Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:3]=1[CH2:4][N:5]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29][CH2:30][C@H:31]([OH:44])[C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:3]=1[CH2:4][N:5]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][CH:26]([NH:29][CH2:30][C@H:31]([OH:44])[C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH:33]=3)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)(=[O:15])=[O:16])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)CN(Cc1cc(F)ccc1F)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N(CC(=O)O)Cc4cc(F)ccc4F)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
This compound was prepared from tert-butyl 2-{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate in substantially the same manner, as described in Example 53, with one change; the mixture was stirred at room temperature for 20 hours. The volatiles were removed and the product was purified by reverse phase chromatography to give a white solid (1.44 9, 42% yield): mp 80-82° C.; MS m/e 669 (M+H)+; 1H NMR (DMSO-d6 400 MHz) 81.62 (m, 2H), 2.11 (m, 2H), 2.85 (m, 2H), 2.94 (s, 3H), 2.96 (m, 1H), 3.11 (m, 1H), 3.34 (m, 1H), 3.88 (s, 2H), 3.99 (m, 2H), 4.37 (s, 2H), 4.79 (m, 1H), 6.01 (br, 1H), 6.90 (d, 1H), 7.05 (m, 3H), 7.18 (m, 3H), 7.21 (s, 1H), 7.59 (d, 2H), 8.58 (brs, 1H), 8.66 (brs, 1H), 8.74 (brs, 1H), 10.01 (brs, 1H); Analysis for C29H34F2N4O8S2×2.0 CF3COOH×0.73 H2O Calc'd: C, 43.52; H, 4.11 ; N, 6.15 Found: C, 42.95; H, 3.93; N, 6.08.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:16]([NH2:28])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:29][C:30](N)=[O:31]>C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[CH:15]=[C:16]4[C:17]([C:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:29][C:30](=[O:31])[NH:28]4)=[CH:18][CH:19]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(N)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3)nc(=O)[nH]c2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
The mixture of 3′-Amino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide from Example 14 (19 mg, 0.051 mmol) and urea (3.7 mg, 0.062 mmol) in 0.5 mL acetic acid was stirred at 120° C. for 4 hours. The solvents were removed under reduced pressure. The crude product was purified by preparative TLC sheet (methylene chloride:methanol=10:1) to give a colorless solid (12 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@@H:11]([CH3:29])[CH2:10]2)=[C:4]([CH3:30])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:40](=[O:42])[CH3:41])=[C:4]([CH3:30])[CH:3]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc(Cl)cc3C)C[C@@H]2C)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3C)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of (2S,4R)-N-(4-chloro-2-methylphenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (140 mg, 0.33 mmol, 1 equ.) in acetyl chloride (1.0 mL) was added diisopropylethylamine (58 uL, 0.33 mmol, 1 equ.). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride/methanol 99/1) to afford pure N-(4-chloro-2-methylphenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (140 mg, 92%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13]C)=[O:12])[CH2:4][CH2:3][NH:2]1.Cl.[Br:16][C:17]1[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:19][C:18]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: COC(=O)c1cccc2c1CNCC2
Reactant: CC(C)(C)OC(=O)c1nc(Cl)ccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)O)c3C2)ccc1Br
Temperature: 120 °C

Procedure:
A solution of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate, hydrochloric acid (13.6 g), tert-butyl 3-bromo-6-chloropicolinate (17.4 g) and cesium carbonate (39 g) were stirred together in N,N-dimethylacetamide (110 mL) and heated at 120° C. under nitrogen overnight. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Silica gel chromatography using 20-100% ethyl acetate in hexanes provided the title compound.
Reaction SMILES: [Al:1].[CH2:2]([O:6][CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][CH3:5].N#N.[CH2:12]([O:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:14][CH3:15]>>[CH2:2]([O:6][CH2:7][CH2:8][O-:9])[CH2:3][CH2:4][CH3:5].[CH2:12]([O:16][CH2:17][CH2:18][O-:19])[CH2:13][CH2:14][CH3:15].[CH2:2]([O:6][CH2:7][CH2:8][O-:9])[CH2:3][CH2:4][CH3:5].[Al+3:1]
Reactant: [Al]
Reactant: CCCCOCCO
Agent: N#N
Product: CCCCOCC[O-]
Product: [Al+3]
Temperature: 160 °C
Reaction time: 6 h

Procedure:
Aluminum tri(2-n-butoxyethoxide) was prepared by incremental addition of pure aluminum turnings to anhydrous 2-n-butoxyethanol. Accordingly, to a 3-liter flask fitted with condenser, stirrer and inlet for dry N2 2-n-butoxyethanol (944 g, 8.0 moles) was added and heated to a reflux temperature of approximately 160° C. Approximately 5 grams of aluminum turnings were added. Evolution of H2 gas is observed after 2 to 10 hours signifying the reaction has begun. A catalytically effective quantity of HAl(OCH2CH2OBu)4 (prepared in Example 1) added to the reaction flask substantially shortens the induction period required.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:29])[C:14](OCC)=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]1CC(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:34].[Na+].[CH3:36][CH2:37][OH:38]>O>[CH2:1]([N:9]1[C:17]2[C:12](=[C:13]([CH3:29])[C:14]([CH2:36][C:37]([OH:34])=[O:38])=[C:15]([CH3:25])[C:16]=2[NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCO
Reactant: [OH-]
Reactant: CCCCCCCCN1c2c(c(C)c(OCC)c(C)c2NC(=O)C(C)(C)C)CC1CC(=O)O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCN1CCc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N-(1-octyl-5-ethoxycarboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml) and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in water (20 ml) and the mixture was washed with AcOEt (20 ml). The aqueous layer was neutralized with 2N-hydrochloric acid and extracted with AcOEt (50 ml). The AcOEt layer was washed with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.4 g of the title compound.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C1O[C@H]1CCl.C12[CH:37]([C:38]3C=C[C:41]([OH:44])=[CH:40][CH:39]=3)C(CCC1)CCC2.C(OCC)(=O)C#CCC>C(O)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:41](=[O:44])[CH:40]=[C:39]([CH2:38][CH3:37])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: Oc1ccc(C2C3CCCC2CCC3)cc1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.26 g, 0.828 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-bicyclo[3.3.1]non-9-yl phenol (prepared with the same procedure as set forth in steps 1 and 2 of Example 20), in ethanol (5 mL) was added ethyl 2-pentynoate (0.157 g, 1.24 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated and loaded onto a silica gel column, and eluted with 4-6% methanol/methylene chloride to afford 120 mg of (S)-2-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −36.89 (c 0.501, CHCl3).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:19])([F:20])[F:21])=[O:49])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:39])([F:40])[CH:26]([F:38])[O:27][C:28]([F:37])([F:36])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
0.45 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 1.6 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.41 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(heptafluoropropoxy)ethoxy}pyrazole.
Reaction SMILES: Br[C@H:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:4][C:3]1=[O:17]>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Ag+]>[C:12]([O:14][C@H:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:4][C:3]1=[O:17])(=[O:13])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCCCC[C@H](Br)C(=O)N1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCCCCC[C@H](OC(C)=O)C(=O)N1
Temperature: 100 °C

Procedure:
Cis ethyl 3-bromo-2-oxo-1-azacyclodecane-10-carboxylate (2.96 g, 9.67 mmol) is dissolved in dimethylformamide (30 mL). Silver acetate (6.35 g, 38 mmol) is added, and the reaction is heated to 100° C. for 3 hours. After cooling back to room temperature, the reaction is diluted with ethyl acetate (100 mL), filtered through a pad of silica gel, and the solvent is evaporated to give crude cis ethyl 3-acetoxy-2-oxo-1-azacyclodecane-10-carboxylate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14]O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[O:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Temperature: 0 °C

Procedure:
{5-[4-(Trifluoromethyl)phenyl]isoxazol-3-yl}methan-1-ol (200 mg) was dissolved in dry dichloromethane (10 ml), and cooled to 0° C. The solution was stirred while adding a solution of thionyl chloride (2.74 ml) in dichloromethane (25 ml), then allowed to warm to room temperature and stirred overnight. Solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with 30% ethyl acetate/hexane, to afford 3-(chloromethyl)-5-[4-(trifluoromethyl)phenyl]isoxazole, a compound of formula (25).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=2[CH:12]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)O)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=2[CH2:12][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH2:2][CH2:3]1
Reactant: CCc1cccc(C2CC2)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(C2CC2)c1Cc1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-(2-cyclopropyl-6-ethyl-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol, triethylsilane and trifluoroacetic acid in dichloromethane. Off-white crystalline solid. MS (ISP): 227.4 ([M+H]+).
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25]Br>>[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: COC(=O)CCBr
Agent: Cl
Product: COC(=O)CCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 41.1 %

Procedure:
The title compound (126 mg, 40.4%) was prepared from 1-(4-Phenoxy-phenyl)-piperazine hydrochloride (165 mg, 0.9 mmol) and 3-bromo-propionic acid methyl ester (158 mg, 0.94 mmol) by the procedure described in step 3 of Example 4: MS (ESI) m/z 341 (M+H); 1H NMR (400 MHz, CD3OD) δ 2.55 (m, 2H), 2.64 (b, 4H), 2.76 (m, 2H), 3.15 (b, 4H), 3.70 (s, 2H), 6.88-7.05 (m, 7H), 7.28 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:26])[O:25][CH2:2][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)CBr)cc1F
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C2=C(c3ccc(Br)cc3)C(=O)OC2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 32 using 4-bromoacetyl-2-(fluoro)benzenesulfonamide from step 2 instead of [2-bromo-1-[4-methylsulfonyl) phenyl]ethanone, 4-bromophenylacetic acid instead of 4-(3-thienyl)phenylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C.[Pd].O=[Pt]=O>[NH:9]1[C:10]2[C:5](=[C:4]([NH:1][C:14](=[O:16])[CH3:15])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cccc2ncccc12
Reactant: CC(=O)O
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1CCCN2
Reaction time: 10.4 h

Procedure:
A solution of 5-nitroquinoline (50 g, 0.29 mol) in 1 L acetic acid and 30 mL acetic anhydride was treated with 5% Pd/C (3 g) and shaken on a Parr apparatus under a H2 atmosphere (50.8 psi) for 10.4 hours. The reaction was then treated with PtO2 (1 g) and recharged with H2 (50.8 psi) and shaken an additional 2 hours. After removing the catalyst by filtration, the filtrate was evaporated and the residue was separated between methylene chloride and water. The aqueous layer was basified with 50% NaOH and washed with methylene chloride. The combined organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was crystallized from ethyl acetate (23 g, 42%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[O:1]=[CH:2][CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10]
Reactant: O=C(NCCC1OCCO1)c1ccc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=CCCNC(=O)c1ccc[nH]1
Yield: 80.1 %

Procedure:
Method A. A mixture of 6 (2.85 g, 13.6 mmol) and p-toluenesulfonic acid monohydrate (1.3 g, 6.84 mmol) in 80 mL of acetone/water (1:1, v/v) was refluxed for 6 h. After cooling, the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The resulting solid was recrystallized from acetone/CH2Cl2 to afford 7 (1.81 g, 80%) as a colorless solid: mp 88-90° C.; 1H NMR (CDCl3) d 2.77 (t, 2H, J=5.8), 3.66 (q, 2H, J=5.8), 6.16 (m, 1H), 6.38 (br, 1H), 6.50 (m, 1H), 6.87 (m, 1H), 9.69 (br, 1H), 9.78 (bs, 1H); 13C NMR (CD3COCD3) d 33.7 (e), 44.6 (e), 109.6 (o), 110.0 (o), 122.1 (o), 127.1 (e), 162.0 (e), 201.9 (o); IR (nujol) 1715, 1622, 1565, 1409, 1328 cm−1; MS m/z (relative intensity) 167 (M++1, 100), 138 (15) , 123 (28), 94 (50); Anal. Calcd for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86; Found: C, 57.68; H, 5.17; N, 16.79. Method B. To a stirred solution of oxalyl chloride (0.12 mL, 1.31 mmol) in 3 mL of CH2Cl2 at −78° C. was added DMSO (0.21 mL, 2.9 mmol) in 0.6 mL of CH2Cl2 under argon. After 2 min, a solution of 5 (0.2 g, 1.19 mmol) in 40 mL of CH2Cl2 was added to the mixture and allowed to stir for 15 min. Next, triethylamine (830 mL, 5.92 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 15 min, the mixture was poured into 10 mL of water and the organic layer was separated and washed successively with 10% citric acid (20 mL), saturated NaHCO3 (20 mL), and saturated NaCl (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (CH2Cl2/MeOH 19:1) to afford 7 (0.14 g, 70%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCCO)cc2c1O
Temperature: 25 °C

Procedure:
A solution of the title compound of Example 5 (540.3 mg), 4-pentyn-1-ol (0.16 mL), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a red-brown residue. The residue is diluted with CH2Cl2 and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from EtOAc/hexanes to yield 0.296 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (341 mg, 1.7 mmol), 1-(-2′,4′-difluoro-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol), and triethylamine (418 μL, 3 mmol) according to the procedure and in the same manner as described in Example 105, step c. The solid was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), and the product (473 mg, 78%) isolated as a white solid, m.p. 127.5-129° C.;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][N:16]3[C:20](=O)[CH2:19]O[CH-]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(OC(C)C)(C)C.[BrH:29]>C(O)(=O)C>[BrH:29].[BrH:29].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:20][CH2:19]3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=C1CO[CH-]N1CCNc1ccc(N2CCOCC2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: c1cc(N2CCOCC2)ccc1N1CCNCC1

Procedure:
A solution of 3-[2-(4-morpholinophenylamino)ethyl]-2-oxazolidone (5 g) in 30% hydrobromic acid in acetic acid (35 ml) was stirred for 24 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration and added to ethanol (35 ml). The solution was refluxed for 8 hours and pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-morpholinophenyl)-piperazine dihydrobromide (7.42 g).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:11](=[O:13])[CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1)c1ccccc1
Reaction time: 12 h

Procedure:
To a solution of N-benzoyl glycine (1.2 equiv.), 4-chlorophenyl piperazine (1 equiv), HOBt (1.2 equiv) and EDC (1.2 equiv) in DMF was added DIPEA (1.2 equiv). Upon completion of addition the resulting mixture was stirred for 12 h. After this time, the mixture was purified directly via preparative HPLC to provide Example 31. MS found 358.3 (M+H).