Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:23][C:24]1[CH:29]=[C:28]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:12])=[CH:10][S:11][C:5]3=[N:4][C:3]=2[C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(Br)c(=O)n12
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: O
Solvent: C1COCCO1
Product: Cc1csc2nc([C@H](C)NC(=O)OC(C)(C)C)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 76.6 %

Procedure:
(S)-tert-Butyl 1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (5.46 g, 14.1 mmol) and (3-fluorophenyl)boronic acid (2.95 g, 21.1 mmol) were suspected in 1,4-dioxane (110 mL). A solution of sodium carbonate (4.47 g, 42.2 mmol) in water (27 mL) was added to the mixture followed by tetrakis(triphenylphosphine)palladium(0) catalyst (0.81 g, 0.70 mmol). The reaction mixture was degassed and heated under nitrogen at 100° C. for 16 h. HPLC indicated the starting material was consumed. The reaction mixture was cooled to room temperature and water (100 mL) was added. The resultant mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel using 1-50% ethyl acetate in hexane as eluent to give (S)-tert-butyl 1-(6-(3-fluorophenyl)-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethylcarbamate (4.34 g, 10.8 mmol, 76%) as an off-white solid. LCMS calculated for C20H23FN3O3S (M+H)+: m/z 404.1. Found 404.1. 1H NMR (500 MHz, DMSO-d6) δ 7.48 (ddd, J=8.1, 7.8, 6.2 Hz, 1H), 7.18 (m, 3H), 7.05 (q, J=1.3 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 4.41 (m, 1H), 2.66 (d, J=1.3 Hz, 3H), 1.33 (s, 9H), 1.13 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]1)=[O:5].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@@:9]2([OH:12])[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([CH3:24])[CH3:23])[CH2:7][C:8]2([CH3:20])[CH3:21])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Product: CC(C)[C@@H](NC(=O)c1ccccc1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
Example 327 was prepared in a similar manner as described in Example 75 from (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride and benzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[N+:9]([C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1)([O-:11])=[O:10]
Reactant: Cc1ccc(O)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc(O)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.45 g (50 mmol) of 5-hydroxy-2-methylpyridine are added to 20 ml of concentrated sulfuric acid while cooling in an ice bath. The temperature is maintained at +6° C. and 2.35 ml of fuming nitric acid are added with stirring. The mixture is left overnight at room temperature. 100 g of ice are added with stirring. The product is filtered off, rinsed with water and dried.
Reaction SMILES: [CH3:1][C:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[C:26](=O)([O-:28])[O-:27].[K+].[K+].C(=O)=O.O>C1C=CC=CC=1>[CH3:1][C:2]([C:19]1[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[C:22]([OH:25])=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][C:4]([CH3:5])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: CC(C)(CC(C)(c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(CC(C)(c1ccccc1)c1ccc(O)c(C(=O)O)c1)c1ccccc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
33.0 g (0.1 mole) of p-(1,3-dimethyl-1,3-diphenylbutyl)phenol and 100 g of anhydrous potassium carbonate were placed in an autoclave and thereto, carbon dioxide gas was introduced at a pressure of 40 Kg/cm2. Then, the mixture was shaken at 180° C. for 5 hours. After cooling to room temperature, the pressure in the autoclave was returned to atmospheric pressure and then, 200 ml of water and 400 ml of benzene were added to the reaction product in the autoclave, followed by heating them in order to dissolve the reaction product in these solvents. The organic phase separated out was taken out of the autoclave and shaken with a dilute hydrochloric acid solution to convert the potassium salt into the corresponding free acid. Then, it was washed with water, dried and then, concentrated in order to remove the benzene. Thus, white needle crystal was separated out. The crystal was filtered off to obtain 31.8 g of 5-(1,3-dimethyl-1,3-diphenylbutyl)salicylic acid (yield: 85%, mp: 153°-155° C.).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.[CH3:39][N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>FC(F)(F)CO>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH3:50])[CH3:39])=[O:49])[CH2:48][CH2:47]3)=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=2)=[N:15][CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN(C)C(=O)CN1CCNCC1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(CC(=O)N(C)C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 82.7 %

Procedure:
DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 207 mg, 0.5 mmol) and N,N-dimethyl-2-piperazin-1-ylacetamide (86 mg, 0.50 mmol) in 2,2,2-trifluoroethanol (2.5 mL). The mixture was heated in a microwave at 140° C. for 1 h then cooled to r.t. The mixture was purified directly by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia to provide crude product after concentration of appropriate fractions. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (234 mg, 83%) as an orange foam; 1H NMR: (CDCl3) 2.71-2.78 (4H, m), 2.97 (3H, s), 3.09 (3H, s), 3.11-3.18 (4H, m), 3.26 (2H, s), 3.99 (3H, s), 6.66 (1H, s), 6.97 (1H, td), 7.35-7.42 (1H, m), 7.52 (1H, s), 8.41 (1H, s), 8.49 (1H, d), 8.56 (1H, d), 8.92 (1H, s), 9.02 (1H, s); m/z: ES+ MH+ 566.52.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:21]#[N:22])=[CH:11][C:12]2[N:13]([C:15]([N+:18]([O-])=O)=[CH:16][N:17]=2)[CH:14]=1.[OH2:23].[OH2:24].[Sn](Cl)Cl>CCO>[NH2:22][CH2:21][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:14][N:13]2[C:15]([NH:18][C:9]([CH:3]3[CH2:4][CH2:5][O:24][CH2:7][CH2:2]3)=[O:23])=[CH:16][N:17]=[C:12]2[CH:11]=1
Reactant: O
Reactant: N#Cc1cc2ncc([N+](=O)[O-])n2cc1-c1ccc(Cl)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: NCc1cc2ncc(NC(=O)C3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of the previously obtained 6-(2,4-dichloro-phenyl)-3-nitro-imidazo[1,2-a]pyridine-7-carbonitrile and Tin(II) chloride dihydrate (3.61 g, 15.7 mmol) in absolute EtOH (10 mL) was refluxed for 10 min, then cooled to RT and concentrated under vacuum. The residue was suspended into a 2M NaOH solution in water (100 mL) and extracted with DCM (4×50 mL). The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH—NH3 99:1→95:5) to yield the title compound (517 mg, 1.71 mmol, 28% for 2 steps). HPLC: AtRet=1.34; TLC: RF 0.47 (DCM/7N NH3 in MeOH 95:5).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=O)[CH2:8][CH2:7]2.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[C:15]([C:14]#[N:18])[C:16]#[N:17])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1F)C(=O)CC2
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1F)C(=C(C#N)C#N)CC2
Temperature: 140 °C
Yield: 27.6 %

Procedure:
To a solution of 38.1 (740 mg, 4.13 mmol) and malononitrile (0.275 mL, 4.96 mmol) in toluene (10.0 mL), was added ammonium acetate (79.6 mg, 1.03 mmol) followed by acetic acid (0.284 mL, 4.96 mmol). The resulting mixture was heated at reflux at 140° C. with a Dean-Stark trap for 18 hours. The reaction was concentrated under reduced pressure, and the residue was purified by medium pressure chromatography to yield 38.2 (260 mg, 27% yield). MS ESI (neg.) m/e: 227.1 (M−H)−.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:20][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: ClCc1cccc2ccccc12
Product: Nc1nc(N)c2c(N3CCN(Cc4cccc5ccccc45)CC3)cccc2n1
Yield: 58 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 1-(chloromethyl)naphthalene (65.4 mg; 0.37 mmol) to obtain 44.7 mg. (58% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.0 (br s, 1H), 8.95 (br s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.92 (m, 2H), 7.69 (m, 1H), 7.55 (m, 1H), 7.49 (m, 5H), 7.23 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 3.99 (s, 2H), 3.0 (m, 6H), 2.38 (m, 2H). ESIMS+385.7 m/z
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCC>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1cc(CO)ccc1O
Solvent: CCCCCC
Solvent: O
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
8-Methylnonanoic acid (1.00 g, 5.80 mmol), vanillyl alcohol (851 mg, 5.52 mmol), and Novozym 435 (50 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 50° C. for 20 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (1.66 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 89.7%, and the purity was 99.5 area % by HPLC. The mixture contained 8.0 wt % of 8-methylnonanoic acid relative to dihydrocapsiate.
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]([OH:29])[CH3:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Solvent: ClCCl
Product: CC(=O)c1cc(CC(C)O)c(OCCCCC#N)cc1O
Reaction time: 5 h
Yield: 70.1 %

Procedure:
To a solution of 5.46 g of 5-[4-acetyl-5-hydroxy-2-allylphenoxy]pentanenitrile in 100 ml of methylene chloride were added 6.1 g of 85% meta-chloroperbenzoic acid. After stirring for 5 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and a cold sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to approximately 35 ml. The solution was placed in a freezer overnight providing 4.08 g of the crystalline title product which were recovered by filtration, m.p. 86°-87° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:3]=1.[Na].[CH3:14][OH:15]>>[N:8]1([C:4]2[CH:3]=[C:2]([O:15][CH3:14])[N:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: Clc1cc(-n2ccnc2)ncn1
Reactant: CO
Agent: [Na]
Product: COc1cc(-n2ccnc2)ncn1

Procedure:
Following the procedure of Example 15, 180 mg of 6-chloro-4-(1-imidazolyl)pyrimidine was reacted with 23 mg of sodium metal and 2 ml of anhydrous methanol to yield 136 mg 4-(1-imidazolyl)-6-methoxypyrimidine, having a melting point of 152°-153° C., recrystallized from a mixture of n-hexane and ethyl acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[NH:10][C:9]=2[CH:8]=[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:6]=1)=[O:4].Cl>[OH-].[Na+]>[N:24]1([C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]3[N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20]([F:21])([F:23])[F:22])[NH:10][C:9]=3[CH:8]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N2CCOCC2)cc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A mixture containing 6-morpholin-4-yl-2-(2-trifluoromethyl-phenyl)-1H-benzoimidazole-4-carboxylic acid methyl ester (75; 670 mg, 1.65 mmol) in 1M NaOH (27 ml) was stirred at 70° C. for 30 min. The reaction mixture was neutralized with 10% aqueous HCl. The resulting precipitate was collected by filtration and dried to afford 6-morpholin-4-yl-2-(2-trifluoromethyl-phenyl)-1H-benzoimidazole-4-carboxylic acid 76 (600 mg, 93%) as a pale yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH2:29]>CN(C=O)C>[NH2:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][NH:29][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NCc1c(N)cccc1F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(F)c1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-amino-6-fluorobenzylamine (60.0 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol) The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.0 mg, 94%): m.p. 165 (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.N1C=CC=[CH:40][CH:39]=1.C(Cl)(=O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:39]([CH3:40])[O:34][N:33]=6)[CH2:30][CH2:31]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Solvent: CC(=O)Cl
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5noc(C)n5)CC4)ccc3C)cc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide (46.5 mg, 0.093 mmol, crude) in pyridine (0.5 mL, 6.18 mmol) at r.t. under N2 was added acetyl chloride (0.020 mL, 0.279 mmol). The mixture was stirred at 115° C. for 2 hours. The mixture was cooled to r.t., diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.64-7.95 min. (UV detection at 220 nm). The residue obtained after evaporation of the combined fractions was further purified by preparative TLC, 10% MeOH/CH2Cl2, two 20 cm×20 cm×0.5 mm plates. Rf about 0.67 (10% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.81 (s, 1H), 7.80 ((m overlapped with s, J=2.14, 1H), 7.66 (d, J=8.55, 1H), 7.65 (d, J=1.22, 1H), 7.43 (d, J=8.55, 1H), 7.36 (dd, J=8.55, 1.83, 1H), 7.28 (m, J=8.70, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H), 1.59 (m, 2H), 1.43 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=525.07, HPLC Rt=1.682 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.67 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.22 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=12.36 min.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=[CH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:29][CH:28]=2)=[CH:43][CH:44]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: Cc1ccc(CC=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Yield: 41.5 %

Procedure:
Starting from p-methylphenethyltriphenylphosphonium bromide (5.04 g, 9.91 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 6.2 mL, 9.91 mmol, 1.0 equiv.) and 3-(4-tert-butylphenyl)-2-methylpropanal (3.04 g, 14.9 mmol, 1.5 equiv.), 1.26 g (42%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[CH:12]=[C:11]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[N:10]=[CH:9][C:8]=3[CH:7]=[CH:6]2)[CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1.CCOC(C)=O>C(Cl)Cl>[Br:34][C:7]1[C:8]2[CH:9]=[N:10][C:11]([NH:14][C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=3)=[CH:12][C:13]=2[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3c(ccn3CC3CC3)cn2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3CC2CC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To an ice-cooled solution of N-(1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide (Example 9, 75 mg, 0.215 mmol) in DCM (4 ml) was added NBS (38.2 mg, 0.215 mmol). The reaction mixture was stirred at 50° C. for 1 h, and then subjected to chromatography (NH—SiO2, EtOAc). The fractions were concentrated in vacuo and purified by preparatory HPLC to give the title compound N-(3-bromo-1-(cyclopropylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(2-hydroxypropan-2-yl)benzamide (60 mg, 0.14 mmol, 65% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.40-0.48 (m, 2 H) 0.52-0.59 (m, 2 H) 1.20-1.32 (m, 1 H) 1.46 (s, 6 H) 4.05 (d, J=7.07 Hz, 2 H) 5.17 (s, 1 H) 7.59 (d, J=8.59 Hz, 2 H) 7.74 (s, 1 H) 8.02 (d, J=8.59 Hz, 2 H) 8.40 (s, 1 H) 8.51 (s, 1 H) 10.69 (s, 1 H); m.p. 193-194° C.
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[OH:3].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CBr
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of the phosphinic acid of Example 20 (0.50 g, 1.1 mmol), methyl bromoacetate (0.2 ml, 2.2 mmol), potassium carbonate (0.24 g, 1.6 mmol) and 2-butanone (20 ml) is heated under reflux overnight. It is then filtered and the filtrate is concentrated to dryness. The crude product is purified by prep. TLC (60% ethyl acetate/hexane) to give methoxycarbonylmethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.