Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Cl[C:15]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:15]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCCC2CC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Tert-butyl 2-(pyrrolidin-2-yl)acetate (1.00 g, 5.40 mmol) was added to a solution of methyl 6-chloro-5-nitronicotinate (1.169 g, 5.40 mmol) in THF (Volume: 10 ml). The reaction mixture was stirred at rt for 1 h and K2CO3 (0.760 g, 5.50 mmol) was added. The reaction mixture was stirred for 2 h and triethylamine (0.379 ml, 2.70 mmol) was added. The mixture was stirred for 1 h, filtered and concentrated in vacuo. Flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 9:1) afforded methyl 6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate (1.79 g, 4.90 mmol, 91% yield) as a yellow oil. [M+H] calc'd for C17H23N3O6, 365; found, 365.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[Si]([O:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])(C(C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH2:28][CH2:27][OH:26])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1Cl
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Product: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)N(CCO)c1ccccc1Cl
Yield: 25 %

Procedure:
Following Example 16, 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid was converted to the acid chloride and reacted with N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloroaniline. Desilylation gave 233 (yield 25%). MS: (ESI+)
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.B1([O-])O[O:25]1.O.O.O.O.[Na+]>C(O)(=O)C>[CH3:1][S:2]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)=[O:25]
Reactant: [O-]B1OO1
Reactant: CSCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
1-[1-(2-Methylthio-ethyl)-1H-benzimidazol-2-ylmethyl]-1 H-benzotriazole (100 mg, 0.31 mmol) was dissolved in acetic acid (5 mL). Sodium perborate tetrahydrate (52 mg, 0.34 mmol) was added. The reaction mixture was stirred at 50° C. under nitrogen overnight. The acetic acid was evaporated under reduced pressure. Column chromatography (EtOAc, then EtOAc:MeOH=4:1) gave 84 mg (80%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].I[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:21][CH3:22])[CH:17]=1)=[O:11]
Reactant: CC(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Reactant: CCI
Product: CCn1cc(C(=O)C(C)c2ccc(Cl)cc2Cl)ccc1=O

Procedure:
In analogy to Example 195, 5-[2-(2,4-dichloro-phenyl)-propionyl]-1H-pyridin-2-one (Example 201, step 4) was alkylated with iodoethane to give the title compound as a colorless oil. MS (m/e)=324.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(C(F)(F)F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-trifluoromethyl-phenylboronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-amine. LC-MS m/e 369(MH+).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=O.[C:14]([OH:33])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=C\CCCCCCCC>>[C:14]([OH:33])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12]
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O

Procedure:
Another preferred embodiment of the invention is based on the preparation of azelaic acid by biooxidation of oleic acid to form 9-octadecenedioic acid followed by oxidation of the 9-octadecenedioic acid to azelaic acid. While any grade of oleic acid can be used as the substrate, a typical technical grade oleic acid consists of the following carboxylic acids: 0.42% C12; 2.7% C14; 0.86% C14:1; 6.3% C16; 4.6% C16:1; 0.93% C17; 2.8% C18; 71.8% C18:1; 8.3% C18:2; 0.58% C18:3. The oleic acid can also be a high grade oleic acid obtained from a fatty oil of a Helianthus annuus (sunflower seed oil) species described, for example, in U.S. Pat. No. 4,627,192, the entire contents of which are incorporated herein by reference. Such oils are very rich in oleic acid and contain at least 80% by weight of oleic.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][N:2]([CH2:3][CH2:4][OH:5])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CNCCO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCO)c1ncccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
2-(Methylamino)ethanol (3.04 ml) is added to a mixture of 2-chloro-3-nitropyridine (3.00 g) and of potassium carbonate (5.22 g) in acetonitrile (90 ml) at 0°. The mixture is stirred for 2.5 hr at 20°-25° and additional 2-(methylamino)ethanol (1.5 ml) is added. The mixture is stirred for 1.5 hr, concentrated to a gum and diluted with methylene chloride (85 ml) and water (20 ml). The layers are separated and the organic phase is washed with water and dried over magnesium sulfate. Removal of solvent under reduced pressure gives the title compound, NMR (CDCl3) 8.27, 8.14, 6.76, 4.38, 3.88 and 2.87δ.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of acetophenone (64 ml), p-anisidine (65 mg), benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(αmethyl-benzylidene)-p-anisidine (VII) (50 g). VII had a melting point of 81°-82° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]>O1CCCC1.[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(F)cc(C=CC(=O)O)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(F)cc(CCC(=O)O)cc1F

Procedure:
A solution of 3-(3,5-difluoro-4-methoxyphenyl)propenoic acid (0.078 mol) in tetrahydrofuran (100 ml) and a slurry of 10% palladium on carbon (2 g) in ethyl acetate were reacted substantially as described in Example 7C above to obtain 16.7 g (99%), white crystals: mp 72°-73°.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(NCCN(C)C)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CCC(c1nc2c(c(=O)n1Cc1ccccc1)CCC2)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-4, 0.070 g, 0.20 mmol) was dissolved in CH2Cl2 (1.0 mL) and treated successively with 4-bromo-benzoylchloride (0.052 g, 0.24 mmol) and TEA (0.08 mL, 0.59 mmol). The reaction was stirred at 25° C. for 1 hour. The reaction was diluted with CH2Cl2 (10 mL), washed with 5% NaHCO3 and dried over MgSO4. The organics were concentrated under reduced pressure and subjected to preparative thin layer chromatography (SiO2, 5% MeOH/CH2Cl2) to provide N-[1-(3-benzyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidin-2-yl) propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5). 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.2 Hz, 2H), 7.31 (m, 5H), 12 (d, J=8.0 Hz, 2H), 5.98 (d, J=15.6 Hz, 1H), 5.85 (m, 1H), 4.99 (d, J=15.8 Hz, 1H), 3.36 (m, 2H), 2.90 (m, 4H), 2.10 (m, 4 H), 1.87 (s, 6H), 1.80 (m, 1H), 1.63 (m, 1H), 0.62 (m, 3H); MS 537.2 found, 537.5 required.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:16]2[CH:17]=[CH:18][O:19][C:15]=2[C:14]([Cl:20])=[CH:13][CH:12]=1>C(#N)C>[Cl:20][C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[O:5])=[C:16]2[C:15]=1[O:19][CH:18]=[CH:17]2
Reactant: Clc1ccc(CBr)c2ccoc12
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of the N-methylmorpholine-N-oxide (37.64 g) in aoetonitrile (370 ml) containing 3 Å molecular sieves (36.6 g) was stirred at room temperature overnight and cooled in ice. A solution of 4-bromomethyl-7-chloro-benzofuran (39.44 g) in acetonitrile (90 ml) was added and the mixture stirred in at 0° C. for 4 h. The mixture was filtered and the filtrate evaporated to dryness. Water and ethyl acetate were added to the residue and the organic phase separated, dried (Na2SO4) and evaporated to give the title compound (21.3 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:24][CH2:25]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 18.6 g of p-methylbenzoyl chloride in 30 ml of methylene chloride is added dropwise, over a period of 15 minutes, to a solution, stirred at room temperature, of 22.4 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 12.1 g of triethylamine in 200 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature. The reaction solution is diluted with 100 ml of methylene chloride, washed with 2N NaOH and with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised twice from alcohol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-methylbenzoyl)-piperazine having a melting point of 105°-106° is thus obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26]([NH2:28])[CH3:27]>C1(C)C=CC=CC=1>[CH2:26]([NH:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:27]
Reactant: BrCCCCOC1=C(c2ccccc2)CCCC1=Cc1ccccc1
Reactant: CCN
Solvent: Cc1ccccc1
Product: CCNCCCCOC1=C(c2ccccc2)CCCC1=Cc1ccccc1
Reaction time: 24 h

Procedure:
1-Bromo-4-[[2-phenyl-6-(phenylmethylene)-1-cyclohexen-1-yl]oxy]butane is dissolved in toluene, treated with two equivalents of ethyl amine and allowed to stand at room temperature for 1 day, and washed with potassium carbonate solution. Evaporation of the toluene yields the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 2,3-dimethylphenylboronic acid (0.333 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.557 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 16 h to give 4-chloro-2-(2,3-dimethylphenyl)-5,7-difluoro-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=318.1 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:16][C@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[N:1]1([C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:7]=2[C:8]([N:19]2[CH2:20][CH2:21][CH2:22][C@H:17]([CH3:16])[C@@H:18]2[CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=2)=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2ccnc2)c(C(=O)O)c1
Product: Cc1ccc(-n2ccnc2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 2-(1H-imidazol-1-yl)-5-methylbenzoic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 458, [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:10]=[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=1
Reactant: C=C(C)C=O
Reactant: Cc1cc(C)cc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)c1
Product: Cc1cc(C)cc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,5-dimethylphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly brown powder (yield 28%), melting at 163-166° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C(C)=O)cc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2cc(C(C)=O)ccc2o1
Yield: 40 %

Procedure:
To a mixture of 5-acetyl-2-(methoxycarbonyl) methoxybenzaldehyde (4.47 g) in toluene, a solution of 1,8-diazabicyclo[5.4.0]-7-undecene (1.30 g) in toluene (8 ml) was added dropwise for 15 hours at refluxing temperature. After being cooled, the resulting mixture was washed with water, dried lover magnesium sulfate and concentrated under reduced pressure. The resulting precipitates were washed with diethyl ether to give 5-acetyl-2-methoxycarbonylbenzofuran (1.65 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:11][C:10](=[O:12])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([CH3:14])[CH3:13])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC(C)(OCc1ccccc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 78.8 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 705 mg of 2-benzyloxy-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.04 g of the title compound as white crystals, melting at between 135° and 136° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[CH:30]1([C:34]2[N:35]=[C:36]([NH2:39])[S:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:27][C:25]([CH3:26])([CH3:28])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:1])[F:29])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:39][C:36]1[S:37][CH:38]=[C:34]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[N:35]=1)=[O:21])[CH:17]=[CH:16][S:15]2
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc(C2CCC2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C3CCC3)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 4-(cyclobutyl)-1,3-thiazol-2-amine (40 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol), DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 50 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 1.84-1.90 (m, 2H), 1.95-2.05 (m, 1H), 2.15-2.30 (m, 4H), 3.58 (s, 2H), 6.73 (s, 1H), 7.18 (t, J=75.0 Hz, 1H), 7.20-7.30 (m, 2H), 7.38-7.44 (m, 1H), 7.66-7.72 (m, 1H), 7.83 (d, J=16.2 Hz, 1H), 8.10-8.18 (m, 1H), 8.62-8.68 (m, 1H), 12.87 (br s, 1H); ESI-MS (m/z) 559.22 (MH)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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>[CH3:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:17]([F:24])=[CH:18][C:19]([F:23])=[CH:20][C:21]=2[F:22])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Reactant: CB1OB(C)OB(C)O1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)O)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (160 mg), trimethylboroxin (117 mg), tetrakis(triphenylphosphine)palladium (23 mg), 2M aqueous sodium carbonate solution (1 mL), and 1,4-dioxane (5 mL) was heated under stirring in an oil bath at 100° C. for 4 hours. The reaction mixture was returned to room temperature and diluted with ethyl acetate, and then the insoluble materials were separated by filtration through Celite. The filtrate was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain 4-methyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylic acid (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:18][O:15][CH2:16]2)[CH2:10][CH2:9]1
Reactant: Fc1cncc(Cl)c1N1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1cncc(Cl)c1N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-(3-chloro-5-fluoropyridin-4-yl)piperazine (900 mg, 4.173 mmol) in THF (9.000 mL) was added 3-oxetanone (601.4 mg, 8.346 mmol). To this mixture, under N2, was added sodium triacetoxyborohydride (2.034 g, 9.598 mmol) portionwise over 5 min and the reaction mixture was stirred at RT overnight. MeOH (2 ml) was added to the flask before the mixture was concentrated in vacuo. The residue was partitioned between water (50 ml) and EtAOc (50 ml). The aqueous phase was basified to pH 7-8 with NH4OH. Combined organics washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(3-chloro-5-fluoro-4-pyridyl)-4-(oxetan-3-yl)piperazine as a cream solid that was used in next step without further purification. MS (ES+) 272.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[O:9][C:10]([C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=O)=[CH:5][CH:4]=1.[NH3:21]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[NH:21][C:10](=[O:9])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(Cc2cc3ccccc3c(=O)o2)cc1
Product: COc1ccc(Cc2cc3ccccc3c(=O)[nH]2)cc1
Temperature: 150 °C
Yield: 12 %

Procedure:
A stirred suspension of 3-(4-methoxybenzyl)isocoumarin (0.35 g, 1.3 mmol) in 15% methanolic ammonia solution (100 ml) was heated at 150° C. in a 300 ml autoclave for 5 hours then cooled to ambient temperature. The resulting solid was collected by filtration, washed with a little cold methanol and dried in vacuo to give 3-(4-methoxybenzyl)-1-isoquinolinone (0.04 g, 12%) as a solid; m.pt. 216-218° C.; δH 3.80 (3H, s), 3.85 (2H, s), 6.25 (1H, s), 6.90 (2H, d, J=8.2 Hz), 7.30 (2H, d), 7.30-7.60 (3H, m), 8.20 (1H, d), 11.20 (1H, br s); m/z (M+H)+. 266 (100% purity).