Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.C([NH:48][S:49](Cl)(=[O:51])=[O:50])(OC(C)(C)C)=O>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:49]([NH2:48])(=[O:51])=[O:50])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 55.7 %

Procedure:
To a stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.46 g, 1.0 mmol) in dichloromethane (10 mL) was added triethylamine (0.42 mL) and N-Boc-sulfamoyl chloride (0.8M, 3.75 mL, 3.0 mmol), the reaction mixture was allowed to stir at room temperature for 45 h, poured into ice-water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded a white solid (0.3 g), which was dissolved in TFA (10 mL) and allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 mL) was added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.21 g, 39%). MS (ISP) 539.3 [(M+H)+]; mp 174° C.
Reaction SMILES: F[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5](F)=[C:4]([F:21])[C:3]=1[F:22].[NH2:23][CH:24]([CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:25]>C(Cl)Cl>[CH2:30]([N:29]([CH2:32][CH3:33])[CH2:28][CH2:27][CH2:26][CH:24]([NH:23][C:5]1[C:6]2[C:7](=[O:19])[C:8]3[C:13](=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[OH:18])[C:14](=[O:16])[C:15]=2[C:2]([NH:23][CH:24]([CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:25])=[C:3]([F:22])[C:4]=1[F:21])[CH3:25])[CH3:31]
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CCN(CC)CCCC(C)N
Solvent: ClCCl
Product: CCN(CC)CCCC(C)Nc1c(F)c(F)c(NC(C)CCCN(CC)CC)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1,2,3,4-tetrafluoro-5,8-dihydroxyanthraquinone (0.47 g, 1.5 mmol) and 2-Amino-5-diethylaminopentane (2.3 mL) in CH2Cl2 (20 mL) was stirred at room temperature for 12 hours. After evaporation of the solvents, the residue was purified by silica gel chromatography using isocratic solvent system of CH2Cl2/MeOH/Et3N (100:10:1) yielding 364 mgs of Dye 2 as dark blue product. Abs (max, PBS pH 7.4)=667 nm; Em=700 nm. The structure of Dye 2 is given below:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18](N(C)OC)=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1.[CH3:24][Mg+].[Br-]>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([CH3:24])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:5][N:4]=1
Reactant: CON(C)C(=O)c1ccc2ncn(-c3ccnc(SC)n3)c2c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: CSc1nccc(-n2cnc3ccc(C(C)=O)cc32)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-methylthio-4-[6-(N-methyl-N-methoxyaminocarbonyl)benzimidazol-1-yl]pyrimidine (26 mg, 0.079 mmol) in CH2Cl2 (0.8 mL) at 0° C. was added CH3MgBr (255 μL, 1.4M) dropwise and stirred for 3 h at 0° C. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were washed with brine and dried over Na2SO4. The crude material was purified by preparative thin layer chromatography eluting with 3% MeOH/CH2Cl2 to obtain 15.7 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.94 (s, 1H); 8.79 (s, 1H); 8.67 (d, J=5.0 Hz, 1H); 8.04 (d, J=7.5 Hz, 1H); 7.9 (d, J=7.5 Hz, 1H); 7.28 (d, J=5.0 Hz, 1H); 2.74 (s, 6H).
Reaction SMILES: O.[NH2:2][NH2:3].CC(N(C)C)=O.[CH3:10][C:11]1[CH:12]=[C:13]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17]>O1CCOCC1>[CH3:10][C:11]1[CH:12]=[C:13]([S:19]([NH:2][NH2:3])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17]
Reactant: NN
Reactant: Cc1cc(S(=O)(=O)Cl)cc(C)c1O
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)NN)cc(C)c1O

Procedure:
15.0 g (0.3 mol) of hydrazine hydrate are first introduced into 60 ml of dimethylacetamide. 22 g (0.1 mol) of 3,5-dimethyl-4-hydroxybenzenesulfonic acid chloride dissolved in 60 ml of dioxane are added dropwise to this solution over the course of 15 minutes. This causes the temperature to rise to 90° C., at which level it is maintained by slight cooling. The mixture is allowed to react for a further 90 minutes and is then completely concentrated under reduced pressure. The residue is recrystallised first from a little water and then from isopropanol. This gives 3,5-dimethyl-4-hydroxybenzenesulphonic acid hydrazide, which melts at 186° C. (with decomposition).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C(OCC)(=O)C>[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: O=C1Cc2ccccc2C1
Reactant: Nc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: c1ccc2c(c1)CC(Nc1ccc3c(c1)OCCO3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-indanone (2 g, 15.1 mmol) in DCE (50 mL) were added 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (2.28 g, 15.1 mmol), Na(OAc)3BH (4.81 g, 22.6 mmol), AcOH (1.8 mL) successively at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was dissolved in ethyl acetate and was washed with 1N NaOH, water and brine. The solution was dried over Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography eluting with 9-10% ethyl acetate-hexane to get compound 57.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[CH:31]1([NH:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][N:36]=2)[CH2:33][CH2:32]1>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:42]=[C:41]([C:38]4[CH:37]=[N:36][C:35]([NH:34][CH:31]5[CH2:33][CH2:32]5)=[CH:40][CH:39]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1ccc(NC2CC2)nc1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(NC5CC5)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 26 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and cyclopropyl-(5-ethynyl-pyridin-2-yl)-amine in the same manner as Example 15. ESI MS m/z 590 [C30H35N7O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20]N(C5C=CC=CC=5)C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41].Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:39]([C:33]5[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=5[Cl:31])[C:40]4=[O:41])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1cccc(Cl)c1Cl

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2,3-dichlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 218°-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]I.[OH-].[Na+].[O-][O-].[Na+].[Na+]>O1CCCC1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13]
Reactant: COc1ccc2cnccc2c1
Reactant: FC(F)(F)CCCI
Agent: [Na+]
Agent: [O-][O-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2cncc(CCCC(F)(F)F)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
2 g 6-Methoxy-isoquinoline were dissolved in 25 mL of dry tetrahydrofuran. 12.56 mL of a 1 M solution of potassium triethyl borohydrate were added dropwise. The solution was allowed to stir at room temperature for 2 h, then 3.29 g of 4,4,4-Trifluoro-1-iodobutane were added dropwise. The solution was allowed to stir overnight, then 32 mL of 1 M sodium hydroxide and 12 mL of sodium peroxide solution (35%) were added. Stirring was continued for another 3 hrs, then the solution was diluted with dichloromethane, extracted with water and brine and the organic layer was dried over sodium sulfate and evaporated to dryness. Silica gel chromatography yields 1.03 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[CH:12]1([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:19][CH2:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: NCC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccc2nc(NCC3CCCCC3)sc2c1
Yield: 61 %

Procedure:
A microwave reaction vial was charged with 6-bromo-2-chlorobenzo[d]thiazole (300 mg, 1.21 mmol), cyclohexylmethanamine (143 mg, 1.27 mmol), triethylamine (183 mg, 1.81 mmol) and 2.4 mL DMF. The vial was sealed, and the mixture was irradiated in the microwave for 20 min at 150° C. The reaction mixture was concentrated twice from toluene and purified by silica gel chromatography (0-50% 90/10 CH2Cl2/MeOH in CH2Cl2), which provided 6-bromo-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine (240 mg, 61%) as a white solid. MS (ESI pos. ion) m/z calc'd for C14H17BrN2S: 325.3/327.3. found 325.0/327.0.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:16]([N:26]([C:28](=[O:43])[C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[CH3:27])=[CH:15][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:27][N:26]([C:16]1[CH:15]=[N:14][C:13]([C:9]2[NH:8][CH:12]=[CH:11][CH:10]=2)=[CH:18][C:17]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:28](=[O:43])[C:29]1[CH:30]=[C:31]([C:39]([F:41])([F:42])[F:40])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1
Reactant: Cc1ccccc1-c1cc(-c2cccn2C(=O)OC(C)(C)C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1cc(-c2ccc[nH]2)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{5-[(3,5-bis-trifluoromethyl-benzoyl)-methyl-amino]-4-o-tolyl-pyridin-2-yl}-pyrrole-1-carboxylic acid tert-butyl ester (39 mg, 64.6 μmol) in CH2Cl2 (2 mL) was added TFA (2 mL) at 0° C. The reaction mixture was stirred for at room temperature for 1 hour and then concentrated under vacuum. The residue was poured on 30 mL aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (32 mg, 98%). MS (ESI): m/z=504.151 [M+H]+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCBr
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCCCCCC

Procedure:
In contrast, the reaction of one equivalent of oleyl bromide with 1.2 equivalents of amyl-magnesium bromide and 5% m/m lithium dichlorocuprate in tetrahydrofuran at -25° to -15° and using a procedure identical to that of Example 7 gave about 80% conversion to crude Z-9-tricosene. The remainder of the product is Z-1,9-octadecadiene.
Reaction SMILES: [SH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11](=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[O-:12].[CH3:22]O>>[CH3:22][O:12][N:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1N=[N+]([O-])c1ccccc1OC
Reactant: CO
Agent: [Na+]
Agent: [SH-]
Product: COc1ccccc1N(Nc1ccccc1)OC
Yield: 72 %

Procedure:
90 parts of an aqueous solution of technical sodium hydrosulfide containing 35 percent NaHS and 4 percent NasS2O3 were added to a mixture comprising 51.6 parts of 2,2'-dimethoxyazoxybenzene in 155 parts methanol at room temperature within 5 hours. Subsequently, the reaction mixture was refluxed at 70° C to 75° C for 2 1/2 hours while the pH was maintained between 8.5 and 9.4. After this period the absence of the starting material was confirmed and the reaction mixture was cooled down to 0° C to 5° C, the reduced product that precipitated filtered off and washed with water until alkali-free. After drying below 70° C, 35 parts of 2,2'-dimethoxyhydrazobenzene of a melting point of 100° C to 102° C were obtained, this representing a commercially acceptible grade in a yield of 72 percent of theory.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([OH:19])=O)[C:11]2=[O:20])=[CH:7][CH:6]=1.[CH3:23][O:24][C:25](=[O:36])[CH:26]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:27]>>[CH3:23][O:24][C:25](=[O:36])[CH:26]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:27][C:17](=[O:19])[CH2:16][N:12]1[C:13](=[O:15])[CH2:14][CH:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:22][CH:21]=2)[C:11]1=[O:20]
Reactant: COC(=O)C(N)CCc1ccccc1
Reactant: NN=Cc1ccc(CC2CC(=O)N(CC(=O)O)C2=O)cc1
Agent: Cl
Product: COC(=O)C(CCc1ccccc1)NC(=O)CN1C(=O)CC(Cc2ccc(C=NN)cc2)C1=O

Procedure:
403 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acid hydrochloride are coupled with 270 mg of D,L-homophenylalanine methyl ester by the process described above. After working up and chromatographic purification, 343 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}-acetyl-D,L-homophenylalanine methyl ester are obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH3:28])[CH:24]([CH3:27])[CH2:25][CH3:26])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH3:28])[CH:24]([CH3:27])[CH2:25][CH3:26])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)N(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)N(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[methyl(1-methylpropyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (385 mg) in DMF (10 mL) was added potassium tert-butoxide (126 mg), and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 20-+50% ethyl acetate/hexane) to give the title compound (300 mg, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[F:28]C1C=C(OCC2C=CC3C(=CC=CC=3)N=2)C=CC=1C(N(OC)C)=O>>[F:28][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1F
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1F

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 2-Fluoro-n-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide provided the title compound. MS: (M+H m/z=373.0).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([OH:46])=[O:45])[C:24]1=[O:47])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:51]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH2:43][C:44]([O:46][CH3:51])=[O:45])[C:24]1=[O:47])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-((3S,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid (741 mg, 1.076 mmol; Example 127, Step B) in 10 mL of a 10% solution of MeOH in DCM at room temperature was added TMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol). Evolution of gas was observed and the yellow mixture was stirred at room temperature for 45 min. More TMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol) was added and the reaction was stirred at room temperature for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([O:23]CC4C=CC(OC)=CC=4)[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]([OH:36])[CH3:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([OH:23])[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]([OH:36])[CH3:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(C(C)O)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1cc(=O)c(O)cn1-c1cccc(-c2c(Cl)cnc3[nH]ccc23)c1

Procedure:
To a 100 mL round-bottom flask containing 2.34 g (4.66 mmol) 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one was added 25 mL 1:1 (v/v) dichloromethane:trifluoroacetic acid and the solution stirred at room temperature for 30 min. Concentration in vacuo, purification by reversed phase HPLC (2 cm×5 cm C18, acetonitrile-water gradient, 0.05% TFA added), and elution from an SCX column (50 g, sulfonic acid, rinsed with MeOH, eluted with 1 N NH3 in MeOH) afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-5-hydroxy-2-(1-hydroxyethyl)pyridin-4(1H)-one. 1H NMR (600 MHz, DMSO, 50° C.): δ 11.96 (s, 1 H); 8.35 (s, 1 H); 7.75 (dd, J=7.9, 7.7 Hz, 1 H); 7.70 (d, J=7.8 Hz, 1 H); 7.60-7.55 (m, 3 H); 7.34 (s, 1 H); 6.46 (s, 1 H); 6.29 (s, 1 H); 4.41 (q, J=6.4 Hz, 1 H); 1.20 (d, J=6.4 Hz, 3 H). HRMS (FT/ICR) Calc (M+H)+ 382.0953 found 382.0955.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3C(C)=NN=C3C(C)(C)N=2)=[CH:4][CH:3]=1.Cl.[NH2:27][C:28]1([C:32]([O:34]CC)=O)[CH2:30][CH:29]1[CH3:31].Cl.NC1(C(O)=O)CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[NH:12][C:32](=[O:34])[C:28]3([CH2:30][CH:29]3[CH3:31])[N:27]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(N)CC1C
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)c1nnc(C)n1-2
Agent: Cl
Agent: NC1(C(=O)O)CC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1C)C(=O)N2

Procedure:
A procedure analogous to that set forth in the synthesis of Compound 214 was followed, with the exception that racemic (1S,2R)-ethyl 1-amino-2-methylcyclopropanecarboxylate hydrochloride was used as starting material instead of 1-aminocyclopropanecarboxylate hydrochloride. LRMS (M+H)+: 345 m/z.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](OC)=[O:26])[CH:7]=[CH:8][CH:9]=1.Cl.[OH-].[NH4+:33]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:26])[NH2:33])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Yield: 60 %

Procedure:
A solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.62 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously for 132 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 150 mg (60%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), and 5.65 (s, 2H). IR (KBr, cm−1) 3431, 3203, 1629, 1601, 1580, 1548, 1446, 1330, 1261, 1215, and 777. MS (ES) m/e 399, 401.