Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[C:6]([O:15][CH3:16])=[C:5]([CH2:17][CH:18]2[CH2:23][CH2:22][C:21]([CH:25](O)[CH3:26])([OH:24])[CH2:20][CH:19]2[C:28]([O:30]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.[K+].[Br-].[OH2:53]>CN(C)C1C=CN=CC=1>[OH:53][CH:25]([C:21]1([OH:24])[CH2:22][CH2:23][CH:18]2[CH:19]([C:28](=[O:30])[C:4]3[C:5]([CH2:17]2)=[C:6]([O:15][CH3:16])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH2:20]1)[CH3:26]
Reactant: O
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2c(OC)cccc12
Agent: CN(C)c1ccncc1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1c2c(c(OC)c3c(OC)cccc13)CC1CCC(O)(C(C)O)CC1C2=O
Yield: 49 %

Procedure:
0.48 g of 1-(1,4,5-trimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane, prepared as described in Example 5, was treated with acetic anhydride and pyridine in the presence of 4-dimethylamino-pyridine. After a night at room temperature the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The crude product was dissolved in methanol and refluxed with cyclohexene in the presence of 10% by weight palladium-on-carbon. The catalyst was then filtered off and the solution, concentrated to a small volume, was treated at 0° C. for 60 minutes with trifluoroacetic anhydride and trifluoroacetic acid. Then the solution was diluted with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and with water, dried and concentrated to dryness under vacuum. The residue was dissolved in methanol in the presence of catalytic amount of sodium methylate. After conventional work-up and purification by chromatography 0.18 g of the title compound was obtained (yield 49%): m/z 400 (M+.); IR (KBr): 3450 cm-1 (OH), 1675 cm-1 (C=O benzylic ketone); PMR (CDCl3): inter alia δ (1.2 (d, CH3 --CH), 3.7-3.9 (s, three OCH3) and 6.4-8.0 (m, three aromatic hydrogen).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[I:22]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[C:5]([I:22])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2ccnc(O)c2c1
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(I)cnc(O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a mixture of methyl 1-hydroxyisoquinoline-7-carboxylate (1.0 g) and pyridine (40 mL) was added iodine (1.2 g), and stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and a 5% aqueous sodium thiosulfate solution. Then, the precipitate was collected by filtration to obtain methyl 1-hydroxy-4-iodoisoquinoline-7-carboxylate (1.1 g).
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: C=CN=C=O
Reactant: OC1CCCCC1
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are introduced into a reaction vessel and heated to 40° C. A mixture of 110 parts of cyclohexanol and 89.5 parts of ethyl acetate (containing 0.02% of dibutyl-tin dilaurate as catalyst) is added in the course of 1 hour. The mixture is then allowed to react for 2 hours at 40° C. A pale yellow solution is obtained, from which the reaction product crystallizes out on cooling. Blocked isocyanate content: 11.7%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH3:18])=[CH:13][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][C:21]1[S:22][CH2:23][CH2:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH3:18])=[CH:13][C:14]=1[C:15]([N:25]1[CH2:24][CH2:23][S:22][C:21]1=[S:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)[nH]1
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(=O)[nH]1
Reaction time: 1 h
Yield: 49.7 %

Procedure:
3-benzyloxy-4-carboxy-6-methyl-2(1H)-pyridinone (5.39 g, 21.1 mmol) was dissolved in dry THF (200 ml). Then 2-mercaptothiazoline (2.71 g, 23.2 mmol) and DMAP (0.25 g, 2.0 mmol) were added and the solution stirred under an atmosphere of N2 for 1 h. Then dicyclohexylcarbodiimide (DCC, 5.12 g, 25.3 mmol) was added in small portions at intervals split over 3 hrs. The reaction was left to stir for 16 h, and then left to stand at 0° C. for a further 24 h. The dicyclohexylurea (DCU) was removed by filtration, and the solvents removed. The remaining residue was dissolved in CH2Cl2, filtered and purified by a gradient flash silica column (2-6% CH3OH in CH2Cl2). The solvents were removed from the appropriate fractions by rotary evaporation, and the residue recrystallized from acetone, yielding yellow crystals (3.78 g, 56%). 1H NMR (CDCl3, 300 MHz): δ=7.32-7.47 (m, 5H, aromatic Bn), 5.98 (s, 1H, CH), 5.34 (s, 2H, Bn CH2), 4.34 (t, J=7.3 Hz, 2H, CH2), 2.92 (t, J=7.3 Hz, 2H, CH2), 2.34 (s, 3H, CH3) ppm. Anal. Calcd (Found) for C17H16N2O3S2: C, 56.65 (56.50); H, 4.47 (4.51); N, 7.77 (7.70). FAB-MS (+): m/z: 361[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.CN(C=O)C.[H-].[Na+].Cl.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccnc2c1ccn2Cc1ccncc1
Temperature: -15 °C
Reaction time: 0.42 h

Procedure:
A 250-mL argon-purged round-bottomed flask equipped with a magnetic stirrer is charged with 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.70 g, 3.55 mmol) and DMF (25 mL) and the solution is cooled to −15° C. A 60% dispersion of sodium hydride in mineral oil (183 mg, 4.58 mmol) is then added and the reaction stirred at −15° C. for 25 min. The reaction is then charged with 4-picolylchloride hydrochloride (376 mg, 2.29 mmol) and stirred at −15° C. for a further 5 min. After such time the cooling bath is removed and the reaction is stirred for 30 min at ambient temperature. Additional 4-picolylchloride hydrochloride (117 mg, 0.71 mmol) and a 60% dispersion of sodium hydride in mineral oil (28 mg, 0.71 mmol) are then added and the reaction is stirred at ambient temperature for a further 30 min. The reaction is then poured into ethyl acetate (100 mL) and the mixture is washed with 3% aqueous sodium bicarbonate (1×100 mL), water (2×100 mL) and brine (1×100 mL). The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to provide a residue, which is then purified by flash chromatography to afford 1b as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]([OH:21])([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:6]([CH3:24])[CH:5]=1.I[CH3:26]>O1CCOCC1>[Cl:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C:10]([O:21][CH3:26])([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:6]([CH3:24])[CH:5]=1
Reactant: Cc1cc(Cl)ccc1OCC(O)(Cn1cncn1)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(COc1ccc(Cl)cc1C)(Cn1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.3 %

Procedure:
27 g (0.9 mol) of 80% strength sodium hydride were introduced in portions into a solution of 290 g (0.86 mol) of 2-(4-chloro-2-methyl-phenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol in 1,600 ml of absolute dioxane at room temperature. The mixture was subsequently stirred at room temperature for 4 hours, and 141.9 g (1 mol) of iodomethane were then added dropwise. The reaction mixture was stirred at 40° C. for 12 hours and another 10 g (0.33 mol) of 80% strength sodium hydride were then added in portions. After the mixture hadbeen stirred at room temperature for three hours, 57 g (0.4 mol) of iodomethane were added and the reaction mixture was subsequently stirred at room temperature for 72 hours. The suspension was filtered, the filtrate was concentrated, the oily residue was taken up in methylene chloride and the methylene chloride mixture was washed twice with water, dried over sodium sulphate and concentrated. 1,5-Naphthalenedisulphonic acid was added to the residue, in acetone, the salt which precipitated wasfiltered off with suction, washed with acetone and suspended in methylene chloride, and saturated sodium bicarbonate solution was added. The organicphase was separated off, washed and concentrated. 155 g (54% of theory) of 2-(4-chloro-2-methyl-phenoxymethyl)-3,3-dimethyl-2-methoxy- 1-(1,2,4-triazol-1-yl)butane were obtained as a light yellow oil of refractive index nD20 =1.5390.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([O:53][CH3:54])[C:39]=1[OH:55]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([O:53][CH3:54])[C:39]([OH:55])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 17.8 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (17 mg, 18% over 2 steps) as a orange-yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.38 (s, 1H), 8.31 (dd, J=8.8, 1.9 Hz, 1H), 8.25 (m, 2H), 8.05 (d, J=8.8 Hz, 1H), 7.89 (dd, J=9.3, 2.6 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.06 (dd, J=9.3, 0.8 Hz, 1H), 6.90 (s, 1H), 4.15 (dt, J=11.2, 5.7 Hz, 1H), 4.04 (dd, J=11.9, 6.5 Hz, 1H), 3.94 (s, 3H), 3.86 (m, 1H), 3.76 (m, 2H), 2.83 (dt, J=12.1, 6.3 Hz, 1H), 2.60 (dt, J=21.4, 6.6 Hz, 1H), 2.31 (td, J=13.4, 5.7 Hz, 1H), 1.21 (m, 4H); ESI MS m/z 529 [C29H28ClN5O3+H]+; HPLC 99.6% (AUC), tR=9.97 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.C([CH:22]1[CH2:25][NH:24][C:23]1=[O:26])(=O)C1C=CC=CC=1>CCCCCC.C1COCC1>[C:3]1([C:1]#[C:2][CH:22]2[CH2:25][NH:24][C:23]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1NCC1C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NCC1C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 500 mL, three necked round bottomed flash with a stirring bar, low temperature thermometer, argon inlet and a septum was added dry THF (100 mL) and ethynylbenzene (60 mmol, 6.1 mL). This solution was cooled to -78° C. and n-butyllithium (60 mmol, 24 mL of a 2.5M solution in hexane) was added with a syringe at such a rate that the temperature was maintained below -50° C. When the addition was complete, the solution was aged 30 min then a solution of 3(R,S)-benzoylazetidinone (15 mmol, 2.87 g) in THF (50 mL) was added slowly with a syringe, maintaining the temperature below -60° C. The resulting solution was aged 1 h at -78° C. then warmed to 0°C. The reaction was quenched at 0°C. by addition of saturated, aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvents in vacuo gave 3(R,S)-phenylethynylazetidinone (15-2) as a crystalline solid, which was used in Step B without further purification. ##STR139##
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([NH:8][C:9](=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:15]#[N:16].[ClH:17].[OH-:18].[Na+]>>[ClH:17].[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]2[C:3]=1[C:15](=[O:18])[NH:16][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[N:8]2
Reactant: CC(C)CC(=O)Nc1nn(C)c(N)c1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)Cc1nc2nn(C)c(N)c2c(=O)[nH]1

Procedure:
5-Amino-4-cyano-1-methyl-3-(3-methylbutanoylamino)pyrazole (10 g), prepared as in Example 27 was heated with 1 M sodium hydroxide solution (90 ml) for 2 hours. The solution was adjusted to pH=7 with concentrated hydrochloric acid, and was evaporated to dryness. The residue was extracted with acetone containing 5% water (100 ml). The extracts were evaporated, and the residue was dissolved in a minimum of hot ethanol. Then the solution was cooled and a precipitate which formed was filtered off. The filtrate was mixed with concentrate hydrochloric acid (5 ml) and the precipitate was recrystallised from water to give the title compound, m.p. 292°-294° C. decomp.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH2:30])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].[C:44](Cl)(=[O:46])[CH3:45].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH:30][C:44]([CH3:45])=[O:46])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:16][CH2:17]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To 2 mL of a chloroform solution containing 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 14 mg of triethylamine and 11 mg of acetyl chloride were added, and stirred at room temperature for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-acetamino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][OH:27])[CH:23]([CH3:24])[CH:22]([CH3:25])[O:21]2)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]([CH3:24])[CH:22]([CH3:25])[O:21]2)=[CH:18][CH:19]=1
Reactant: CC1OC(CO)(c2ccc(Cl)cc2)C1C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1OC(COS(C)(=O)=O)(c2ccc(Cl)cc2)C1C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
0.13 ml (1.68 mmole) of methanesulfonyl chloride, followed by 0.24 ml (1.708 mmole) of triethylamine were added at 0° C. to a solution of 123 mg (0.543 mmole) of 2-(4-chlorophenyl)-3,4-dimethyl-2-hydroxymethyloxetane in 10 ml of methylene chloride, and the resulting mixture was stirred for 4 hours, during which time the reaction temperature was allowed to rise to room temperature. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, eluted with a 10:1 by volume mixture of hexane and ethyl acetate, to afford 107 mg (yield 65%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=[O:8].[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:12]([C:3]1([C:7]([OH:9])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: O=C(O)C1CCCC1=O
Product: C=CCC1(C(=O)O)CCCC1=O

Procedure:
A lower alkyl ester of 2-oxocyclopentanecarboxylic acid is alkylated with allyl bromide to yield the lower alkyl ester of 1-(2-propenyl)-2-oxocyclopentanecarboxylic acid. Treatment with anhydrous ammonia yields the ester of 5-carboxy-oct-7-enoic acid amide. Treatment with thionyl chloride yields the ester of 5-carboxy-oct-7-enenitrile. The ester is reduced, e.g. with sodium borohydride to the corresponding alcohol. A reactive ester thereof, e.g. the methanesulfonyl ester is reacted with a diester of malonic acid and the resulting malonate ester is decarboxylated to yield the ester of 4-(3-cyanopropyl)-6-heptenoic acid which is then reacted with 3-bromopyridine under conditions of the Heck reaction to obtain the ester of 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoic acid which is hydrogenated under conditions known in the art, e.g. in ethanolic ammonia with rhodium on carbon catalyst, to the ester of 8-amino-4-[3-(3-pyridyl)-propyl]-octanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 7.25 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride, prepared using substantially the procedure of Step A of Example 1 from the corresponding acid, in 20 ml of acetonitrile was added to solution of 1.43 g (7.25 mmol) of 4-aminobenzotrifluoride, hydrochloride and 1.83 g (18.1 mmol) of triethylamine in 10 ml of acetonitrile. The reaction mixture was warmed at reflux for a period of 4 hours and then poured over crushed ice. The resulting precipitate was collected by filtration and then recrystallized from acetonitrile to give 2.40 g (68 percent of theoretical) of the above-named product as a tan solid which melted at 176°-178° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 5)
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: [Br-]
Reactant: CC(C)(C)c1ccccc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)ccc1N
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 2-tert-butylaniline (50 g, 335 mmol) in THF (500 mL) was added tetrabutylammonium tribromide (234.5 g, 335 mmol) at 0° C. After the solution was stirred for 30 minutes at that temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated Na2S2O3 solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=100:0 to 20:80) to provide 4-bromo-2-tert-butylaniline (74.6 g, 98%) as a pink oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:26]1[NH:25][CH:24]=[C:23]2[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=12)(=[O:5])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: CC1C=CC(CN)=CC=1.[CH3:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][NH:16][C:17]2[C:18]([NH2:32])=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH:22]=2)=[CH:13][CH:12]=1.[CH3:35][C:36]1([CH3:44])[C@@H:41]2[C@H:37]1[C:38](=[O:43])[O:39][C:40]2=O>>[CH3:35][C:36]1([CH3:44])[C@H:41]([C:40]2[N:16]([CH2:15][C:14]3[CH:13]=[CH:12][C:11]([CH3:10])=[CH:34][CH:33]=3)[C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=[CH:19][C:18]=3[N:32]=2)[C@@H:37]1[C:38]([OH:43])=[O:39]
Reactant: Cc1ccc(CNc2cc(OCc3ccc(C)cn3)ccc2N)cc1
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c([C@@H]3[C@H](C(=O)O)C3(C)C)nc3ccc(OCc4ccc(C)cn4)cc32)cc1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using p-tolylmethanamine in Step A then for Intermediate I using N1-(4-methylbenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione followed by the hydrolysis according to Example Example 111. MS (ESI): mass calcd. for C28H29N3O3, 455.22; m/z found, 456.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.58 (d, J=8.9, 1H), 7.54-7.48 (m, 1H), 7.40 (d, J=7.9, 1H), 7.13 (d, J=7.9, 2H), 7.04 (dd, J=8.8, 2.3, 1H), 6.98-6.87 (m, 3H), 5.31 (d, J=16.5, 1H), 5.24 (d, J=16.6, 1H), 5.18 (s, 2H), 2.34 (s, 6H), 2.28 (d, J=8.2, 1H), 2.07 (d, J=8.2, 1H), 1.21 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN1CCCC1=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccccc1S
Reactant: COc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Sc2ccccc2C(=O)O)cc1
Temperature: 165 °C

Procedure:
First, 2-(4-methoxyphenylthio)benzoic acid was prepared. A stirred mixture of thiosalicylic acid (10.0 g, 65 mmol), 4-iodoanisole (15.18 g, 65 mmol), potassium carbonate (19.72 g, 143 mmol), copper powder (0.82 g, 13 mmol), and N-methylpyrrolidinone (100 mL) was deaerated by sparging with nitrogen for 10 min, heated at 165° C. for 18 h, and then cooled to ambient. The reaction mixture was poured onto a mixture of 500 g of ice plus 40 mL or concentrated HCl. The resulting precipitate was collected, washed with water, and dried. The product was purified by recrystallization from a mixture of water, ethanol, and tetrahydrofuran. A white powder was obtained, mass: 12.06 g (71% of theory).