Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>CSC>[CH3:21][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a suspension of p-aminophenylacetic acid (56.8 g, 376 mmol) in DMS (150 mL) was added o-tolyl isocyanate (50 g, 376 mmol) dropwise. The reaction mixture was allowed to stir 1 hour, and was poured into EtOAc (1.75 L) with stirring. The precipitate was collected and washed with EtOAc (400 mL) and MeCN (400 mL) to provide oMePUPA (80 g, 75%). ESMS m/z (M+H+) 285.1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11]3.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:17])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]3
Reactant: CN1C(=O)Cc2cc3ccccc3cc2S1(=O)=O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(=O)C(C(=O)Nc2ccccc2)c2cc3ccccc3cc2S1(=O)=O
Reaction time: 20 h
Yield: 36.8 %

Procedure:
To a solution of 1.3 g (5 mmol) 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide and 0.7 ml (5 mmol) triethylamin dissolved in 10 ml DMSO at room temperature was added 0.6 g (5 mmol) phenylisocyanate. After stirring for 20 hr the resulting mixture was quenched with dilute HCl in an ice bath and then extracted with ether (2 times). The combined ether extracts were washed, dried and concentrated to give 1.9 g crude product. This material was recrystallized from ethanol followed by recrystallization from ethylacetate to give 0.7 g 3,4-dihydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21]O[CH:19]([C:23]3[NH:27][C:26]4[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=4[N:24]=3)[CH2:18]2)[N:3]=1.[OH2:33].[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:34][NH:35]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:33][CH:19]([C:23]3[NH:27][C:26]4[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=4[N:24]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cc(F)ccc5[nH]4)C3)nc(N)n2)cc1F
Reactant: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc4cc(F)ccc4[nH]3)C2)n1
Yield: 30 %

Procedure:
To a solution of 4-{2-amino-6-[2-(5-fluoro-1H-benzimidazol-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (120 mg, 0.277 mmol) in ethanol (3.0 mL) at room temperature was added hydrazine hydrate (139 mg, 2.77 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial high to 120° C. for 1 hour. After cooling the reaction, the solvent was evaporated in vacuo to give the crude product which was triturated with EtOAc (1×5 mL). The resulting solid was filtered through a medium fritted glass funnel, and collected to afford the title compound (37 mg). LC-MS (ES) m/z=446 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.10-3.17 (m, 2H), 3.81 (t, J=9.6 Hz, 1H), 4.12 (d, J=10.4 Hz, 1H), 4.34 (d, J=12.0 Hz, 1H), 4.82-4.84 (m, 2H), 5.39 (s, 2H), 6.23 (s, 2H), 6.71 (s, 1H), 7.02-7.09 (m, 1H), 7.25 (d, J=8.8 Hz, 0.5H), 7.41-7.49 (m, 1H), 7.61 (d, J=9.6 Hz, 1.5H), 7.71 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 11.53 (s, 1H), 12.7 (bs, 1H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:6])[CH:4]=[CH2:5].[F:7][CH2:8][CH:9]([NH2:12])[CH2:10][F:11].[N-]=C=O>ClCCCl.CO>[F:7][CH2:8][CH:9]([N:12]1[CH2:5][CH2:4][C:3](=[O:6])[CH2:2][CH2:1]1)[CH2:10][F:11]
Reactant: NC(CF)CF
Reactant: C=CC(O)C=C
Agent: [N-]=C=O
Solvent: ClCCCl
Solvent: CO
Product: O=C1CCN(C(CF)CF)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
1,4-Pentadien-3-ol (200 mg, 2.38 mmol) and IBX (999 mg, 3.57 mmol) were dissolved in DCE (15 mL) and heated at 70° C. for 3 h. The reaction mixture was filtered, diluted with MeOH (10 mL) and 2-fluoro-1-fluoromethyl-ethylamine (226 mg, 2.38 mmol) was added. The reaction mixture was stirred at 70° C. for 3 h. Isocyanate resin was added and the reaction mixture stirred at room temperature for 6 h, filtered and concentrated in vacuo to give the crude title compound (160 mg, 38%) as an orange gum. LCMS (ES+): 178.1 [MH]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[NH2:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH2:1]([O:3][CH2:4][C:5]([NH:8][C:9]1[N:14]=[N:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:20]2)=[CH:11][CH:10]=1)=[O:7])[CH3:2]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCOCC(=O)O
Product: CCOCC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use ethoxyacetic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a yellow solid (67% yield). 1H NMR (300 MHz, CDCl3) δ 9.18, 8.35, 7.75, 7.63, 7.56, 7.37, 7.04, 4.08, 4.04-3.88, 3.70-3.64, 3.60-3.58, 3.35-3.33, 1.31. MS (ES+) m/z 438.4 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH3:16][C:3]1([CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3ccncc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (0.85 g), 4-(4-piperidinyl)pyridine (0.97 g), and triethylamine (1.3 mL) was stirred under nitrogen gas at 180° C. for 15 hours. To this reaction mixture were added saturated aqueous NaHCO3 and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20.1) and crystallized from ethyl acetate/hexane to provide 0.77 g of the title compound. Yield 70%.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:21]([O-:24])([O-])=[O:22].[Na+].[Na+].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2NC(=O)OC(C)(C)C)O1>C1(C)C=CC=CC=1.CCO.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>[C:6]([O:24][C:21]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)=[O:22])([CH3:17])([CH3:7])[CH3:5]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C(=O)OC(C)(C)C)[nH]c2c1
Yield: 153.3 %

Procedure:
A slurry of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (1.75 g, 5.22 mmol), LiCi (880 mg, 21.0 mmol), 1M aqueous Na2CO3 (13 mL, 13.0 mmol), Pd(PPh3)4 (600 mg, 0.52 mmol) and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (2.5 g, 7.8 mmol) in toluene (19 mL) and EtOH (19 mL) was heated at relfulx for 2 h. The reaction mixture was cooled and concentrated to dryness under vacuum. The residue was treated with H2O (120 mL) and extracted with EtOAc (2×200 mL). The combined organics were washed with brine (2×20 mL), dried (MgSO4), filtered, concentrated and purified by SiO2 chromatography (5-25% EtOAc/hexanes) to yield methyl 2-(2-(tert-butoxycarbonyl)phenyl)-3-cyclohexyl-1H-indole-6-carboxylate (1.8 g, 4.0 mmol, 77%) as a yellow-pink solid. 1HNMR (500 MHz, CDCl3) 8.26 (d, J=8.5 Hz, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.82 (dd, J=8.2, 1.5 Hz, 1H), 7.43 (ddd, J=8.5, 7.3, 1.5 Hz, 1H), 7.28 (d, J=7.6, 1.5 Hz, 1H), 7.11 (ddd, J=7.6, 7.3, 1.2 Hz, 1H), 6.67 (br s, 1H), 3.94 (s, 3H), 2.56 (tt, J=12.1, 3.5 Hz, 1H), 1.97-1.22 (m, 10H), 1.45 (s, 9H). LCMS: m/e 449 (M+H)+, ret time 2.39 min, column C, 2 minute gradient, start at 0% B.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].C(O)(=O)CCCCCCCCCCCCCCC(C)C.S(Cl)(Cl)=O.[CH2:45]([NH2:53])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].CN(C)C>CCOCC.CN(C)C=O>[CH2:45]([NH:53][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCN
Agent: CC(C)CCCCCCCCCCCCCCC(=O)O
Agent: CN(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCNC(=O)CCCCCCCCCCCCCCC(C)C

Procedure:
Isostearoyl chloride, prepared from 20 g isostearic acid, 10.1 g thionyl chloride and 0.2 ml dimethyl formamide, according to the procedure of Example 1, is added to 11 g (0.09 mole) n-octylamine and 10 g (0.10 mole) trimethylamine in 100 ml ether. The reaction mixture is treated in accordance with the procedure of Example 2, yielding 22 g of an amber oil, which exhibits infrared spectra values typical of a secondary amide.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]\[C:4]([OH:6])=O.CCO[C:12]([CH3:14])=[O:13]>>[OH:13][C:12]1[CH:14]=[C:1]2[C:3](=[CH:2][CH:1]=1)[C:4](=[O:6])[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CCOC(C)=O
Product: O=C1CCCc2cc(O)ccc21

Procedure:
6-[(2-Pyrimidinyl)oxy]-tetralone (3.2 mmol), N-cyclohexylpiperazine (3.2 mmol) and Ti(O-2-Pr)4 (3.2 mmol) were dissolved in CH2Cl2 (10 mL). The solution was stirred at room temperature for 20 hours and then quenched with NaCNBH3 (6.4 mmol in 5 mL EtOH). Water (20 mL) was added, the resulting mixture was filtered through a pad of `Celite`, and the residue was rinsed with CH2Cl2 (10 mL). The organic layer was dried with Na2SO4 and evaporated to yield the crude product as an oil. Purification by column chromatography on TLC-grade silica gel and 100:3:1 CH2Cl2 :EtOH:NH4OH as eluant gave the pure product, 4-cyclohexyl-1-piperazinyl-[6-[(2-pyrimidinyl)oxy]]-1,2,3,4-tetrahydro-naphthalene. This was converted to the dimaleate salt, m.p. 179-181.5° C., by dissolving in EtOAc and heating with 2 equivalents of maleic acid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[C:3](=[O:13])[O:2]1.Cl[CH2:15][Cl:16].S(Cl)(Cl)=O>CO.CC(OC)(C)C>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:15][Cl:16])=[N:11][OH:12]
Reactant: ClCCl
Reactant: O=C1OCc2ccccc2C1=NO
Solvent: COC(C)(C)C
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=NO)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of isochroman-3,4-dione 4-oxime (98% pure, 3.5 g, 0.02 mol) in methanol (35 g) and dichlormethane (32 g) was added dropwise at 20-30° C. thionyl chloride (24.0 g, 0.2 mol). The resulting mixture was stirred at ambient temperature for 3 d. The reaction was monitored by HPLC. After completion of the reaction, the mixture was concentrated in vacuo and a crude residue was obtained (5.5 g). A part of this residue (5.1 g) was dissolved in MTBE and was washed with water. The mixture was concentrated and the resulting residue was purified by silica column chromatography by yield (2-chloromethyl-phenyl)-hydroxyimino-acetic acid methyl ester as a colorless solid (3.4
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]2[CH2:19][C:18](=[C:20]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
A solution of 0.280 g (1 mmol) of 1-[bromo(phenyl)methyl]4-chlorobenzene, 0.120 g (0.5 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 22, Step 1) and 0.12 mL (0.7 mmol) of diisopropylethylamine in 10 mL of acetonitrile was heated at 40° C. for 18 h. The solution was concentrated and the residue was dissolved in 20 mL of ethyl acetate. This solution was washed with 10 mL water and the aqueous layer was washed with a second aliquot of 20 mL ethyl acetate. The organic extracts were washed with brine, combined, and concentrated. The residue was dissolved in acetonitrile and purified by reverse phase chromatography (Waters Xterra C18, 19 mm×50 mm) using a gradient of acetonitrile-water-triethylamine (30:70:1 to 60:40:1) to afford the title compound; 1NMR (CDCl3) δ 3.74 (s, 3H), 3.88 (m, 2H), 4.24 (m, 2H), 4.55 (s, 1H), 6.70-6.86 (m, 3H), 7.21-7.43 (m, 911); Mass Spectrum: m/e=440 (M+1 35Cl) and 442 (M+1 37Cl).
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[N:10][C:11]=1[CH3:12].[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][N:27]=1)[C:22](O)=[O:23])([CH3:18])[CH3:17])#[N:15].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:5][C:6]1[CH:7]=[C:8]([NH:13][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][N:27]=[C:19]([C:16]([C:14]#[N:15])([CH3:17])[CH3:18])[CH:20]=2)[CH:9]=[N:10][C:11]=1[CH3:12]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccn1
Reactant: Cc1ncc(N)cc1Br
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc(NC(=O)c2ccnc(C(C)(C)C#N)c2)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
EDC (1.3 equiv.) was added to a solution of 5-bromo-6-methylpyridin-3-amine (1.05 equiv), 2-(2-cyanopropan-2-yl)isonicotinic acid (1.0 equiv), HOAt (1.3 equiv) in DMF (0.17 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified by ISCO(50% EtOAc/Heptane). Combined fractions still contained 17% 5-bromo-6-methylpyridin-3-amine. Add 2-(2-cyanopropan-2-yl)isonicotinic acid (0.3 equiv), EDC (0.3 equiv), HOAt (0.3 equiv) in DMF (0.17 M). After stirred at rt overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated to yield N-(5-bromo-6-methylpyridin-3-yl)-2-(2-cyanopropan-2-yl)isonicotinamide in 71% over three steps. LCMS (m/z) (M+H)=359.0, Rt=0.73 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:9]([NH2:11])[N:10]=1)=[O:5])[CH3:2].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH:8]=[C:9]([NH:11][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:20][CH:21]=2)=[O:27])[N:10]=1)=[O:5])[CH3:2]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1nc(N)cn1CC1CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1CC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.49 g (35.8 mmol) of 4-amino-1-(cyclopropylmethyl)-1H-imidazole-2-carboxylic acid ethyl ester is mixed in 18 ml of THF under argon with 6 g (35.8 mmol) of 4-(trifluoromethoxy)phenylisocyanate and stirred for 4 hours at room temperature. The reaction mixture is concentrated by evaporation in a vacuum, and the product that crystallizes out in this case is stirred in 40 ml of ethyl acetate and suctioned off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:36][C:33]3[S:34][CH:35]=[C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)[N:32]=3)=[O:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: COc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (17) (118 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(6-methoxy-3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off-white solid. Yield: 56 mg (39%). 1H-NMR: 8.64-8.61 (m, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.01 (d, J=7.5 Hz, 1H), 7.94-7.88 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.58-7.45 (m, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 6.83 (dd, J=9.0, 3.0 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 3.79-3.70 (m, 5H), 2.33 (t, J=7.0, 2H), 1.57-1.48 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([OH:11])=O)[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C@@H:3]1[CH2:8][NH:7][C@H:6]([C:9]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:11])[C@@H:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: COC(=O)[C@H]1C[C@H](OC)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2S,3S,5S)-5-methoxy-3-(methoxycarbonyl)piperidine-2-carboxylic acid (14.0 mg, 0.0000644 mol), 1-phenyl-piperazine (0.01231 mL, 8.056E-5 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (35.63 mg, 8.056E-5 mol) in N,N-dimethylformamide (0.20 mL, 0.0026 mol)was added N,N-diisopropylethylamine (0.01403 mL, 8.056E-5 mol). The mixture was stirred at rt for 2 h. After quenched with water, the mixture was extracted with ethyl acetate. The combine organic layers were washed with brine, dried and concentrated to dry. The residue was used directly in next step without further purification. MS (ESI): (M+H)+=362.1.
Reaction SMILES: [Si]([O:8][CH2:9][C:10](=[CH:20][F:21])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:21]/[CH:20]=[C:10](\[CH2:9][OH:8])/[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18].[F:21]/[CH:20]=[C:10](/[CH2:9][OH:8])\[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=CF)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC/C(=C/F)CO
Product: CC(C)(C)OC(=O)NC/C(=C\F)CO
Reaction time: 0.5 h
Yield: 6.5 %
Yield: 15.6 %

Procedure:
To a stirring solution of tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-fluoroallylcarbamate (E/Z=1:1; 12.0 g, 37.6 mmol) in THF (30 mL) at room temperature was added TBAF (1:0 M in THF; 45.1 mL, 45.1 mmol). The resulting solution was left to stir for 30 min. The reaction mixture was partitioned between water (70 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organics were washed with saturated aqueous NH4Cl (70 mL) followed by brine (70 mL). After drying over Na2SO4, the organics were concentrated in vacuo. Purification of the crude material over silica gel eluting with 20% ethyl acetate and 5% THF in n-hexane gave (Z)-tert-butyl 3-fluoro-2-(hydroxymethyl)-allylcarbamate (0.5 g, 6.5%), (E)-tert-butyl 3-fluoro-2-(hydroxymethyl)allylcarbamate (1.2 g, 15.6%) and a mixture of the E/Z isomers (5.5 g, 71.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=O.[OH2:25]>>[NH2:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:25])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: O
Agent: Cl
Product: Nc1c(-c2ccc(Br)cc2)nc2ccc(Cl)cc2c1C(=O)O

Procedure:
A solution of 5.45 g of 5-chloroisatin in water was reacted with 10.0 g of 2-amino-1-(4-bromophenyl)ethanone hydrochloride by the procedure described in example 1, giving 9.31 g of the desired compound as a yellow solid, mp 241°-242° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:14]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)Cc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)Cc1cc(OC)ccc1C(=O)c1ccccc1

Procedure:
Methyl 3-methoxy-phenylacetate was treated with benzoyl chloride and aluminum chloride as described in J. Chem. Soc., Perkin Trans I 1991, 171 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: COC(=O)c1cccc2nc(OC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 79.8 %

Procedure:
To a solution of methyl 2-methoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.22 g) in methanol (10 ml) was added 1N-NaOH (1.5 ml). The mixture was heated for 6 hours under reflux. The reaction mixture was concentrated to dryness and to the residue was added water. The mixture was adjusted to pH 3-4 with 1N-HCl to give crystals. Recrystallization from methanol-chloroform gave colorless needles (0.17 g, 77%), m.p. 208°-209° C.