Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([Mg]Br)[CH3:12].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CCC(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 15 g (73.9 mmol) 5-bromo-2-fluorobenzaldehyde in diethyl ether (100 ml) at 0° C. were slowly added 27.1 ml (81.3 mmol) of ethyl magnesium bromide solution (3 M in diethyl ether). After stirring at 0° C. for 3 h, water (20 ml) was carefully added upon which a white precipitate formed. The solid was filtered off and washed with tert-butylmethyl ether. The combined filtrates were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (16.1 g, 93% of th.) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCCC2)C1
Reaction time: 1 h

Procedure:
To a solution of [1-(4-chloro-phenyl)-cyclopentyl]-(3-hydroxymethyl-piperidin-1-yl)-methanone (0.5 g, 1.55 mmol) in dichloromethane (9.5 mL) at room temperature was added iPr2NEt (0.5 g, 3.9 mmol) followed by MsCl (0.214 g, 1.86 mmol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (gradient 2.5-100% EtOAc in hexane). The desired compound was obtained as an oil (0.345 g, 56%). 13C (100 MHz, CDCl3, partial) δ174.0, 144.0, 131.8, 128.8, 126.5, 70.8, 58.1, 35.3, 26.5, 24.9. 1H (300 MHz, CDCl3) δ7.26-7.24 (m, 2H), 7.13-7.10 (m, 2H), 4.61-1.86 (m, 19H), 1.67 (s, 3H).
Reaction SMILES: [K].[CH3:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][NH:6][C:5](=[O:15])[N:4]=1.[CH3:16]I>CO>[CH3:16][N:6]1[C:5](=[O:15])[N:4]=[C:3]([CH3:2])[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7]1
Reactant: Cc1nc(=O)[nH]nc1-c1ccccc1
Reactant: CI
Agent: [K]
Solvent: CO
Product: Cc1nc(=O)n(C)nc1-c1ccccc1
Yield: 56.3 %

Procedure:
Potassium salt of 5-methyl-6-phenyl1,2,4-triazin-3(2H)-one (20 g) was dissolved in methanol (200 ml). Methyl iodide (37.8 g) was added thereto, and the solution was refluxed for 2.5 hours, and evaporated under reduced pressure. The resultant residue was washed with water and dissolved in chloroform. The solution was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was washed with ethyl acetate and dried to give 2,5-dimethyl-6-phenyl-1,2,4-triazin-3(2H)-one (12.11 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>ClCCl>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:20](=[O:22])[CH3:21])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:3])[CH3:2]
Reactant: CC(=S)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Yield: 95 %

Procedure:
A solution of 5-(S)-thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one (0.070 g, 0.247 mmol), acetic anhydride (0.25 mL), pyridine (0.38 mL), and dichloromethane (0.75 mL) was stirred at r.t. for 4 h. Solvent was removed under vacuum and the crude prtoduct purified by PTLC (10% MeOH in DCM) to give a white solid (0.076 g, 95%). M.p. 200-1° C.; MS (m/z): (M+H)+=326.
Reaction SMILES: C([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)(=O)C.O=C(Cl)OC(Cl)(Cl)Cl.O.[O:23]1CCO[CH2:25][CH2:24]1>>[OH:13][C:7]1[CH:6]=[C:5]([C:24](=[O:23])[CH3:25])[CH:4]=[CH:12][C:8]=1[C:9]#[N:11]
Reactant: C1COCCO1
Reactant: CC(=O)c1ccc(O)c(C(N)=O)c1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc(C#N)c(O)c1
Reaction time: 18 h

Procedure:
5-acetylsalicylamide (10.04 g, 56 mmol) and diphosgene (18.4 g, 93 mmol) were heated in dioxane (65 ml) to70° C. under nitrogen for 18 hours. The mixture was cooled, cautiously poured into cold water (700 ml) and stirred for 1 hour to destroy excess diphosgene reagent. The mixture was extracted with ethyl acetate, and the organic solution washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was recrystallized from toluene/acetonitrile to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
4'-hydroxy 4-biphenylcarboxylic acid (5.0 g) was added to a stirred suspension of sodium hydride (60% w/w dispersion in mineral oil, 2.34 g) in dry dimethylformamide (45 ml) whilst maintaining the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at 10° C. for 20 minutes. A solution of benzyl bromide (8.4 g) in dry dimethylformamide (10 ml) was added over a period of 10 minutes. The reaction mixture was stirred at 70° C. for 2 hours and the mixture was then poured into cold water (900 ml) to precipitate a solid. The solid was collected by filtration, washed with water (3×200 ml) and added to a mixture of 2M aqueous sodium hydroxide solution (100 ml) and ethanol (100 ml). The mixture was stirred at 100° C. for 12 hours. The ethanol was removed by evaporation and the aqueous residue taken to pH 1.0 by the addition of 12M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, washed with water (3×100 ml), ethyl acetate (3×100 ml) and dried to give 4'-benzyloxy-4-biphenylcarboxylic acid (100% yield) as a colourless solid, m.p. >300° C.; m/z 304 (M).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:27])[C:4](=[O:28])[C:3]=1[CH:29]([CH3:31])[CH3:30].[H-].[Na+].I[CH3:35]>C1COCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH3:27])[C:4](=[O:28])[C:3]([CH:29]([CH3:31])[CH3:30])=[C:2]3[NH:1][CH3:35])=[CH:17][CH:16]=1
Reactant: CC(C)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1c(C(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reaction time: 0.17 h

Procedure:
The product of EXAMPLE 54 (30 mg) in THF (2.5 mL) was combined with sodium hydride (5 mg, 60% in mineral oil). The suspension was stirred for 10 min were upon iodomethane (37 uL) was added. The reaction was stirred for about 6.5 hours at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The EtOAc solution was dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 35% EtOAc in hexane affording the title compound. HPLC/MS: 486.2 (M+1), 488.2 (M+3); Rt=4.72 min.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]#[N:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.[Li+].[OH-:26]>O1CCOCC1>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:19])=[O:26])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: [OH-]
Reactant: N#Cc1cccc2c(NCc3cccc(C(F)(F)F)c3)ccnc12
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 90 °C
Yield: 34 %

Procedure:
To a solution of 4-{[3-(trifluoromethyl)benzyl]amino}quinoline-8-carbonitrile (20 mg, 0.05 mmol) in 2 mL of dioxane, 2N LiOH solution (250 μL, 0.5 mmol, 10 equiv.) was added. The resulting mixture was heated at 90° C. by microwave for 20 min. After work-up, the crude was purified by preparative HPLC to yield the title compound as a white solid in 34% yield. 1HNMR (in DMSO): 4.92 (d, J=5.8 Hz, 2H), 6.93 (d, J=7.4 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 7.85 9s, 1H), 7.87 (d, J=8.1 Hz, 1H), 8.22 (s, 1H), 8.48-8.54 (m, 2H), 8.75 (s, 1H), 8.80 (d, J=8.4 Hz, 1H), 10.06 (s, 1H). Mass: M+H+: 346.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(OCC)(=O)[CH2:14][C:15]([O:17]CC)=[O:16]>>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Product: O=C(O)Cc1c(F)cc([N+](=O)[O-])cc1F

Procedure:
The title compound 2,6-difluoro-4-nitrophenylacetic acid (16.0 g) was prepared from 3,4,5-trifluoronitrobenzene (14.8 g) and diethyl malonate (35 mL) in the same manner as described for REFERENCE EXAMPLE 1. MS (EI+) m/z: 217 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:30])[O:3]1.CCN(C(C)C)C(C)C.[CH:41]1([CH2:46][CH2:47][C:48](Cl)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42]1.Cl>C(Cl)Cl>[CH:41]1([CH2:46][CH2:47][C:48]([N:12]([CH2:13][C:14]2[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[CH:16][CH:15]=2)[C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:31])([CH3:1])[O:3][C:4](=[O:30])[C:5]=3[CH:11]=2)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C(=O)OCc4ccccc4)cc3)ccc2O1
Reactant: O=C(Cl)CCC1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)OCc4ccccc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a cold (0° C.) solution of benzyl 4-{[(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}benzoate (430 mg) and DIEA (146 mg) in anhydrous DCM (5 nm) was added a solution of 3-cyclopentylpropanoyl chloride (182 mg, 1 M in DCM). The mixture was stirred 1 h at 0° C. then 3 h at rt. An aqueous solution of HCl (1N, 50 mL) was added and the resulting mixture was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over MgSO4, filtered and evaporated under vacuum to give a light orange oil. Purification by chromatography (SiO2, DCM/c-Hex) gave the title compound as a colorless oil (499 mg, 89%). 1H NMR (CDCl3) δ 8.00 (d, J=8.3 Hz, 2H), 7.69 (d, J=2.3 Hz, 1H), 7.49-7.32 (m, 5H), 7.27 (d, J=7.5 Hz, 2H), 7.11-7.03 (m, 1H), 6.91 (d, J=8.6 Hz, 1H), 5.37 (s, 2H), 4.93 (s, 2H), 2.13-2.05 (m, 2H), 1.85 (s, 6H), 1.71-1.37 (m, 9H), 1.06-0.89 (m, 2H). M+(ESI): 542.3.
Reaction SMILES: I.[NH:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1.[H-].[Li+].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[N:18]=[C:19]=[O:20]>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[NH:18][C:19]([N:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1)=[O:20]
Reactant: O=C=Nc1c(Br)cccc1Br
Reactant: N=C1NCCN1
Agent: I
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(N=C1NCCN1)Nc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a manner similar to that described in Examples II and III, a solution of 12.0 grams (0.0563 mole) of 2-iminoimidazolidine hydroiodide in 50 milliliters of dry dimethylformamide is added dropwise with cooling and under an atmosphere of nitrogen to a suspension of 447 milligrams (0.0563 mole) of lithium hydride in 50 milliliters of dry dimethylformamide. After completion of the addition the mixture is allowed to warm to room temperature over a period of about half an hour, then cooled to 0°-5° C., and a solution of 7.8 grams (0.0282 mole) of 2,6-dibromophenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period while maintaining the cooled temperature range. The mixture is then allowed to warm to room temperature and stirred overnight under nitrogen to obtain the desired N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea product in the reaction mixture. The product is recovered from the reaction mixture by pouring the mixture into 400 milliliters of ice water, acidifying with 10 percent hydrochloric acid to pH below 3, filtering to remove impurities, saturating the filtrate with solid sodium chloride and basifying with potassium carbonate to a pH of 8-9 to precipate the N-(2,6-dibromophenyl)-N'-(2-imidazolidinylidene)urea product as a white solid, m.p. 185°-190° C. (dec.)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[OH-].[CH2:20]([N+:24]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CO>[CH2:33]([N+:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:8]=1[C:9]([NH-:11])=[O:10])([OH:3])=[O:2]
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: [NH-]C(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
A 3.26 g. portion of 4-carboxy-1-(3-chlorophenyl)-5-pyrazolecarboxamide wasslurred in 50 ml. of methanol and 12 ml. of 1M tetrabutyl ammonium hydroxide solution was added. The mixture was stirred for 30 minutes, and evaporated to dryness under vacuum to obtain 5.2 g. of product, m.p. 120°-121°. The product was identified by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].C(=O)([O-])[O-].[K+].[K+].[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43].[Cl-].[NH4+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([S:18]([NH:21][C:45](=[O:46])[NH:44][CH2:42][CH3:43])(=[O:19])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCN=C=O
Reactant: NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(=O)NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
7-(2-Chlorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.098 mmol) obtained in Example 6 step 5 was dissolved in acetone (0.5 mL), potassium carbonate (0.041 g, 0.293 mmol) and ethylisocyanate (0.017 g, 0.245 mmol) were added, and the mixture was stirred at 50° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=99/1) to give the title compound (0.027 g, 48%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:16][CH3:17])(=[O:15])[C@@H:12]([CH3:14])[OH:13].C(OC(C)C)(C)C>CN(C)C=O.O1CCCC1.O>[CH2:1]([O:13][C@H:12]([CH3:14])[C:11]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: COC(=O)[C@@H](C)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
At −30° C., benzyl bromide (9.86 g) and 60% sodium hydride (2.11 g) were dissolved in a mixed solution of dimethyl formamide (DMF) and tetrahydrofuran (THF) (50 mL, 3:2 volume ratio). (R)-Methyl lactate (5.0 g, 99% ee) was added to the solution. At the same temperature, the resultant mixture was stirred for 30 minutes. Thereafter, the mixture was stirred at room temperature for 30 minutes and further at 50° C. for 30 minutes. Water and diisopropyl ether were added to the reaction mixture, and the organic layer was washed with water and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resultant residue was subjected to chromatography on a silica gel column to afford the title compound as a yellow oil (8.87 g, 92.1% ee).
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(OCC)(=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:1][C:2]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Yield: 54 %

Procedure:
8.1 g (20 mmol) of phenylmethyl 1-aminocyclohexanecarboxylate ·p-toluenesulfonate was added to 50 nm of water, and then 4.1 g (20 mmol) of 4-methoxybenzenesulfonylchloride and 50 ml of ethyl acetate was added to the mixture with stirring. After stirring at room temperature, the reaction mixture was put into a separatory funnel and water layer was removed therefrom. Subsequently, organic layer was washed with successive, 10% potassium hydrogensulfate solution, and saturated brine, and then, was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained crystal was stirred overnight in ether, whereby 4.36 g of phenylmethyl 1-[N-(4-methoxybenzenesulfonyl)amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pd].CO>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N)c(Oc2ccccc2C(C)(C)C)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2a (580 mg, 1.9 mmol) in a 1:1 mixture of ethyl acetate and methanol (6 mL) was added palladium on charcoal (10% wt, 300 mg, 0.28 mmol). The mixture was stirred under 40 psi atmosphere of hydrogen. After 30 min, the solution was filtered over Celite® and the resulting solution was concentrated to afford the title compound 2b as a dark solution (500 mg, 96% yield). 2b was used in the next step without any further purification. [M+H]+=273.21. 1H NMR (500 MHz, CD3OD) δ ppm 1.43 (m, 9H), 3.58 (m, 3H), 6.33 (d, J=8.25 Hz, 1H), 6.93 (d, J=8.25 Hz, 1H), 7.09 (m, 2H), 7.17 (t, J=7.70 Hz, 1H), 7.41 (d, J=8.25 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:25])[C:9]=2[N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)[NH:4][CH:3]=1.C[N:27]1[C:31](=[O:32])C[CH2:29][CH2:28]1.N1C=CC=CC=1.N(CC)=C=O>O.C(#N)C>[Br:25][C:8]1[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:12]2)=[C:10]2[C:2]([NH:1][C:31]([NH:27][CH2:28][CH3:29])=[O:32])=[CH:3][NH:4][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Reactant: CN1CCCC1=O
Agent: CCN=C=O
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
(R)-tert-Butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.150 g, 0.366 mmol; Example 98, Step A) was placed in 1:1 NMP:pyridine (2 mL total volume). Isocyanatoethane (0.146 mL, 1.83 mmol) was then added, and the reaction was stirred at room temperature for 30 minutes and then concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 5:95 ACN in water) to give (R)-tert-butyl 1-(5-bromo-3-(3-ethylureido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.130 g, 74% yield).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:33]4[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=4[F:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1c(F)cccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1c(F)cccc1F
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 33.2 mg (0.21 mmol) of 2,6-difluorophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 40 mg (75.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:23])[C:14]=1[N+:24]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:23])[C:14]=1[NH2:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1N
Yield: 59.8 %

Procedure:
Crude ethyl-[2-amino-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (65 gm, 170 mmol) was dissolved in ethanol (1000 mL) and 10% Pd—C (6 g m) was added. Hydrogenation at 40° C. and 40 psi for 1 hour gave complete reduction of the nitro group. The catalyst was removed by filtration and the filtrate evaporated to dryness under reduced pressure to give a light brown semi-solid. Trituration with t-butyl methyl ether (150 mL) followed by filtration and washing with the same solvent (30 mL) gave ethyl-[2,3-diamino-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (36 gm, 60% yield) as a white solid.