Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(C#N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1OCCCN1CCOCC1
Temperature: 85 °C
Yield: 98.3 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzonitrile (34.3 kg), potassium carbonate (54.5 kg) and N,N-dimethylformamide (226 kg) was stirred and heated to approximately 85° C. A toluene solution (91.4 kg) containing N-(3-chloropropyl)morpholine (41.1 kg) was added to the heated mixture and the resultant mixture was heated to about 85° C. for an additional 10 hours. The bulk of the N,N-dimethylformamide was removed by vacuum distillation and the residue was diluted with water (286 liters). The aqueous mixture was extracted with three portions of a 1:1 mixture of heptane and ethyl acetate (239 liters, 139 liters and 139 liters respectively). The combined organic layers were washed with water, concentrated to approximately 150 liters by vacuum distillation and diluted with glacial acetic acid (133 kg). Additional solvent was removed by vacuum distillation. Addition of glacial acetic acid (84 kg) provided a solution of 4-methoxy-3-(3-morpholinopropoxy)benzonitrile (62.5 kg) in acetic acid (122 kg) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[C:22]([N:6]1[C:5]2[CH:26]=[CH:27][C:2]([C:32]3[CH:33]=[N:34][C:29]([NH2:28])=[N:30][CH:31]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]=[C:18]([CH3:20])[N:17]([CH3:21])[N:16]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)nn1C
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)nn1C
Temperature: 110 °C
Yield: 76 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (38 mg, 0.09 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (24 mg, 0.109 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) and 2 M aqueous Na2CO3 (0.2 mL, 0.4 mmol). The reaction mixture is heated under Argon at 110° C. for 3 hours. The residue is diluted with EtOAc (20 mL), washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-10% MeOH/CH2Cl2 as the eluent to afford the title compound (30 mg, 76%) as an off-white solid. LCMS (ESMS): m/z 439.72 (M++1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH3:16])[CH:9]=1)=[O:7])(=[O:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:19][CH2:20][Cl:21])=[C:10]([O:15][CH3:16])[CH:9]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)COC(C)=O)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)COC(C)=O)ccc1OCCCCl
Yield: 91.9 %

Procedure:
A mixture of 31.5 g (0.14 mol) of 2-(acetyloxy)-1-(4-hydroxy-3-methoxyphenyl)ethanone, 44.1 g (0.28 mole) of 1-bromo-3-chloropropane and 58 g (0.42 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 16 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 38.7 g (92%) of title compound as a pale-yellow solid. An analytical sample, mp 93°-96° C., was prepared from 2-propanol.
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CS(C)=O>[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:14]3[CH2:15][CH2:16][N:17]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:18][CH:19]=3)=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1

Procedure:
To 5 mL of dry ethanol were added 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.54 g, 6.61 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (1.25 g, 6.61 mmol). The mixture was heated at the reflux temperature for about 6 hours, and was then cooled and concentrated. The residue was purified by silica gel chromatography with 95/5 chloroform/methanol. The product was isolated as a yellow foam. Yield 1.52 g (55%). mp 200°-202° C. FDMS m/e=421 (M+ of free base). α[D]589 =+4.39 (c=1.00, dimethylsulfoxide)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12](=[O:15])(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:9][C@H:4]([CH2:3][CH3:2])[CH2:12][OH:15]
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CCO
Product: CC[C@H](CO)Nc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C

Procedure:
A mixture of 118 g (0.74 mole) of 3,4-difluoronitrobenzene and 85 g (0.95 mole) of R-(+)-2-amino-1-butanol was dissolved in 400 mL of absolute ethanol. To this solution was then added 62.2 g (0.74 mole) of sodium bicarbonate. The suspension was stirred and heated at reflux temperature for 12 h when TLC indicated complete conversion of the 3,4-difluoronitrobenzene. After cooling to room temperature, the reaction mixture was filtered with the aid of additional ethanol and the ethanol was then evaporated. The crude product thus obtained was distilled under reduced pressure (10–112° C., 2 mm Hg) to afford (2R)-(+)-2-(2-fluoro-4-nitrophenyl)amino-1-butanol as a red solid. Yield, 162 g (96%). [α]D=+95.4 (CHCl3, c 22.7); 1H NMR (CDCl3) δ7.88 (1H, dd, J=2.4, 8.9), 7.76 (1H dd J=2.4, 11.7), 6.66 (1H, dd, J=8.7), 4.88 (1H, m), 3.76 (1H dd, J=4.2, 11.2), 3.68 (1H, dd J=4.2, 11.2), 3.52 (1H, m), 2.63 (1H, bs), 1.70 (1H, m), 1.59 (1H, m), 0.97 (3H, t, J=7.5). 13C NMR: ppm 150.1, 147.7, 142.8, 142.7, 136.1, 122.3, 110.9, 110.7, 109.5, 63.6, 55.8, 24.4, 10.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Cl:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzyl alcohol (1 g, 6.5 mmol) in dichloromethane (10 mL) were added under ice-cooling triethylamine (1.8 mL, 13 mmol) and methanesulfonyl chloride (0.60 mL, 7 mmol) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an almost pure title compound (1.1 g, 100%).
Reaction SMILES: [CH3:1][CH:2](O)[CH3:3].[Bi](Br)(Br)Br.[OH:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11]>ClC(Cl)(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([CH:10]([O:9][CH:2]([CH3:3])[CH3:1])[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To the solution of propan-2-ol (100 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth(III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, then methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added to the solution, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl4-(1-isopropoxyethyl)benzoate (161 mg, 43%) as oil. 1H-NMR (300 MHz, CD3OD) δ 7.96 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 4.68-4.61 (m, 1H), 3.54-3.46 (m, 1H), 1.38 (d, 3H), 1.15 (d, 3H), 1.06 (d, 3H),
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15]C)=[O:14])[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:8]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
A 12 liter, three-neck, round bottom flask equipped with mechanical stirrer was charged with Methyl [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetate (235 g, 0.72 mol), THF (3.5 L), methanol (1.2 L), and 2 M LiOH (1.2 L). The resulting solution was stirred at room temperature for 1.5 hours. After LC-MS showed the absence of starting material, the majority of the THF was removed by rotary evaporation. The solution was then acidified with 2 M HCl (pH=3) and the white precipitate was filtered and washed with water. After being dried under reduced pressure, 210 g (93%) of the title compound was obtained. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.53 (d, 2 H), 7.68 (d, 2 H), 7.31 (t, 2 H), 7.14 (t, 2 H), 6.57 (s, 1 H), 5.00 (s, 2 H), 4.01 (s, 2 H); m/z (APCI+) for C17H14N3O2F 312.2 (M+H)+.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][NH2:21]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:21][CH3:20])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
In an argon atmosphere, 5.24 g (22.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding 25.0 mL (48.8 mmol) of a tetrahydrofuran solution (concentration: 1.95 mol/L) of methylamine, the mixture was stirred at room temperature for 1 hour. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./3.8×102 Pa) to obtain 1,3-di-tert-butyl-2-methylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHMe) as a pale yellow liquid (yielded amount: 4.41 g, yield: 86%).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].CN[C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1NC.IC1C=CC=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(C)cc1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: Ic1ccccc1
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 868.7 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), N-ethyl-p-toluenesulfonamide (240 mg, 1.20 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), iodobenzene (112 μL, 1.00 mmol) and toluene (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting pale brown suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate 4:1, 15 mL fractions). Fractions 10-17 provided 244 mg (89% yield) of the desired product.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([S:19]([CH3:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30](N(C)OC)=[O:31])[CH2:23]2.P(=O)(O)(O)O>O1CCCC1>[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30](=[O:31])[CH2:21][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])[CH2:23]2
Reactant: CS(=O)c1ccccc1
Reactant: CON(C)C(=O)C1CN2CCC1CC2
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CS(=O)c1ccccc1)C1CN2CCC1CC2
Temperature: -20 °C
Yield: 109.2 %

Procedure:
To a stirred solution of n-butyllithium (2.7 ml of a 1.6M solution in hexanes, 4.3 mmol) in dry tetrahydrofuran (5 ml) cooled to -78° C. under nitrogen was added dropwise a solution of diisopropylamine (0.44 g, 4.3 mmol) in dry tetrahydrofuran (5 ml). The mixture was allowed to warm to -20° C., and was maintained at this temperature for 15 min. After cooling to -78° C. a solution of methyl phenyl sulphoxide (0.55 g, 3.9 mmol) in dry tetrahydrofuran (2 ml) was added dropwise while maintaining the temperature below -65° C. The reaction was stirred for a further 5 rain and then a solution of (±) 1-azabicyclo[2.2.2] oct-3-yl-N-methyl-N-methoxycarboxamide (EP 322182, Description 22) (0.65 g, 3.3 mmol) in dry tetrahydrofuran (5 ml) was added rapidly while ensuring that the temperature did not rise above -60° C. After stirring at -78° C. for 1 h, the reaction was allowed to warm to -30° C., and maintained at this temperature for 30 min. The reaction was then poured into vigorously stirred orthophosphoric acid (20ml of a 5% H3PO4 solution) cooled below 0° C. The aqueous layer was separated, washed with ether (3×20 ml) and then saturated with potassium carbonate. After extraction with chloroform (3×25 ml) the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to give the title compound (D1) as an oil (1.0 g) consisting of a 1:1 mixture of diastereomeric keto sulphoxides. 1H NMR (CDCl3) δ:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH:19]=[O:20])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][OH:20])=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2cc(-c3ccccc3)nc2CO)cc1
Yield: 96 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-formyl-4-phenylimidazole (1.75 g, 5.99 mmol) in CH2Cl2/MeOH (1:1, 60 mL) with NaBH4 (480 mg, 12.7 mmol) at room temperature for 15 minutes. Quench with H2O (50 mL), extract with CH2Cl2 (2×100 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, CH2Cl2/MeOH 20:1→7:1) to provide 1.69 g (96% yield). MS(ES+): m/z=295 (M+H)+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].FC(F)(F)C(O)=O.[F:28][C:29]([F:42])([F:41])[C:30]1[S:34][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:32][N:31]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:38]2[CH2:37][CH2:36][N:35]([C:33]3[S:34][C:30]([C:29]([F:41])([F:28])[F:42])=[N:31][N:32]=3)[CH2:40][CH2:39]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an off-white solid (yield 52%). MS (m/e): 533.0 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH2:17]2)=[CH:14][CH:15]=3)[CH:5]=[CH:4][CH:3]=1.[CH:30]1([C:33]#[N:34])[CH2:32][CH2:31]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[N:24]1([C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:16]([C:13]3[N:12]=[C:11]4[N:29]=[C:8]([C:6]5[N:7]=[C:2]([C:30]6([C:33]#[N:34])[CH2:32][CH2:31]6)[CH:3]=[CH:4][CH:5]=5)[NH:9][C:10]4=[CH:15][CH:14]=3)[CH2:17]2)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: N#CC1CC1
Reactant: O=C([C@@H]1CCCN(c2ccc3[nH]c(-c4cccc(Br)n4)nc3n2)C1)N1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC1(c2cccc(-c3nc4nc(N5CCC[C@@H](C(=O)N6CCCC6)C5)ccc4[nH]3)n2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 7 %

Procedure:
To a stirred solution of (R)-(1-(2-(6-bromopyridin-2-yl)-1H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (300 mg, 0.658 mmol) in toluene was added cyclopropane carbonitrile. The mixture was cooled to 0° C. then a 1M solution of sodium bis(trimethylsilyl)amide in THF was added dropwise. The reaction mixture was stirred for 16 h at room temperature. The mixture was quenched with water and then was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified via preparative TLC (twice) to afford (R)-1-(6-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)cyclopropanecarbonitrile (20 mg, 7%) MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.969 min (Method C1); 1H NMR (400 MHz, CDCl3) δ 1.24-1.31 (m, 4H), 1.65-1.71 (m, 2H), 1.78-2.04 (m, 6H), 2.69 (m, 1H), 3.01 (t, 1H), 3.07-3.18 (m, 1H), 3.43-3.56 (m, 3H), 3.60-3.72 (m, 1H), 4.35 (br s, 1H), 4.54 (d, 1H), 6.72 (d, 1H), 7.48 (d, 1H), 7.79-7.95 (m, 2H), 8.58 (d, 1H), 10.28 (br s, 1H).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)C.[O:17]=[C:18]1[N:29]([C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([CH:36]=O)[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1.O>O1CCCC1>[O:17]=[C:18]1[N:29]([C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32](/[CH:36]=[CH:7]/[C:6]([OH:5])=[O:16])[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1
Reactant: O=C[C@H]1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/[C@H]1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in oil) (15 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (84 μl). After stirring at ambient temperature for 5 minutes, cis-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (100 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by praparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (500 μl), and 1M NaOH solution (352 μl) was added, then stirred at 100° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (352 μl) and pH 4 buffer (10 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[cis-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylic acid (21 mg) as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[CH3:10]>>[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCc1ccc(N)cc1
Reactant: N#Cc1ccccn1
Product: CCc1ccc(NC(=N)c2ccccn2)cc1
Yield: 71 %

Procedure:
The title compound was prepared from 2-cyanopyridine (8.5 g, 82 mmol) and 4-ethylaniline (10 g, 82 mmol) by following the procedure described in preparation 10 (13.22 g, yield 71%, mp 75-77 C, purity 99.9% by HPLC). 1H-NMR (CDCl3):δ 1.22-1.26 (t, 3H), 2.61-2.66 (q, 2H), 6.93-6.95 (d, 2H), 7.18-7.25 (m, 2H), 7.36-7.39 (m, 1H), 7.78-7.82 (m, 1H), 8.40-8.42 (d, 1H), 8.56-8.57 (d, 1H). MS m/z: 227.3 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]([NH2:19])[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:17][CH3:18])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: CCNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 64.1 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and ethylamine (5 mL, 10.0 mmol, 2.0 M in THF) were stirred together for 16 hours. 4-bromo-N-ethyl-2-(trifluoromethoxy)benzenesulfonamide (0.23 g, 64%) was provided after purification. MS (ESI) m/z 348. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][C:15]([C:14]1[CH:19]=[CH:20][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: Cc1ccc(C(=O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)COc2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure given in Example 13a 2,4-dichlorophenol was interacted with an equimolar quantity of 4-methylphenacyl chloride in the presence of potassium carbonate to give w-(2,4-dichlorophenoxy)-p-methylacetophenone. Recrystallized from 2-ethoxyethanol, this product melted at 96.5-98.5° C.