Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[C:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:24])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(C(=O)CCc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCN(C(=O)CCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To 3.2 g (13.8 mmol) of 135 in 125 mL of anhydrous methanol was added 21.3 g of ammonium acetate and 20 g of 3A molecular sieves. After stirring 30 min, 3.47 g (55.2 mmol) of sodium cyanoborohydride was added portionwise with stirring. After 3 hours, the mixture was gravity filtered, and the methanol evaporated under vacuum. The residue was partitioned between ice/HCl and ether. The acidic aqueous phase was extracted twice more with ether. The aqueous phase was made basic with ice and 50% aqueous NaOH. The mixture was extracted with CH2Cl2, dried, and evaporated under vacuum to give 1.5 g (47%) of the title amine 136. GC/MS indicated 100% purity with a molecular ion of 232.
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[O:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1.C(Cl)Cl>[C:18]([CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([O:21][C:44](=[O:46])[CH3:45])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[NH2:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reaction time: 2 h
Yield: 106.6 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide (1.01 g, 2.14 mmol) in pyridine (4 mL) was added dimethylaminopyridine (DMAP) (65 mg, 0.533 mmol) and acetic anhydride (0.400 mL, 4.23 mmol). The resulting solution was stirred for 2 hours, then diluted with methylene chloride and washed with 1 M hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (1.16 g, >100%).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCCc1ccco1
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1ccco1

Procedure:
To a mechanically stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (WRAIR, 4.00 g, 0.017 mol), 1-bromo-5-(2-furyl) pentane (3.65 g, 0.017 mol) and HMPA (25 ml), at 105°-110° C., was added dropwise, during 60 min, a solution of Et3N(3.5 ml) and propylene oxide (6.5 ml). The mixture was heated at 105°-110° C. for 2 hr, allowed to cool and extracted with a solution of pet. ether (20°-40° C.) and Et2O (1:1 v/v, 200 ml), leaving behind a black residue. The organic layer was washed with 10% NaOH solution (3×50 ml). The combined basic wash solutions were re-extracted with a pet. ether (20°-40° C.)-Et2O solution (1:1 v/v, 2×75 ml) and the combined organic layers were washed with H2O (2×50 ml), dried (Na2SO4), treated with Darco, filtered and concentrated to give 5-[5-(2-furyl) pentoxy]-6-methoxy-4-methyl-8-nitroquinoline as a yellow solid, 2.5 g (40%) mp. 47°-49° C. This material was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22][C:21]4=[O:30])[CH2:16][CH2:15]3)=[O:13])=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:35]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22][C:21]4=[O:30])[CH2:18][CH2:19]3)=[O:13])=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:3][CH2:2]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (150 mg, 0.27 mmol) from Example 190 in methylene chloride (10 mL) was added acetic anhydride (0.050 mL, 0.54 mmol) and DIEA (0.050 mL, 0.27 mmol) and the reaction was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water (2×) and brine, and was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:20][O:21]C(Cl)Cl.Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:8]([CH:20]=[O:21])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)cc1C(N)=O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2cccc(Cl)c2)c(C=O)c1C(N)=O
Temperature: 4 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
1.0M Titanium tetrachloride in dichloromethane solution (2 mL, 2.0 mmol) was added to a suspension of 2-aminocarbonylamino-5-(3-chlorophenyl)pyrrole-3-carboxamide (Compound No. 1-25, 140 mg, 0.50 mmol) in dichloromethane (3 mL) at −30° C. and the mixture was stirred for 40 minutes. Moreover, dichloromethyl methyl ether (0.27 mL, 3.0 mmol) was added thereto and the whole was stirred overnight at 4° C. Under ice-cooling, 1N hydrochloric acid (4 mL) was added thereto and the mixture was stirred for 1 hour, and then water (10 mL) was add thereto. The precipitated solid was filtered off, washed with chloroform (10 mL) and water (10 mL), and dried under reduced pressure to give the target compound (120 mg) as a brown solid (Yield 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Product: CN(C)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Prepared from 1-chloro-2,4-dinitro-benzene and N,N-dimethyl-ethylenediamine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 46.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.036 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1occc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccoc1C(=O)O

Procedure:
3-Methyl-2-furancarboxylic acid (41 g, m.p. 136°-138° C.) was prepared by refluxing methyl 3-methyl-2-furancarboxylate 54g, (Organic Synthesis, Coll. Vol. IV, p. 649), sodium hydroxide (20 g), water (100 ml) and ethanol (100 ml), then cooling and acidifying with concentrated hydrochloric acid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]1)=[O:11].Br[C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([C:24]([F:27])([F:26])[F:25])=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-n2cnc(C(F)(F)F)n2)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 473 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]2[CH2:18][C:19]([OH:21])=[O:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:31]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][C:19]([O:21][CH3:31])=[O:20])=[O:11])=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)C[C@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2R,4R)-1-p-Nitrobenzyloxycarbonyl-2-carboxymethyl-4-hydroxypyrrolidine (5.39 g) was dissolved in 54 ml of dry methanol, and 0.9 ml of conc. sulfuric acid was added thereto, followed by refluxing for 4 hours. The reaction mixture was neutralized with 1N sodium hydroxide solution and distilled to remove the solvent. To the residue was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-methoxycarbonylmethyl-4-hydroxypyrrolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C([BH3-])#N.[Na+]>CC(O)=O.C(Cl)Cl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCN
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)CCNCc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 3-nitrobenzaldehyde (127 mg, 0.84 mmol), N,N-dimethylethylenediamine (184 μL, 1.7 mmol), and HOAc (5 drops) in DCM (10 mL) was stirred at rt for 6 h and then heated to 40° C. for 1 hour. The reaction was cooled to 0° C., and sodium cyanoborohydride (360 mg, 1.7 mmol) was added in one portion. The reaction was stirred overnight at rt. After 16 h, the reaction mixture was washed with 4 N NaOH, dried over Na2SO4, and concentrated. The crude product was used in the next reaction without further purification. ES-LC/MS m/z=224 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[F:14][CH:15]([F:21])[C:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:17])[CH:15]([F:21])[F:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)C(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)F
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of 2,5-dibromopyridine (15.21 g, 64 mmol) in anhydrous toluene (150 mL) at −78° C. under nitrogen was added dropwise with n-BuLi (2.5 M in hexane, 25 mL, 62 mmol). Stirring was continued at −78° C. for 2 h, then ethyl difluoroacetate (11 g, 80 mmol) was added dropwise at −78° C. The mixture was stirred overnight while the temperature rose to room temperature. The mixture was partitioned between EtOAc and brine, the water layer was extracted with EtOAc, the combined organic extracts were dried and concentrated, flash chromatography on silica gel afforded 8.53 g of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.O[CH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]2[CH:28]=[CH:29][C:30]3[S:35][CH2:34][C:33](=[O:36])[NH:32][C:31]=3[CH:37]=2)=[O:26])[CH2:20][CH2:19]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[O:36]=[C:33]1[NH:32][C:31]2[CH:37]=[C:27]([C:25]([NH:24][C@H:21]3[CH2:22][CH2:23][C@H:18]([CH2:17][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:19][CH2:20]3)=[O:26])[CH:28]=[CH:29][C:30]=2[S:35][CH2:34]1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Reactant: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](CO)CC3)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-Methoxy-quinoline-3-carboxylic acid (27 mg, 0.13 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (trans-4-hydroxymethyl-cyclohexyl)-amide (47 mg, 0.13 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol, 1.10 eq) and 4-(dimethylamino)pyridine (24 mg, 0.20 mmol, 1.50 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-cyclohexylmethyl ester as a white solid (7 mg, 10% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].CS(O[CH2:37][CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:43][C:40]1([CH3:44])[O:39][CH:38]([CH2:37][O:31][C:27]2[N:26]=[C:25]([CH2:24][N:5]3[C:6]4[C:11](=[C:10]([NH:12][C:13]([C:15]5[N:19]6[CH:20]=[CH:21][CH:22]=[CH:23][C:18]6=[N:17][CH:16]=5)=[O:14])[CH:9]=[CH:8][CH:7]=4)[C:3]([CH2:1][CH3:2])=[N:4]3)[CH:30]=[CH:29][CH:28]=2)[CH2:42][O:41]1
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cccc(OCC3COC(C)(C)O3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 90 °C
Yield: 58.4 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (17, Step A) (16 mg, 0.039 mmol) in DMA (2 mL) was added (2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (8.2 mg, 0.039 mmol) and Cs2CO3 (25 mg, 0.078 mmol). The reaction vial was sealed and the mixture was heated at 90° C. for 6 hours. The DMA was removed under reduced pressure. The residue was diluted with EtOAc (20 mL). The organic solution was washed with saturated NaHCO3 aqueous solution and brine, and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:0.5) gave the product (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](COCC[Si](C)(C)C)[C:10]([C:19]3[CH:20]=[C:21]4[CH:27]=[CH:26][NH:25][C:22]4=[N:23][CH:24]=3)=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:43])C(=O)C1.Cl>C(#N)C>[Cl:43][C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:10]3[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:12][C:11]=3[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:20]=2)[NH:25][CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)nc(-c2ccncc2)c1-c1cnc2[nH]ccc2c1
Agent: Cl
Solvent: CC#N
Product: Fc1ccc(-c2nc(-c3ccncc3)c(-c3cnc4[nH]cc(Cl)c4c3)[nH]2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of 5-(2-(4-fluorophenyl)-4-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (18 mg, 0.04 mmol) in ACN (0.6 mL) was added NCS (5 mg, 0.04 mmol). After stirring for 18 h, the reaction mixture was partitioned between EtOAc (20 mL) and aqueous saturated NaHCO3 (10 mL). The layers were separated and the organic phase was washed with aqueous 0.1 M HCl solution (10 mL), brine (10 mL), and dried (Na2SO4). After concentrating in vacuo, the resulting crude product was dissolved in ethanol (1.5 mL) and conc. HCl (0.25 mL, 3 mmol) was added and the reaction was heated at 60° C. for 20 min and then concentrated in vacuo. The crude material was dissolved in DMSO (1.3 mL) and purified by reverse phase HPLC, which after lypholization, yielded 7 mg (38%) of the title compound as the TFA salt: —LC/MS (m/z): 390.1 (MH+), tR=0.67 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([CH:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=1)#[N:55]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([CH:48]3[CH2:49][CH2:50][N:51]([C:60](=[O:61])[C:59]4[CH:63]=[CH:64][C:56]([C:54]#[N:55])=[CH:57][CH:58]=4)[CH2:52][CH2:53]3)=[CH:46][CH:47]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(C3CCNCC3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 89 %

Procedure:
Condensation of 21 with 4-cyanobenzoic acid on a 0.10 mmol scale via General Procedure F furnished 24 (63 mg, 89%): δH (400 MHz, CDCl3) 1.59-1.72 (m, 4H, CH2), 1.83-1.94 (m, 2H, CH2), 2.39 (s, 3H, CH3), 2.79-3.21 (m, 8H, CH3, CH and CH2), 3.65 (s, 2H, CH2), 4.77 (s, 2H, CH2), 4.95 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.34 (s, 2H, CH2), 6.60 (t, J=8.4 Hz, 1H, CH), 6.69 (dd, J=8.0 and 1.6 Hz, 1H, CH), 7.03-7.12 (m, 4H, 4 CH (Ar)), 7.21-7.82 (m, 12H, 12 CH (Ar)); δC (100 MHz, CDCl3) 21.4, 29.5, 35.9, 42.0, 48.1, 51.3, 52.7, 66.9, 70.6, 113.3, 113.9, 119.9, 120.7, 126.7, 126.9, 127.3, 127.4, 127.9, 128.1 (2), 128.4, 128.5, 129.0, 129.4, 132.3, 132.9, 134.8, 135.0, 135.5, 135.6, 140.0, 143.3, 144.0, 144.8, 158.6, 165.2, 167.0, 168.3; LRMS (ES+) calcd for [C51H48N4O7S+H] 861.33 found 861.38.
Reaction SMILES: [N:1]([C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6])=[N+]=[N-].[ClH:23].[H][H]>O1CCCC1.O.[Pd]>[ClH:23].[NH2:1][C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
To a solution of (R)-α-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (3.5 g, 1.9 mmol) in tetrahydrofuran (75 mL), water (10 mL), and concentrated hydrochloric acid (1 mL) is added palladium on carbon (0.5 g, 20%). The mixture is shaken under 52 pounds per square inch (psi) of hydrogen at 25° C. for 6 hours. Solid is filtered. The filtrate is concentrated in vacuo to give a light green solid, which is recrystallized in 3N hydrochloric acid (with activated charcoal) to give the title compound as a white solid, 2.84 g; mp 313°-314° C. (dec), [α]D =-47.6° (c=1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCC(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.329 g, 1.51 mmol) and 4-(4-trifluoromethylphenyl)piperidine (0.40 g, 1.66 mmol) were dissolved in DMF (5 ml) followed by stirring at 70° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenyl)piperidin-1-yl]propan-2-ol (0.361 g, yield 54%) as a brown oil.