Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCCCCCNCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and di-n-hexylamine (2.04 g, 11 mmol). The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=10:1) to give the title compound as pale yellow oil (2.79 g, 86%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][C:5]=1[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[N+:22]=[N-:23]
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
The mixture of 3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.05 g; 2.81 mmol) and sodium azide (0.547 g; 8.43 mmol) in DMF (8 mL) was stirred for 18 hours at 80° C. and was concentrated in vacuo. The residue was partitioned between water and dichloromethane. After separation, the dichloromethane solution was dried over magnesium sulfate and was evaporated to give 0.943 g (100%) of 3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=O)[N:3]=1.Cl[CH2:12]C=O.Cl.C(OCC)(=O)C>C(O)C>[F:1][C:2]1[N:3]2[CH:12]=[CH:9][N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: O=CNc1cccc(F)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoro-6-formylaminopyridine (5 g) was dissolved in 50 mL of ethanol. To the solution was added 23.5 mL (4 equivalents) of 40% chloroacetaldehyde. The mixture was stirred for one hour under reflux. The reaction mixture was gradually cooled to room temperature, to which were added a 1N—HCl aqueous solution (100 mL) and ethyl acetate (100 mL). The ethyl acetate solution was subjected to extraction with a 1N—HCl aqueous solution (100 mL×2). The aqueous solutions were combined, to which was added NaHCO3 for neutralization (pH 0.35-7.30). To the neutralized aqueous solution was added ethyl acetate (100 mL×3) to extract the product. The extract solutions were combined and dried over magnesium sulfate, which was concentrated under reduced pressure to afford 5-fluoroimidazo[1,2-a]pyridine as a black liquid product (1.5 g, yield 31%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:22]([NH:21][CH2:18][CH2:19][CH3:20])=[O:23])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1I
Reactant: CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCNC(=O)NS(=O)(=O)c1ccccc1I

Procedure:
4 g of iodobenzene-sulfonamide and 40 ml of acetone were mixed together and 3.92 g of potassium carbonate were added. The reaction was heated to reflux and 1.46 ml of n-propyl isocyanate were added. The medium was maintained at reflux for 2 hours, and after concentrating, 200 ml of water were added. Then, while cooling the reaction mixture to approximately 0°-5° C., a 2N hydrochloric acid solution was added until a pH of 3 was obtained. After crystallizing from acetone-isopropyl ether, 4.9 g of the expected product melting at 211°-212° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:14][CH2:15][CH3:16])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.S(=O)(=O)(O)O.[CH3:22]O>>[OH:1][C:2]1[C:3]([CH2:14][CH2:15][CH3:16])=[C:4]([CH2:10][C:11]([O:13][CH3:22])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CO
Reactant: CCCc1c(O)cc(OC)cc1CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCc1c(O)cc(OC)cc1CC(=O)OC

Procedure:
2-(3-Hydroxy-5-methoxy-2-propylphenyl)acetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3-hydroxy-5-methoxy-2-propylphenyl)acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CO)CC3
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCO
Solvent: C1CCOC1
Product: O=CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
A mixture of 9-bromo-5-hydroxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (520 mg, 1.67 mmol) and Dess-Martin periodinane (945 mg, 2.27 mmol) in THF (140 mL) was stirred for 5 h at room temperature. The excess reagent was decomposed by addition of ethanol and the resulting mixture was concentrated. The residual solids were triturated with dichloromethane and the insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography with 0.2% acetic acid/ethyl acetate to give 330 mg of the title compound (64%): 1H NMR (270 MHz, DMSO-d6) δ12.30 (bs, 1H), 9.57 (s, 1H), 7.21 (d, 1H, J=2 Hz), 7.19 (d, 1H, J=2 Hz), 5.31~5.37 (m, 1H), 2.85 (dm, 1H, J=15.8 Hz), 2.45~2.68 (m, 2H), 1.92~2.10 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1[N:18]([C:19]2[S:20][C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:22][C:23]=2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:17]([CH3:38])=[N:16][N:15]=1>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([C:23]1[CH:22]=[C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[S:20][C:19]=1[N:18]1[C:17]([CH3:38])=[N:16][N:15]=[C:14]1[CH2:13][NH:12][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)=[O:32]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccc(Cl)c(Cl)c2)s1

Procedure:
3,4-Dichlorobenzoyl chloride and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3,4-dichlorobenzoylaminomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][S:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][S:30][CH2:31][CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CSCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCSC)ccc21
Yield: 37.9 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methylsulfanyl-ethyl)-amide (67.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methylsulfanyl-ethylamine (45.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 481; and 1H NMR (DMSO-d6, 400 MHz): δ 8.59 (1H, br. s), 8.26 (1H, br. s), 8.11 (1H, br. s), 7.76-7.68 (2H, m), 7.56 (1H, m), 4.25 (2H, bs. s), 3.51-3.46 (2H, q), 3.32 (2H, s), 2.70-2.66 (2H, t), 2.12 (3H, s), 1.35-1.32 (3H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([NH2:12])[CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([NH:12][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][CH2:2]2)[CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cnccn1
Reactant: NC1CCC1
Solvent: O
Product: C1=CN(NC2CCC2)CC=N1
Temperature: 110 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 2-chloropyrazine (26.12 g, 228.0 mmol) and cyclobutylamine (40.00 mL, 468.5 mmol) was heated in a pressure reaction flask with stirring to 110° C. for 16 hours. The brown reaction was allowed to cool to room temperature and was diluted with water (750 mL). The aqueous solution was extracted with ethyl acetate (2×250 mL). The combined organic solutions were washed with water (1×250 mL), saturated NaHCO3 (1×250 mL) and brine (2×250 mL). The organic solution was dried (MgSO4), filtered, and concentrated. The crude product was purified by MPLC (20% ethyl acetate-40% ethyl acetate/hexanes) to afford N-cyclobutylaminopyrazine (EX-115A) in 93% yield: 1H NMR (300 MHz, DMSO) δ 7.97-7.96 (m, 1H) 7.82-7.79 (m, 2H), 5.12 (br s, 1H), 430-4.18 (m, 1H) 2.51-2.39 (m, 2H), 1.97-1.73 (m, 4H); 13C NMR (75 MHz, DMSO) δ 149.3, 137.6, 128.3, 126.9, 42.2, 26.7, 10.7; HRMS (ES) calcd for C8H12N3 150.1031, found 150.0992.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH3:10][C:9]([CH3:12])([OH:11])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a stirred solution of 24.2 g (0.16 mole) of phenoxy-2-propanone (Eastman) in 150 mL of dry ethyl ether was added 56 ml (0.17 mole) of methylmagnesium bromide (3.0M solution in ethyl ether, Aldrich) and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 4 hr. The reaction mixture was treated with 100 ml of saturated ammonium chloride solution and vigorously stirred for 1 hr. The layers were separated and the organic layer was washed twice with 200 ml portions of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield 24.3 g (91%) of a vicous oil. A 2.3 g sample of the oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500 A, PrepPak® 500 silica, ethyl acetate-hexanes, 1:20, flow rate 150 ml/min). The desired fractions were combined and the solvents evaporated under reduced pressure to yield 2.1 g (91% recovery) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11](Br)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4].Br[C:20]1C=CC2C3C(=CC=CC=3)CC=2C=1>>[Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([CH3:20])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Product: Cc1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1-2

Procedure:
Following the same procedure, 2-(chloroacetyl)-7-bromofluorene was prepared from 2-bromofluorene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][NH2:16])[CH:10]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:26])=O)=[CH:20][CH:19]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][N:16]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH3:26])[CH:10]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: COc1ccccc1-c1cc(NN)ncn1
Solvent: CCO
Product: COc1ccccc1-c1cc(NN=C(C)c2ccc(C)cc2)ncn1

Procedure:
The title compound was prepared from [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (500 mg, 2.3 mmol) and 4-methylacetophenone (310 μL, 2.3 mmol) in 10 mL of ethanol by a procedure similar to example 1, step 4 yielding 302 mg (39%) of a pale solid. HPLC Purity: 91%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18]I.Cl>[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1cc(I)c(O)c(OCc2ccccc2)c1
Temperature: 77.5 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of 3-Benzyloxy-4-hydroxy benzaldehyde (15 g, 0.065 mol) and Iodine (17.54 g, 0.13 mol) was added 3.2% NaOH solution (150 ml). The reaction mixture was stirred at 75-80° C. for 8 h. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid was added and the solid was filtered. Then the compound was recrystalized with isopropanol. The solid was filtered and dried to give 3-benzyloxy-4hydroxy-5-Iodo benzaldehyde (18.40 g, 79%). TLC: Ethyl acetate:light petroleum (2:5), Rf=0.4; 1H NMR (CDCl3, 200 MHz): δ 5.20 (s, 2H), 7.23-7.45 (m, 6H), 7.8 (d, J=1.42 Hz, 1H), 9.73 (s,1H).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=O)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([OH:14])=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1
Reactant: CC(=O)c1[nH]c(=O)c2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-acetyl-4-hydroxyisoquinolin-1(2H)-one (10.0 g, 49.2 mmol) and phosphoryl chloride (45.87 mL) was heated at 70° C. for 24 hours. After cooling to room temperature, the mixture was poured onto crushed ice and stirred for 30 minutes. The precipitated solid was collected by filtration in vacuum and air dried (9.82 g, 90%). LCMS calculated for C11H9ClNO2 (M+H)+: m/z=222.0; Found: 222.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[N:35]=[CH:34][CH:33]=[N:32]2)[C:23]=1[C:24](O)=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:24]([C:23]4[C:27]([N:31]5[N:35]=[CH:34][CH:33]=[N:32]5)=[CH:28][CH:29]=[CH:30][C:22]=4[F:21])=[O:25])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3cnc4cc(F)c(F)cc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H18F3N7O, 465.2; m/z found 466.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.32-8.24 (m, 1H), 7.90-7.79 (m, 2H), 7.68 (s, 1H), 7.65 (ddd, J=10.7, 8.5, 4.2, 1H), 7.55-7.38 (m, 2H), 7.22-7.10 (m, 1H), 4.13-3.48 (m, 7H), 3.40-3.05 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:31]([NH2:33])[CH3:32])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:33]([CH:31]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])=[C:17]([Cl:16])[CH:18]=3)[CH3:32])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1cnc(OCC(F)(F)C(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 53 %

Procedure:
The title compound is prepared in 53% yield (420 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (580 mg, 1.8 mmol, Amine-60, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2[N:26]2[CH2:30][CH2:29][C@@H:28]([F:31])[CH2:27]2)=[CH:6][CH:5]=1>[Ni].C1COCC1>[F:33][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C:12]2[CH:17]=[C:16]([NH2:18])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2[N:26]2[CH2:30][CH2:29][C@@H:28]([F:31])[CH2:27]2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1N1CC[C@@H](F)C1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c(N2CC[C@@H](F)C2)cc1NCC(F)F
Reaction time: 8 h

Procedure:
A mixture of (R)—N-(4-trifluoromethoxyphenyl)-2-[3-fluoro-pyrrolidinyl]-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid amide (100 mg, 0.20 mmol), Ra—Ni (40 mg) and THF (10 mL) is stirred under 3 bar H2-atmosphere overnight. The mixture is filtered, and the filtrate is concentrated. Yield: 94 mg. HPLC Rt=1.41 min (method A). MS m/z: 463 [M+H]+.
Reaction SMILES: C[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12](CC3N=CNC=3C)[CH2:13][CH2:14][C:3]=12.[ClH:23]>CO.C(O)C>[ClH:23].[CH:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[C:3]1[CH:14]=[CH:13][CH2:12][C:11](=[O:22])[N:4]12
Reactant: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=C1CC=Cc2cc3ccccc3n21
Reaction time: 8 h

Procedure:
The suspension of 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (2.0 g) in methanol (60 ml) was treated with hydrogen chloride in ethanol and then diluted with hot aqueous ethanol (water:ethanol, 1:4) to give a clear solution. After filtration of the insoluble materials, the filtrate was evaporated under reduced pressure to about 40 ml and allowed to stand at room temperature overnight. Filtration, followed by washing with ethanol, gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl[pyrido[1,2-a]indol-6(7H)-one hydrochloride (2.10 g) as crystals.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][CH:20]=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][CH:20]=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:23])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nncs3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nncs2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-([1,3,4]thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.17 g, 0.5 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added a solution of LiOH (0.024 g, 1.01 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl (1 mL) at 0° C. The mixture was extracted with EtOAc (2×10 mL) and the organic extracts washed with water (10 mL), dried and concentrated in vacuo. The residue was purified by preparative HPLC to give [1-hydroxy-4-methyl-6-([1,3,4]thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.15 g, 96%). 1H NMR (400 MHz, DMSO): δ 9.24 (s, 1H), 9.15 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 5.51 (d, J=6.8 Hz, 1H), 3.06 (d, J=15.6 Hz, 1H), 2.30 (s, 3H), 2.18-2.12 (m, 1H). MS (ESI) m/z=305 [M−H]−.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[CH3:23])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Cc1ccsc1Br
Product: CCSc1ncc(C(=O)c2sccc2C)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-3-methyl-thiophene (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19](Br)=[C:18]([CH3:23])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:14][C:15]([C:16]2[CH:21]=[CH:20][C:19]([C:35]3[CH:34]=[CH:33][C:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)=[CH:37][CH:36]=3)=[C:18]([CH3:23])[CH:17]=2)=[O:24])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)c(C)c2)cc1OCCN(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3ccc(-c4ccccn4)cc3)c(C)c2)cc1OCCN(C)C

Procedure:
The title compound was prepared from N-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl)-4-bromo-3-methylbenzamide (163 mg) and 4-(2-pyridyl)phenylboronic acid (D77, 154 mg) using the same procedure as in Description 15 and isolated as a white solid (171 mg, 89%). Mp 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]CC)=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1cccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(O)c1cccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Yield: 144.2 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (35.3 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (25.9 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:29]1([CH2:28][O:27][C:15]2[CH:14]=[CH:13][C:12]([CH2:10][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:26][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(CN2CCCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Pyrrolidine (25 uL, 0.30 mmol) and acetic acid (17 uL, 0.30 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.30 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50° C. then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight then quenched with NaHCO3 solution (7 ml) and extracted with dichloromethane (5 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a yellow solid. The residue purified by MDAP to yield the title compound as an opaque solid. 34 mg.