Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]([F:39])([F:38])[CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:35]2[CH2:34][CH2:33][N:32]([CH2:31][C:30]([F:38])([F:39])[F:29])[CH2:37][CH2:36]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)CN1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CC(F)(F)F)CC3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-(2,2,2-trifluoroethyl)piperazine were reacted to give 267. LCMS: M+H+=530.2
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:11][S:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][CH2:27][CH2:28][CH:29]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[CH2:30][N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:48][C:44]1[CH:43]=[C:42]([CH:29]([CH2:28][CH2:27][CH2:26][N:2]2[CH2:7][CH2:6][C:5]3([CH2:11][S:10][C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=4)[CH2:4][CH2:3]2)[CH2:30][N:31]([CH3:41])[S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:47]=[CH:46][CH:45]=1
Reactant: CN(CC(CCCBr)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(CCCN1CCC2(CC1)CSc1ccccc12)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Temperature: 52 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
Spiro(benzo[b] thiophene-3(2H),4'-piperidine) hydrochloride (16.5 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 27 mg, 0.21 mmol) were added to a solution of N-(5-bromo-2-(3-chlorophenyl)pentyl)-N-methylbenzenesulfonamide (24.6 mg, 0.057 mmol) in 0.30 mL of acetonitrile, and the mixture was heated in an oil bath at 52° C. After 2 days, tetrabutylammonium iodide (5.5 mg, 0.011 mmol) was added and the reaction was continued for an additional 24 h. Without work-up, the reaction mixture was purified by preparative TLC. Elution with 30% ethyl acetate in dichloromethane gave 13.5 mg the title compound. 1NMR (400 MHz, CD3OD): δ 7.74 (d, 2H, J=8 Hz), 7.64 (tt, 1H, J=8, 1 Hz), 7.57 (t, 2H, J=8 Hz), 7.33-7.22 (m, 3H), 7.18 (d, 1H, J=8 Hz), 7.13-7.01 (m, 4H), 3.32-3.25 (m, 3H), 3.11 (dd, 1H, J=13, 8 Hz), 3.00-2.84 (m, 3H), 2.61 (s, 3H), 2.48-2.35 (m, 2H), 2.21 (bq, 2H, J=12 Hz), 1.99 (tt, 2H, J=13, 4 Hz), 1.84-1.75 (m, 3H), 1.67-1.56 (m, 1H), 1.52-1.34 (m, 2H). Mass spectrum (ESI): m/z=555 (M+1).
Reaction SMILES: C[OH:2].[CH3:3][C:4]1[O:8][C:7]([CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.ClCl>O>[CH3:11][C:10]1[O:12][C:5]([CH2:4][CH3:3])=[C:6]([OH:2])[C:7](=[O:8])[CH:9]=1
Reactant: CO
Reactant: Cc1ccc(CC(C)O)o1
Agent: ClCl
Solvent: O
Product: CCc1oc(C)cc(=O)c1O
Temperature: -15 °C
Yield: 30 %

Procedure:
In a three necked round bottom flask were combined 28 ml of methanol and 38 ml of water. The solution was cooled to -15° C. and 0.166 mole of 5-methyl-2(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1673, 1960) and 0.416 mole of chlorine were added simultaneously. During the addition, the reaction was maintained between -16° and -8° C. When addition was completed, the solution was warmed to 80° C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2.1 and extracted with chloroform (3×100 ml). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of white solid. Sublimation yielded pure product, m.p. 157°-159° C.
Reaction SMILES: C(O)(C)C.CC1C=CC(C(C)C)=CC=1.[F:15][C:16]([F:26])([F:25])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(N(CC)CC)C.C(O)=O>[F:15][C:16]([F:25])([F:26])[CH:17]([OH:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOC(=O)CC(O)C(F)(F)F
Temperature: 35 °C
Reaction time: 15 h

Procedure:
To 10 mL of i-propanol were added 5 mL of a mixture of formic acid-triethylamine (5:2 in molar ratio), 7 mg of RuCl[(1R,2R)-p-TsNHCH(C6H5)CH(C6H5)NH2] (p-cymene), and 1.0 g of ethyl 4,4,4-trifluoro-3-oxobutanoate, and the whole was stirred at 35° C. for 15 hours, followed by concentration under reduced pressure using an evaporator. To the resulting concentrate were added 10 mL of water and 10 mL of ethyl acetate, and then a saturated sodium carbonate aqueous solution was added thereto under stirring until the pH became 7 or higher. The ethyl acetate layer separated from the aqueous layer was concentrated to obtain optically active ethyl 4,4,4-trifluoro-3-hydroxybutanoate. Upon the measurement under the above conditions, the optical purity and conversion were found to be 94.8% e.e. and 99.9%, respectively.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32]C(O)C[CH:15]3[C:14]=2[CH:13]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:15]3[C:14]=2[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Yield: 82.7 %

Procedure:
Add acetic anhydride (53 mg, 0.52 mmol) to a solution of alcohol 25 (200 mg, 0.52 mmol), Et3 N (0.14 mL, 1.03 mmol), and DMAP (6 mg, 0.052 mmol) in CH2Cl2 (5 mL) and stir the reaction at room temperature for 1 hour. Dilute the solution with EtOAc and wash with H2O, saturated aqueous sodium bicarbonate and brine. Dry (Na2SO4), filter and concentrate the solution in vacuo. Purify the product by flash chromatography (10 g SiO2, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40% EtOAc/Hexanes for 13 minutes) to afford acetate 42 (183 mg, 0.43 mmol, 83%) as a yellow oil. HRMS(FAB+) calcd for C24H28O7: 428.1835; found: 428.1833 (M+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[CH2:8][N:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].CC#N.O.CC#N>O>[CH:2]([C@@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[CH2:8][N:9]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:1]
Reactant: CC(C)CN(C[C@@H]1CNC[C@H]1CO)S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(C)CN(C[C@@H]1CNC[C@H]1C=O)S(=O)(=O)c1ccccc1

Procedure:
The title compound is prepared as described above for Example 9/step E (Scheme 5) from N-((3S*,4S*)-4-Hydroxymethyl-pyrrolidin-3-ylmethyl)-N-isobutyl-benzenesulfonamide. MS (LC-MS): 325.0 [M-Boc+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow 0.6 mL/min): 4.24 min.
Reaction SMILES: [CH3:1][C:2]([CH3:30])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[C:7]([CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=2[O:28][CH3:29])=[CH:6]1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH:3]=[C:2]([CH3:30])[CH3:1])[CH:6]=[C:7]2[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29]
Reactant: COC(=O)c1ccc(Cc2cn(CC=C(C)C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2cn(CC=C(C)C)c3ccc(N)cc23)c(OC)c1
Yield: 68.7 %

Procedure:
A slurry of methyl 4-[1-(3-methylbut-2-enyl)-5-nitroindol-3-ylmethyl]-3-methoxybenzoate (0.22 g.) and stannous chloride dihydrate (1.6 g.) in absolute ethanol (8 ml.) was heated and stirred under reflux under an atmosphere of nitrogen for 24 hours. The cooled mixture was poured into saturated sodium bicarbonate solution (30 ml.). The mixture obtained was extracted with dichloromethane (2×30 ml.). The combined extracts were washed with saturated brine (25 ml.) , dried and evaporated to give methyl 4-[5-amino-1-(3-methylbut-2-enyl)indol-3-ylmethyl]-3-methoxybenzoate (F) (0.14 g.; 69%) an oil; NMR: 1.68(s,3H, =C--CH3 ), 1.76(s,3H, =C--CH3), 3.82(s,3H, CO.OCH3), 3.89 (s,2H, CH2.Ar), 3.91(s,3H, OCH3), 4.57(d,2H, CH2N), 5.27(t, 1H, CH2CH), 6.48(m,2H), 6.91(s,1H), 7.04(d,1H), 7.08(d,1H), 7.46(m,2H).
Reaction SMILES: [Na+:1].[Na+].[O:3]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]2[C:47]([NH2:48])=[CH:46][CH:45]=[C:44]3[C:39]=2[CH:40]=[CH:41][C:42]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:43]3)=[CH:32][C:31]=1[N+:53]([O-])=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:17]3)=[CH:6][C:5]=1[N+:27]([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].O>C(O)(=O)C>[Na+:1].[Na+:1].[O:3]([C:30]1[CH:35]=[CH:34][C:33]([N:36]=[N:37][C:38]2[C:47]([NH2:48])=[CH:46][CH:45]=[C:44]3[C:39]=2[CH:40]=[CH:41][C:42]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:43]3)=[CH:32][C:31]=1[NH2:53])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:17]3)=[CH:6][C:5]=1[NH2:27]
Reactant: Nc1ccc2cc(S(=O)(=O)[O-])ccc2c1N=Nc1ccc(Oc2ccc(N=Nc3c(N)ccc4cc(S(=O)(=O)[O-])ccc34)cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(N=Nc2c(N)ccc3cc(S(=O)(=O)[O-])ccc23)ccc1Oc1ccc(N=Nc2c(N)ccc3cc(S(=O)(=O)[O-])ccc23)cc1N

Procedure:
A mixture of 4.0 g. of 5,5'-[oxybis(2-nitro-p-phenyleneazo)]bis-[6-amino-2-naphthalenesulfonic acid] disodium salt and 4.0 g. of sodium sulfide nonahydrate is dissolved in 50 ml. of water by heating on a steam bath for 15 minutes. The solution is cooled and 1.6 ml. of acetic acid is added. The mixture is then filtered through diatomaceous earth. The product is salted out of the filtrate with 25 g. of sodium acetate trihydrate at room temperature, filtered and washed with a small amount of 33% aqueous solution of sodium acetate trihydrate then with ethanol and ether. The product is dissolved in 30 ml. of hot water and filtered through diatomaceous earth. An 18 g. portion of sodium acetate trihydrate is added to the filtrate and this mixture is filtered and the product is washed with ethanol and ether to give 5,5'-[oxybis(2-amino-p-phenyleneazo)]bis-[6-amino-2-naphthalenesulfonic acid] disodium salt.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:34])[CH:6]([O:32][CH3:33])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:10][C:9]=1[F:31]>C1COCC1.O>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:6]([O:32][CH3:33])[C:5]([OH:34])=[O:4])=[C:9]([F:31])[CH:10]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F)C(=O)O
Reaction time: 8 h
Yield: 83.2 %

Procedure:
1N aqueous lithium hydroxide solution (1.37 mL) was added to a solution of 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid methyl ester (0.075 g, 0.17 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred overnight, diluted with water (10 mL), and extracted with diethyl ether (3×20 mL). The aqueous layer was acidified with 1N HCl to pH 1 and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid as a white solid (60 mg, 83%). 1H-NMR (200 MHz, CDCl3): 7.56–7.29 (m, 7H), 7.18–7.09 (m, 1H), 6.98 (d, 2H, J=8.6), 6.66–6.60 (m, 2H), 4.17 (dt, 4H, J=8.9, 5.9), 4.03 (dd, 1H, J=6.7, 4.8), 3.40 (s, 3H), 3.23–3.14 (m, 1H), 2.97 (dd, 1H, J=14.0, 6.7), 2.26 (q, 2H, J=5.9)ppm.
Reaction SMILES: C(O[C:6](=[O:38])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])(C)(C)C.FC(F)(F)C(O)=O.[CH2:46]([N:48](CC)CC)[CH3:47].C(N=C=O)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH2:46]([NH:48][C:6](=[O:38])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCN(CC)CC
Agent: CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 2 h
Yield: 71.5 %

Procedure:
{2-[(1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (25 mg, 0.049 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 h. Solvent and excess TFA was removed by evaporation, and to the residue were added CH2Cl2 (3 mL), triethylamine (0.068 mL, 0.49 mmol), and ethyl isocyanate (17 mg, 0.24 mmol). The resulting mixture was stirred overnight. EtOAc (50 mL) and 0.1 M HCl (20 mL) were added, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-8% MeOH/CH2Cl2) to give 17 mg of the title compound as a pale yellow solid. MS: (+) m/z 486.39 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH:21]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[C:19]3[CH:37]=[CH:38][CH:39]=[CH:40][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH:21]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[C:19]3[CH:37]=[CH:38][CH:39]=[CH:40][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic anhydride (175 mg, 1.71 mmol, 1.0 equiv.) was added to a solution of 2-[2-(4-amino-phenyl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide hydrogen chloride (example 34) (74 mg, 1.71 mmol, 1.0 equiv.) and pyridine (13 mg, 1.71 mmol, 1.0 equiv.) in dichloromethane (2 mL). The reaction was stirred at room temperature for 16 hours then retreated with pyridine (13 mg, 1.71 mmol, 1.0 equiv.) and acetic anhydride (17 mg, 0.17 mmol, 0.1 equiv.) and stirred at room temperature for a further 24 hours. The reaction mixture was added to 1 N HCl (2 mL) and the resultant precipitate was filtered and washed with dichloromethane. The solid was dissolved in hot ethyl acetate (3 mL) and filtered, the filtrate was concentrated in vacuo to afford 2-[2-(4-acetylamino-phenyl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide as a cream solid, 26 mg (32%), MS (ES+): 473 (M+H).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)([CH2:14][CH2:15]S(C)(=O)=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[C:45]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CO>O1CCCC1.O.ClCCl>[C:1]([N:9]1[CH2:13][CH2:12][C:11]([CH2:14][CH2:15][N:50]2[CH2:51][CH2:52][CH:47]([C:45]([C:37]3[N:36]([CH2:35][C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:54][CH:53]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)=[O:46])[CH2:48][CH2:49]2)([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3ccccc3)C2)cc1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C2(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(C(=O)c3ccccc3)C2)cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine 1-benzoyl-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.54 g, 1.3 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.46 g, 1.4 mmol), and sodium bicarbonate (0.2 g, 2.5 mmol) in tetrahydrofuran/water (15/4) (30 mL). Heat to reflux. After 48 hours, cool to ambient temperature. After 72 hours, evaporate in vacuo to obtain a residue. Partition the residue between dichloromethane/chloroform and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5/1 ethyl acetate/methanol to give a solid. Combine the solid with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Dry the residue in vacuo at 82° C. to give the title compound: Rf=0.28 (silica gel, 5/1 ethyl acetate/methanol); mp; 88-90° C. Elemental Analysis calculated for C41H43FN4O4: C 72.20; H 6.47; N 8.21; Found: C 71.96; H 6.38; N 8.17.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:7])[CH:5]=[CH2:6].Cl.Cl[CH:10]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19].Cl>CO.CC(C)=O.C(O)(C)C.CCOCC.O>[CH2:4]([S:7][CH:10]([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH:5]=[CH2:6]
Reactant: C=CCS
Reactant: Clc1ccc(CC(Cl)n2ccnc2)c(Cl)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C=CCSC(Cc1ccc(Cl)cc1Cl)n1ccnc1

Procedure:
To a solution of 1.08 g (0.02 mole) of sodium methoxide in 50 ml of methanol was added 1.48 g (0.02 mole) of allyl mercaptan. To this solution was added a solution of 3.12 g (0.01 mole) of 1-(α-chloro-2,4-dichlorophenethyl) imidazole hydrochloride as prepared in Examples 1A to 1C, in 50 ml of methanol. The mixture was heated at reflux for 5 hours, cooled, and poured into 400 ml of H2O. The organic phase was extracted with ether, the combined ether extracts washed with H2O, and dried over MgSO4. Evaporation gave a dark brown oil. The oil was dissolved in a minimum of acetone and treated with an excess of HCl in isopropyl alcohol. Addition of ether caused a gummy solid to separate. Trituration of the gum with ether converted it to a solid that was recrystallized from ethanol-ether with a charcoal treatment. The product, 0.6 g (19%), was a white crystalline solid, m.p. 97°-102° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:13]1[CH:23]=[CH:22][C:16]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:15]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:14]=1)[CH3:12])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:13]1[CH:23]=[CH:22][C:16]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[C:15]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:14]=1)[CH3:12])([OH:7])=[O:5]
Reactant: CC(=NOCC(=O)OC(C)(C)C)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(=NOCC(=O)O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Yield: 65.5 %

Procedure:
A solution of 4'-[1-(tert-butyloxycarbonylmethoxyimino)ethyl]-2'-(2,4-difluorophenoxy)methanesulfonanilide (2.6 g), anisole (2 ml), and trifluoroacetic acid (6 ml) in dichloromethane (50 ml) was stirred for 5 hours at room temperature. The mixture was concentrated, and the residue was dissolved in an aqueous solution of sodium bicarbonate and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was recrystallized from a mixture of hexane and ethyl acetate to give pale yellow powder of 4'-[1-(carboxymethoxyimino)ethyl]-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g).
Reaction SMILES: O1C[CH2:5][N:4]([CH:7]=[O:8])[CH2:3]C1.CNC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32](C(O)=O)[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([C:25]3[CH:26]=[C:27]4[C:31](=[C:32]([C:7]([N:4]([CH3:5])[CH3:3])=[O:8])[CH:33]=3)[NH:30][N:29]=[CH:28]4)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][C:14]=1[CH3:37]
Reactant: O=CN1CCOCC1
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N(C)C)c3[nH]ncc3c2)ccc1F

Procedure:
5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide was prepared analogous to the preparation of 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone by the reaction of dimethyl amine (0.55 mL, 1.1 mmol, 2M in THF) with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) in acetonitrile (4 mL). Extractive work-up followed by preparative HPLC purification and neutralization procedure as discussed previously provided desired 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N,N-dimethyl-1H-indazole-7-carboxamide as a white solid. 1H NMR (DMSO-d6): δ 13.05 (s, 1H), 8.63 (dd, 1H, J=1.7 and 4.7 Hz), 8.13 (s, 1H), 7.87 (dd, 1H, J=1.4 and 7.6 Hz), 7.81 (s, 1H), 7.46 (dd, 1H, J=4.7 and 7.6 Hz), 7.32 (d, 1H, J=7.3 Hz), 7.02-6.98 (m, 1H), 6.95-6.89 (app m. 2H), 2.93 (br s, 3H), 2.57 (br s, 3H), 2.09 (s, 3H).19F NMR (DMSO-d6): δ −118.91. LCMS: rt 4.63 min (A), purity 97%, MS (m/e) 375 (MH+).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2cc[nH]c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1ccc2ccc(F)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 6-fluoro-1H-pyrrolo[2,3-b]pyridine (250 g, 1.84 mol) in dimethylformamide (2.50 L) is added potassium carbonate (507.6 g; 3.67 mol), followed by methyl iodide (171.6 mL, 2.75 mol). The reaction is stirred at room temperature overnight. The reaction mixture is poured into water (3000 mL) and extracted with Et2O (3×1500 mL). The organic extracts are combined and washed with water (4×1000 mL), then brine, and dried over Na2SO4. The solvent is evaporated to give a light brown oil which, on standing, gives clear colorless crystals, with a little mobile liquid on top of the crystals. The liquid is decanted off and discarded to leave the product as a crystalline solid (257.3 g, 1.71 moles). 1H-NMR (400 MHz, CDCl3): δ 7.93 (t, 1H), 7.11 (d, 1H), 6.69 (d, 1H), 6.46 (d, 1H), 3.83 (s, 3H).