with ethyl acetate (100 ml), washed with saturated solution of sodium bicarbonate (20 ml), and brine (20 ml). The organic layer was dried, filtered, and evaporated to give 2-(5-(chloromethyl)-1-(2-fluorobenzyl)-1H-pyrazol-3-yl)pyridine as crude yellow solid. This crude solid (115 mg) was dissolved in THF (1.9 ml) in a separate flask equipped with a stir bar and a balloon filled with argon. The mixture was cooled to 0° C. To this mixture, was added dropwise, a solution of Superhydride (1.1 ml, 1.0 M in THF). The mixture was removed from the ice bath and stirred at room temperature for 24 h. Upon completion of the reaction, the mixture was cooled to 0° C. and sequentially treated with water (120 μl), 15% sodium hydroxide solution in water (240 μL), and water (120 μl). The resulting mixture was diluted in chloroform (100 ml) and washed with brine (50 ml). The organic layer was dried, filtered, and evaporated to give crude solid. The crude solid was purified using SiO2 chromatography (ethyl acetate/hexanes) to give I-55 as off-white solid (44.6% yield over three steps). 1H NMR (400 MHz, CDCl3) δ 8.63-8.59 (m, 1H), 7.93-7.89 (m, 1H), 7.68 (td, 1H), 7.27-7.20 (m, 1H), 7.19-7.14 (m, 1H), 7.09-7.01 (m, 2H), 6.93-6.88 (m, 1H), 6.71 (s, 1H), 5.42 (s, 2H), 2.27 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)OC(C)(C)C)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.F[C:18](F)(F)[C:19](O)=O.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.C1(B(O)O)CC1>ClCCl.C(OCC)(=O)C.ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:19][CH2:18]2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)cnc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OB(O)C1CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)c(NC2CC2)c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Tert-butyl (2-chloro-5-fluoropyridin-3-yl)carbamate (Intermediate 36) (0.500 g, 2.027 mmol) was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.5 mL). The mixture was stirred at 45° C. for 1 hour then cooled to room temperature. The solution was evaporated to dryness under reduced pressure and the crude amine partitioned between 50% saturated sodium bicarbonate (80 mL) and ethyl acetate (60 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The solid amine intermediate was combined with anhydrous cupric acetate (0.375 g, 2.065 mmol), sodium carbonate (1.00 g, 9.43 mmol), 2,2′-bipyridyl (0.325 g, 2.081 mmol) and cyclopropylboronic acid (0.305 g, 3.55 mmol). 1,2-Dichloroethane (5 mL) was added and the mixture heated at 70° C. in air. After 2 hours, the mixture was cooled and diluted with ethyl acetate (300 mL). It was washed with a mixture of saturated ammonium chloride (50 mL), water (100 mL), and ammonium hydroxide (20 mL) before drying with magnesium sulfate and evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave 2-chloro-N-cyclopropyl-5-fluoropyridin-3-amine (0.270 g, 1.447 mmol, 71.4% yield).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH:13]1([CH2:19][CH2:20][C:21](OC)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1.C(O)(=O)C.O>[CH:13]1([CH2:19][CH2:20][C:21](=[O:22])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)CCC1CCCCC1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COP(=O)(CC(=O)CCC1CCCCC1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
n-Butyl lithium (1.63N, 45.1 ml, 73 mmol) was added dropwise to a stirred solution of dimethyl methylphosphonate (9.05 g, 73 mmol) in 100 ml of anhydrous THF at -78° C. under argon atmosphere. After 30 minutes, a solution of methyl 3-cyclohexylpropionate (5.0 g, 29.4 mmol) in 10 ml of anhydrous THF was further added dropwise and the mixture was stirred for 30 minutes. This reaction solution was allowed to warm to 0° C., diluted with 4.4 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml ×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 4-cyclohexyl-2-oxobutylphosphonate (6.3 g, 24 mmol, yield 81.7%, b.p. 138°-142° C./0.05 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [F:1][CH:2]([F:24])[CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:4][NH:5]C(=O)OCC1C=CC=CC=1.[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>[Pd].CO.C(Cl)Cl>[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[NH2:5][CH2:4][CH:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:2]([F:24])[F:1]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)C(F)F
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CN)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl tert-butyl (3,3-difluoropropane-1,2-diyl)biscarbamate (195 g, 567 mmol) and palladium on carbon (10% w/w, 20 g) in methanol (2000 mL) was stirred at room temperature under a hydrogen atmosphere. After 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with DCM (2500 mL) and oxalic acid (2.84 M solution in methanol, 200 mL, 567 mmol). After 2 hours, the mixture was filtered, and the collected solids were washed with DCM (500 mL) and dried in an oven under reduced pressure to afford tert-butyl (3-amino-1,1-difluoropropan-2-yl)carbamate oxalic acid salt. MS ESI calc'd. for C8H17F2N2O2 [M+H]+ 211. found 211. 1H NMR (400 MHz, D2O) δ 6.14-5.86 (m, 1H), 4.25 (d, J=12.8 Hz, 1H), 3.36 (d, J=14 Hz, 1H), 3.11-3.05 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[O:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1>O1CCCC1>[OH:26][CH:25]([C:22]1[CH:21]=[C:20]([Si:19]([CH3:28])([CH3:27])[CH3:18])[O:24][CH:23]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]CCCCCCCCCc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCCCCCCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 9-phenylnonylmagnesium bromide (1.35 mmol, prepared from 0.383 g, 1.35 mmol of 1-bromo-9-phenylnonane and 4.11 mmol magnesium) in tetrahydrofuran (5 ml) at 0° under argon was added dropwise, 5-trimethylsilyl-3-furaldehyde (0.227 g, 1.35 mmol) in tetrahydrofuran (3 ml). The solution was warmed to room temperature and stirred for 30 minutes, quenched with 5% ammonium chloride and extracted into ethyl ether. The organic portion was washed with saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Purification by flash chromatography (silica, 5 to 20% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[C:24]=1[OH:30].OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:26]4[CH:27]=[CH:28][N:23]=[C:24]([OH:30])[C:25]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1nccnc1O
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccnc(O)c3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 130 °C
Reaction time: 15 h

Procedure:
The mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.22 mmol), 2,3-pyrazinediol (74 mg, 0.66 mmol), CuI (21 mg, 0.11 mmol), 8-hydroxyquinoline (16 mg, 0.11 mmol), potassium carbonate (152 mg, 1.1 mmol) in 2 mL DMSO in a sealed tube was stirred for 15 hrs at 130° C. The title compound was isolated directly from the reaction mixture using reverse phase prep HPLC. MS found for C18H13ClN6O3S (M+H)+ 429.1, 431.1 (Cl pattern).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1>CCCCO>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: COCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Yield: 35.2 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide (100 mg, 0.3 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (199 mg, 1.0 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube. After concentration, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (51 mg, 32% yield) as a solid.