Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:25]3([CH2:24][CH2:23][N:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[CH2:27][CH2:26]3)[NH:1][C:2]=2[CH:6]=1
Reactant: O=C1CCN(c2ccccn2)CC1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCN(c3ccccn3)CC1)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide (111 mg, 0.50 mmol), 1-(2-pyridyl)-piperidin-4-one (264 mg, 1.50 mmol), CSA (11.6 mg, 0.05 mmol), MgSO4 (120 mg, 1.00 mmol) and DMA (4 mL) was stirred at 100° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH). The obtained yellow solid (190 mg) was triturated with MeOH/EtOAc and collected by filtration to afford the title compound (147 mg, 77%) as a pale yellow solid:
Reaction SMILES: [OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=4)[CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14].[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46]>C(#N)C>[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]4[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][O:43][CH2:46][CH2:45][C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:39][CH:40]=4)[CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N,N-Trimethyl-1-phenylmethanaminium hydroxide (40% in water, 0.51 mL) was added to a solution of (2-ethylthiazol-4-yl)(9-(4-(2-hydroxyethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone [Example 3, step c] (1.9 g) and tert-butyl acrylate (1.32 mL) in acetonitrile (1.5 mL) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo and the crude product purified by flash silica chromatography, elution gradient 50 to 75% ethyl acetate in isohexane with 5% triethylamine. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a colourless oil. Yield 2.19 g.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[N:16]=1>CC(O)C.CS(C)=O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=3)[CH2:26][CH2:27]2)[N:16]=1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Reactant: OCc1cccc(OCC2CO2)c1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3cccc(CO)c3)CC2)n1
Yield: 9 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 24 h), using 200 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give the title compound with 9% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) (LCMS: detected [M+1]=387.2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH2:17][CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:15])=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH2:17][CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:15])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4cccnc4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4ccc[n+]([O-])c4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 52.1 %

Procedure:
To a solution of N-[4-(3-pyridyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in tetrahydrofuran (50 ml) was added 3-chloroperbenzoic acid (70%, 0.34g) at 0° C., and the mixture was stirred at room temperature for 68 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:1), and recrystallized from ethanol-chloroform to give N-[4-(1-oxidopyridin-3-yl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 165) (216 mg) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=[O:14]>[Cl-].[Al+3].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=[CH:12]2
Reactant: O=C(O)c1ccco1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cccc2cc(F)ccc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 6.1 %

Procedure:
To a 1 liter round-bottomed flask equipped with condenser and N2 inlet were added 345 ml (3.68 mol) of fluorobenzene and 48 g (0.428 mol) of furoic acid. To the stirring suspension was added in portions 120 g (0.899 mmol of aluminum chloride. The reaction mixture was stirred at 95° C. for 16 hours and then quenched by addition to ice/water/1N HCl. After stirring 1 hour, the aqueous layer was decanted, and benzene and a saturated aqueous solution of sodium bicarbonate were added. After stirring 1 hour, the layers were separated, the aqueous layer washed with benzene, acidified, and extracted into ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, and evaporated to a solid. The solid was triturated with isopropyl ether to give 5.0 g (6.1%) of a white solid, NMR (DMSO-d6): 7.0-8.0 (m, 5H), 8.6 (m, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:39])[N:9]([CH2:18][CH2:19][O:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([CH2:27][CH2:28][CH:29]([CH2:37][CH3:38])[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:22]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH:1]1([NH:7][C:8](=[O:39])[N:9]([CH2:18][CH2:19][O:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([CH2:27][CH2:28][CH:29]([CH2:37][CH3:38])[C:30]([OH:32])=[O:31])[CH2:22]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(CC[C@H]1CCC[C@@H](OCCN(Cc2ccc(C)cc2)C(=O)NC2CCCCC2)C1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC(CC[C@H]1CCC[C@@H](OCCN(Cc2ccc(C)cc2)C(=O)NC2CCCCC2)C1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
160 mg of tert-butyl 4-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyrate are dissolved in 16 ml of dichloromethane, and 4 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 12 hours. 50 ml of toluene are then added, and the solvents are removed under reduced pressure. The residue is purified by RP-HPLC. Freeze drying gives 123 mg of 4-(cis-3-{2-[3-cyclohexyl-1-(4-methylbenzyl)ureido]ethoxy}cyclohexyl)-2-ethylbutyric acid as a colorless oil. C29H46N2O4 (486.70), MS(ESI): 487 (M+H+).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH2:12]1[O:13][C:14]2([CH2:19][CH2:18][C:17]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=3)([OH:20])[CH2:16][CH2:15]2)[O:21][CH2:11]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
In an argon atmosphere, 20.3 g of magnesium was suspended in THF (40 mL), and a solution of 3,5-difluorobromobenzene (149 g) in THF (450 mL) was added dropwise to the resultant suspension at an inside temperature of 40 to 65° C. After stirring at room temperature for 1 hour, a solution of 1,4-cyclohexanedione monoethylene ketal (100 g) in THF (300 mL) was added dropwise at an inside temperature of 40 to 60° C., followed by stirring at room temperature for 1 hour. Then, water (250 mL), 10% hydrochloric acid (200 mL), and 750 mL of toluene were added in that order, and the mixture was stirred at room temperature for 30 minutes to separate an organic layer. The organic layer was washed with saturated brine two times, and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield 178 g of 4-(3,5-difluorophenyl)-4-hydroxycyclohexanone ethylene ketal as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:4].[F:13][C:14]1[N:19]=[C:18](F)[CH:17]=[CH:16][N:15]=1.[H-].[Na+]>CN(C=O)C>[F:13][C:14]1[N:19]=[C:18]([N:6]2[CH:5]([CH:3]([CH3:4])[C:2]([F:1])([F:11])[F:12])[CH2:9][O:8][C:7]2=[O:10])[CH:17]=[CH:16][N:15]=1
Reactant: CC(C1COC(=O)N1)C(F)(F)F
Reactant: Fc1ccnc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C1COC(=O)N1c1ccnc(F)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
A solution of 4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (270 mg, 1.474 mmol) and 2,4-difluoropyrimidine (171 mg, 1.474 mmol, 1 eq) in DMF (4 mL) was treated with NaH (60%, 88 mg, 2.212 mmol, 1.5 eq), then the resulting mixture was stirred at 0° C. for 10 minutes, then room temperature for 1 h. The reaction mixture was quenched with sat. Na2SO4 (15 mL) diluted with EtOAc (20 mL), washed and 4% aqueous NaCl (3×20 mL), dried over Na2SO4, concentrated in vacuo. Flash column chromatography (silica, 120 g, 15 m) 5% EtOAc/DCM to provide 3-(2-fluoropyrimidin-4-yl)-4-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one (100 mg, white solid). 1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J=5.8, 2.1 Hz, 1H), 8.20 (dd, J=5.8, 3.7 Hz, 1H), 5.04-4.84 (m, 1H), 4.68 (dd, J=9.5, 2.6 Hz, 1H), 4.54 (t, J=9.2 Hz, 1H), 3.34 (ddddd, J=13.3, 9.3, 7.1, 3.9, 1.6 Hz, 1H), 1.29 (d, J=7.3 Hz, 3H). MS 279.0631 m/z.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[O:11][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(O)c(Cl)c(C)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OC(=O)C(C)(C)C)c(Cl)c(C)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
To a mixture of 5.91 g of 2-chloro-3,5-dimethylbenzene-1,4-diol, 8.13 g of pyridine and 30 ml of dichloromethane, 10 ml of a dichloromethane solution containing 4.54 g of pivaloyl chloride were added dropwise under ice cooling, followed by stirring at the same temperature for one hour and at room temperature for 90 minutes. The reaction mixture was concentrated by evaporation. Water was added to the concentrate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=10/1), whereby 8.02 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1C#N.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:6](=[O:7])[NH:8][C:9]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[C:20]([F:30])([F:29])[F:19])=[CH:18]2
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CNC(=O)c1cc(N2CCOCC2)c(Cl)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2cc(Cl)c(N3CCOCC3)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
167 μl of a 1.8 M lithium diisopropylamide THF solution (0.3 mmol) was diluted with 1.5 ml of THF. Thereafter, 1 ml of a THF solution containing 27 mg (0.10 mol) of the 4-chloro-2,N-dimethyl-5-morpholin-4-ylbenzamide prepared in Step B was added dropwise to the diluted solution at −78° C. Thereafter, 1 ml of a THF solution containing 17 mg (0.10 mmol) of 2-(trifluoromethyl)benzonitrile was further added thereto, and the obtained mixture was then stirred at −78° C. for 1 hour. The temperature of the reaction solution was increased to 0° C., and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. Thereafter, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 1:1), so as to obtain 5.4 mg (13%) of 6-chloro-7-morpholin-4-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)N3CCN(C)CC3)CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(C2(CN3CCN(C)CC3)CCOCC2)cc1
Yield: 93 %

Procedure:
The title compound (428 mg, 93%) was prepared using 1-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]carbonyl}-4-methylpiperazine and lithium aluminium hydride similarly to the procedure used for example 142. HRMS ESI+ m/z 305.2220 [MH]+.
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][CH2:9][N:8]2[C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-]#N.[Na+].[C:35](O)(=[O:37])C>CO.O=[Mn]=O>[O:31]=[C:20]([N:8]1[CH2:9][CH2:10][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:18][C:19]=2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:37][CH3:35])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccccc2)cc1
Reaction time: 5 h
Yield: 70.1 %

Procedure:
To a solution of Example 9 (0.2 g, 0.49 mmol) in 20 mL of MeOH was added activated MnO2 (0.59 g, 14 equiv.), sodium cyanide (0.05 g, 2 equiv.) and acetic acid (0.05 g, 1.7 equiv.). The resulting mixture was stirred for 5 hours. Tlc monitoring showed a new compound (SiO2,DCM:MeOH (95:5), Rf=0.82). The mixture was filtered through a short column of celite using 150 mL of a mixture of MeOH:EtOAc:CHCl3 (1:25:25). After evaporation in vacuo the residue was purified via flash chromatography on a 2×20 cm2 column using DCM as eluting solvent. Evaporation and recrystallization from EtOH gave the title compound (0.15 g, 70%) as yellow crystals.
Reaction SMILES: [NH3:1].[CH:2]([NH:5][C:6]1[NH:11][C:10]2[CH:12]=[C:13]([CH2:16][C:17](OCC)=[O:18])[CH:14]=[CH:15][C:9]=2[S:8](=[O:23])(=[O:22])[N:7]=1)([CH3:4])[CH3:3].[C-]#N.[Na+]>CO>[CH:2]([NH:5][C:6]1[NH:11][C:10]2[CH:12]=[C:13]([CH2:16][C:17]([NH2:1])=[O:18])[CH:14]=[CH:15][C:9]=2[S:8](=[O:23])(=[O:22])[N:7]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)Cc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O
Reactant: N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NC1=NS(=O)(=O)c2ccc(CC(N)=O)cc2N1
Temperature: 57.5 °C

Procedure:
Ammonia gas was passed through a solution of ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.20 g) and sodium cyanide (20 mg) in 10 ml of methanol at room temperature for 5 min. The solution was heated at 55-60° C. in a sealed flask overnight. The solvent was removed in vacuo and the residue was treated with 25 ml of water. On standing, a crystalline precipitate was formed. The crystals were filtered off and dried to give the title compound; m.p. 321-325° C.
Reaction SMILES: ClC1C(F)=C(C=CC=1)CN1C2=CN=C(C(OCC)=O)C=C2C=C1.N1C2=CN=C(C(OCC)=O)C=C2C=C1.ClC1C(F)=C(C=CC=1)CBr.ClC1C(F)=C(C(F)=CC=1)CN1C2=CN=C(C(O)=O)C=C2C=C1.[Cl:70][C:71]1[C:72]([F:92])=[C:73]([C:88](F)=[CH:89][CH:90]=1)[CH2:74][N:75]1[C:79]2=[CH:80][N:81]=[C:82]([C:84]([NH:86][OH:87])=[O:85])[CH:83]=[C:78]2[CH:77]=[CH:76]1.ClC1C(F)=C(C=CC=1)CN1C2=CN=C(C(O)=O)C=C2C=C1.Cl.NO>>[Cl:70][C:71]1[C:72]([F:92])=[C:73]([CH:88]=[CH:89][CH:90]=1)[CH2:74][N:75]1[C:79]2=[CH:80][N:81]=[C:82]([C:84]([NH:86][OH:87])=[O:85])[CH:83]=[C:78]2[CH:77]=[CH:76]1
Reactant: O=C(NO)c1cc2ccn(Cc3c(F)ccc(Cl)c3F)c2cn1
Agent: CCOC(=O)c1cc2cc[nH]c2cn1
Agent: CCOC(=O)c1cc2ccn(Cc3cccc(Cl)c3F)c2cn1
Agent: Cl
Product: O=C(NO)c1cc2ccn(Cc3cccc(Cl)c3F)c2cn1

Procedure:
Ethyl 1-(3-chloro-2-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. The title compound was prepared by alkylation of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate and 3-chloro-2-fluoro-benzyl bromide in a manner similar to step (a) of example 1. 1H NMR (CDCl3) δ: 9.05 (s, 1H), 8.50 (s, 1H), 7.55 (d, 1H, J=3.0 Hz), 7.40 (m, 1H), 7.00 (m, 2H), 6.80 (d, 1H, J=3.0 Hz), 5.55 (s, 2H), 4.50 (q, 2H, J=7.0 Hz), 1.50 (t, 3H, J=7.0 Hz). LCMS (API-ES, M+H+): 333.0. (b) 1-(3-Chloro-2-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(3-chloro-2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6): δ: 8.96 (s, 1H), 8.35 (s, 1H), 7.84 (d, 1H, J=3.0 Hz), 7.56 (t, 1H, J=7.4 Hz), 7.19 (t, 1H, J=7.9 Hz), 7.09 (t, 1H, J=7.3 Hz), 5.75 (s, 2H). LCMS (API-ES, M+H+): 305.0. (c) 1-(3-Chloro-2-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(3-chloro-2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid with hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (DMSO-d6) δ: 11.16 (s, 1H), 8.95 (s, 1H), 8.85 (s, 1H), 8.23 (s, 1H), 7.79 (d, 1H, J=2.8 Hz), 7.55 (t,1H, J=7.5 Hz), 7.19 (t, 1H, J=7.5 Hz), 7.10 (t, 1H, J=7.5 Hz), 6.73 (d, 1H, J=3.0 Hz), 5.74 (s, 2H). LCMS (API-ES, M+H+): 320.0. HRMS calcd for C15H12CIFN3O2 (M+H) 320.0602, found 320.06045. HPLC: 100% purity.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7](OCC)(=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[O-]CC.[Na+]>C(O)C>[OH:5][C:3]([CH:2]([CH3:6])[CH3:1])=[CH:4][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(=O)C(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C=C(O)C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a mixture of 17.2 g of 3-methyl-2-butanone, 27.1 g of diethyl oxalate and 130 ml of ethanol was added 95 ml of sodium ethoxide (20% ethanol solution), and the resulting mixture was stirred at 60° C. for 5 hours. After allowed to cool to room temperature, a deposited precipitate was collected by filtration and washed with ethanol. The filter cake was partitioned between 2N hydrochloric acid and methyl t-butyl ether. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 28.8 g of ethyl 4-hydroxy-5-methyl-2-oxo-3-hexenoate of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[C:17]([OH:23])=[N:18][CH:19]=[CH:20][C:21]=1[OH:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([NH:15][C:16]3[C:17]([OH:23])=[N:18][CH:19]=[CH:20][C:21]=3[OH:22])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1c(O)ccnc1O
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
A mixture of 2-chloroquinoline-8-carboxylic acid (0.42 g, 2.023 mmol), 3-aminopyridine-2,4-diol (Example 179b, 0.383 g, 3.03 mmol), HATU (1.154 g, 3.03 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.083 ml, 6.07 mmol) in DMF (2.023 ml) was stirred at RT for 16 h. The mixture was diluted with EtOAc (200 ml), added to a separatory funnel, and washed with water (3×100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-chloro-N-(2,4-dihydroxypyridin-3-yl)quinoline-8-carboxamide (181b, 24% yield as a yellow solid). MS (ESI, pos. ion) m/z: 316.2 (M+1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:12][C:13]1[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH:17]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.CCOC(C)=O>[CH3:22][C:19]([CH3:23])([CH2:20][O:21][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[CH2:18][N:16]1[CH:17]=[C:13]([I:12])[CH:14]=[N:15]1
Reactant: CC(C)(CO)Cn1cc(I)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(COC1CCCCO1)Cn1cc(I)cn1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
p-Toluenesulfonic acid (44 mg, 0.26 mmol) was added to a stirring solution of 3-(4-iodopyrazol-1-yl)-2,2-dimethyl-propan-1-ol (Compound 47E, 500 mg, 1.79 mmol) in DCM (2.58 mL). The mixture was stirred under argon, chilled in an ice-bath, then dihydropyran (0.261 mL, 2.86 mmol) was added, stirred and gradually warmed to rt over 16 hrs. The reaction mixture was diluted with EtOAc and washed with brine (2×), dried over sodium sulfate, filtered and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→10% EtOAc/Heptanes] to afford 597 mg of the title compound (92%). 1H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 7.48 (s, 1H), 4.57 (t, J=3.5 Hz, 1H), 4.04-4.12 (m, 2H), 3.86 (d, J=3.0 Hz, 1H), 3.48-3.56 (m, 1H), 3.45 (d, J=9.3 Hz, 1H), 3.03 (d, J=9.6 Hz, 1H), 1.81-1.91 (m, 1H), 1.67-1.78 (m, 1H), 1.51-1.66 (m, 4H), 0.93 (d, J=4.8 Hz, 6H).