Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:6]([C:17]([C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:18])[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([C:17]([C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:18])[CH:5]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C(=O)c1cnn(-c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCC(=O)O)c(C(=O)c2cnn(-c3ccccc3)c2)c1
Reaction time: 12 h

Procedure:
A mixture of ethyl 4-nitro-2-(phenyl-1H-pyrazole-4-carbonyl)phenoxyacetate (190 mg, 0.48 mmol) and 10% Pd/C (100 mg) in MeOH (50 mL) was stirred under an atmosphere of hydrogen of 12 h, then filtered through a pad of celite and concentrated, and the product was hydrolyzed according to GP3 to give the title compound.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[F:26][C:27]([F:34])([F:33])[C@@H:28]([OH:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@H:28]([OH:32])[C:27]([F:34])([F:33])[F:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)[C@H](O)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)[C@H](O)C(F)(F)F

Procedure:
The title compound, white solid (14.7 mg, 47.3%), MS (ISP) m/z=457.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and (S)-3,3,3-trifluoro-2-hydroxypropanoic acid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.Cl[C:35]([O:37][C:38]1[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=1[CH3:46])=[O:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[NH:24][C:35](=[O:36])[O:37][C:38]4[C:43]([CH3:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=4[CH3:46])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Reactant: NC1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(OC(=O)NC2CC2c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Reaction time: 0.08 h
Yield: 79 %

Procedure:
2-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]phenyl}cyclopropylamine (46.0 mg, 0.13 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.55 mL) under N2. 4-Dimethylaminopyridine (DMAP; 0.8 mg, 0.006 mmol, 0.05 equiv) and Et3N (27 μL, 0.19 mmol, 1.5 equiv) were added, followed by mesityl chloroformate prepared above (33 mg, 0.17 mmol, 1.2 equiv). The reaction was stirred for 5 min and was then quenched with NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The combined organic extracts were concentrated, and the crude product was purified by silica gel chromatography (EtOAc-hexanes gradient) to afford the title compound as a white solid (53.0 mg, 79%): mp 199-202° C.; 1H NMR (400 MHz, CDCl3, data for major rotamer) δ 8.54 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=0.7 Hz, 2H), 7.32-7.21 (m, 2H), 6.86 (s, 2H), 5.71-5.36 (m, 0.7H), 5.22-4.82 (m, 0.3H), 3.09-2.81 (m, 1H), 2.26 (s, 4H), 2.17 (s, 6H), 1.43-1.26 (m, 2H); ESIMS m/z 523 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[O:20]=[C:21]1[NH:26][C:25](=[O:27])[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][NH:22]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:22]2[CH:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:25](=[O:27])[NH:26][C:21]2=[O:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1c[nH]c(=O)[nH]c1=O
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Product: CCOC(=O)c1cn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)[nH]c1=O

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate. M/e+ 425 for C21H18ClN4O4 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.32 (d, J=6.9 Hz, 1H), 7.67 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H), 6.93 (t, J=6.96 Hz, 1H), 5.49 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.16 (t, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH:2][CH3:1])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCBr
Reactant: CN
Solvent: C1CCOC1
Product: CNCCc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl amine in THF (2 M, 200 mL) was added 1-(2-bromo-ethyl)-4-chloro-2-nitro-benzene (17.5 g, 0.066 mole) in a pressure bottle, the reaction mixture was stirred at 60° C. overnight and the solvent was removed. The solid residue was treated with sodium hydroxide (1 N, 100 mL) and the aqueous extracted with methylene chloride (2×100 mL). The combined organic layers were washed with water (100 mL), saturated sodium chloride (100 mL), dried (sodium sulfate) and concentrated to provide 14.9 g of the title compound as a brown oil. 1H NMR (DMSO-d6): 7.95 δ (d, 1H); 7.67 δ (dd, 1H); 7.50 δ (t, 1H); 3.28 δ (broad, 1H); 2.85 δ (t, 2H); 2.64 δ (t, 2H); 2.20 δ (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2].O=S(Cl)Cl.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:18](=[O:20])[NH:50][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])[CH2:8][C@@H:7]1[CH3:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(C(=O)O)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(C(=O)NCCN(C)C)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 1.5 h

Procedure:
A mixture of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,6-dicarboxylic acid 1-ethyl ester (Example 60) (75 mg, 1.26 mmol) and 1.5 ml SOCl2 was heated at reflux for 1.5 h. The cooled solution was evaporated to dryness and the residue dried under high vacuum for 30 min. The residue was diluted with 0.75 ml dichloromethane, and triethylamine (0.021 ml) and N,N-dimethyl ethylenediamine (11 mg, 1.26 mmol) were added sequentially. After 1.5 h, the reaction mixture was concentrated and the residue was chromatographed (5% MeOH-dichloromethane) to afford the desired product (72 mg (86%). MS m/z 663 (M++1); 1H NMR (CDCl3) δ 3.75 (s, 3H), 7.22 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:34]O)=[CH:17][CH:16]=1.S(Cl)(Cl)=O.[C:40]([O:43][CH2:44][CH3:45])(=[O:42])[CH3:41]>>[CH2:44]([O:43][C:40]([CH:41]([CH2:34][C:24]1[N:25]=[C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:27][C:23]=1[CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:20][CH:19]=1)[C:40]([O:43][CH2:44][CH3:45])=[O:42])=[O:42])[CH3:45]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCc2oc(-c3ccccc3)nc2CO)cc1
Reactant: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(Cc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A mixture of (5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-2-phenyl-1,3-oxazol-4-yl)methanol (0.78 g) and thionyl chloride (2 mL) was stirred at 0° C. for 30 min. After concentration of the reaction mixture, ethyl acetate was poured into the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a solution of the obtained residue in tetrahydrofuran (10 mL) was added a mixture of diethyl malonate (1.36 g), sodium hydride (60% in oil, 0.33 g) and tetrahydrofuran (30 mL) at 0° C. After stirring at room temperature for 15 hr, the mixture was refluxed for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 2-ethoxycarbonyl-3-(5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-2-phenyl-1,3-oxazol-4-yl)propionate (0.55 g, yield 53%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[NH2:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[OH:13][S:12]([NH:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[C:22]([S:19]([NH2:18])(=[O:21])=[O:20])[CH:23]=[CH:24][CH:25]=3)[CH:3]=2)[CH2:7]1)([OH:14])[CH:15]([CH3:17])[CH3:16]
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Product: CC(C)S(O)(O)NC1Cc2ccc(-c3cccc(S(N)(=O)=O)c3)cc2C1

Procedure:
The title compound was prepared from N-(5-iodo-2,3-dihydro-1H-inden-2-yl)-2-propanesulfonamide and [3-(aminosulfonyl)phenyl]boronic acid (WO2003004472) in a similar manner to Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH:10]=2)[C:5]([F:28])=[CH:4][N:3]=1.[OH:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>>[CH2:26]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][N:17]([C:15]([C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([OH:29])[CH:31]=4)[N:7]=3)[CH:14]=[CH:13][CH:12]=2)=[O:16])[CH2:18][CH2:19]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Cl)ncc3F)c2)CC1
Reactant: Nc1cccc(O)c1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Nc4cccc(O)c4)ncc3F)c2)CC1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to provide N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.93 (d, 1H, J=3.6 Hz), 7.89 (t, 1H, J=1.8 Hz), 7.83 (td, 1H, J=1.2 and 8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.11-6.95 (m, 4H), 6.41 (td, 1H, J=1.8 and 7.2 Hz), 4.44 (bd, 1H, J=12.9 Hz), 4.10 (q, 2H, J=7.2 Hz), 3.73 (bd, 1H, J=12.3 Hz), 3.18-2.98 (m, 2H), 2.67-2.55 (m, 1H), 2.05-1.53 (m, 4H), 1.23 (t, 3H, J=7.2 Hz); 19F NMR (282 MHz, CD3OD): −47483; LCMS: purity: 99%; MS (m/e): 480 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:34][CH2:35]I>>[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:35][Cl:34])=[O:14]
Reactant: ClCI
Reactant: O=C([O-])CCCC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: O=C(CCCC(=O)OCc1ccccc1)OCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of 1.5 g (3.75 mmole) tetrabutylammonium benzyl glutarate and 20 ml chloroiodomethane is stirred at room temperature for three hours and concentrated in vacuo to a viscous oil. The oil is taken up in 20 ml ethyl acetate and 30 ml hexane and filtered to remove tetrabutylammonium iodide. The solvent is evaporated in vacuo and the residue purified by chromatography on 75 g silica gel, eluting with 70:30 ethyl acetate/hexane by volume. Fractions (15 ml) were collected every 0.7 minutes. The fractions containing the desired product (fractions 8-11) are combined and the solvent evaporated in vacuo to yield 0.55 g (62.5%) of the desired product. 1H-NMR (CDCl3) ppm (delta): 1.65-2.2 (m, 2H), 2.26-2.64 (m, 4H), 5.1 (s, 2H), 5.65 (s, 2H), 7.3 (s, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[NH:7]1[CH:11]=[N:10][CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:7]1([CH2:2][C:3]([CH2:5][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH2:4])[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: C=C(CCl)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cn1cncn1)Cn1cncn1
Yield: 60.5 %

Procedure:
A mixture of 25 g (0.2 mol) of 3-chloro-2-chloromethyl-propene, 27.6 g (0.4 mol) of 1,2,4-triazole and 27.6 g (0.2 mol) of potassium carbonate in 200 ml of acetone is heated under reflux for 15 hours. After cooling, the mixture is filtered and the filtrate is concentrated in vacuo. The oily residue is chromatographed (silica gel 60, Merck, chloroform). 23 g (63% of theory) of 3-(1,2,4-triazol-1-yl)-2-(1,2,4-triazol-1-yl-methyl)-propene of melting point 52° C. are obtained.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([OH:24])(=[S:23])[CH3:22]>C(OCC)C>[C:21]([S:23][CH:15]([CH2:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:16]([OH:18])=[O:17])(=[O:24])[CH3:22]
Reactant: CC(O)=S
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CC(=O)SC(CC(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Reaction time: 5 h

Procedure:
2.68 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of diethyl ether, then 0.8 ml of thioacetic acid was added, and the mixture was stirred for 5 hours. After the diethyl ether was distilled off under reduced pressure, the residue was purified first by silica gel chromatography, eluted with a mixture of hexane and dichloromethane, then by recrystallization from a mixture of hexane and dichloromethane to give 2.96 g of 2-acetylthio-3-(4-phenoxybenzoyl)propionic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:26][N:27](C=O)C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:26]#[N:27])[CH2:10][C@H:9]1[C:18]([N:20]1[CH2:24][CH2:23][S:22][CH2:21]1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCSC1
Reactant: CN(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)N1CCSC1
Temperature: 50 °C

Procedure:
To a solution of Example 17B (16.55 g, 44 mmol) in dry DMF (100 mL) under nitrogen was added tetrabutylammonium cyanide (50 g, 200 mmol). The mixture was heated to 50° C. for 60 hours and then poured into cold water and extracted with ethyl acetate (3×250 mL). The combined organic layers were dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with 50% ethyl acetate/50% hexane to provide the titled compound (12 g). MS (ESI) m/e 312 (M+H)+, 310 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.44 (m, 9H) 2.10 (m, 1H) 2.79 (m, 1H) 3.05 (m, 1H) 3.17 (m, 1H) 3.33 (m, 1H) 3.57 (dd, 1H) 3.83 (m, 2H) 3.96 (m, 1H) 4.48 (m, 1H) 4.65 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32])=[O:28].C(O)(=O)C.C1COCC1>O>[F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])=[O:28]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
The compound (56) (0.514 g) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, THF and water (4:2:1) and the solution was kept overnight at the room temperature. The resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (46). Yield: 0.272 g (61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(F)cc1

Procedure:
A solution of 43.6 g of 3-(4-fluorophenyl)propionic acid in 300 ml of tetrahydrofuran is added dropwise to a suspension of 19.7 g of lithium aluminum hydride in 300 ml of tetrahydrofuran at a reaction temperature of about 45° C., while stirring. When the addition is complete, the above temperature is maintained for a further 2.5 hours and 80 ml of water and 20 ml of 4 N sodium hydroxide solution are then successively added dropwise. The precipitate is filtered off and rinsed several times with diethyl ether and the combined solutions are dried over sodium sulfate and concentrated. 39.7 g of 3-(4-fluorophenyl)propan-1-ol remain as an almost colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:5]=1[C:6]#[N:7])([O-])=O.C(O)(=O)C.C>[Fe].CC(O)C>[NH2:1][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:5]=1[C:6]#[N:7]
Reactant: COc1ccc([N+](=O)[O-])c(C#N)c1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(N)c(C#N)c1OC
Yield: 88.3 %

Procedure:
Iron powder (8.70 g, 156 mmol) was added to a suspension of (9.30 g, 44.5 mmol) of 2-nitro-5,6-dimethoxybenzonitrile in an acetic acid (30 ml) and 2-propanol (30 ml) mixture. The mildly exothermic reaction which resulted was allowed to reach 100° and a gentle reflux was maintained for 1 hour with application of heat. Charcoal (10 g) was added, the reaction mixture filtered, and the solid residue obtained was washed with hot 2-propanol (100 ml). The combined filtrates were evaporated to an oily residue which was redissolved in CHCl3 and washed with 5% aqueous NaHCO3 and saturated aqueous NaCl solution. The CHCl3 phase was dried with Na2SO4 and evaporated in vacuo to yield 7.0 g (88.4%) of the target compound as an oil.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C@H:26]([OH:31])[C:27]([O:29][CH3:30])=[O:28])=[O:22])[N:4]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C:26](=[O:31])[C:27]([O:29][CH3:30])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)[C@@H](O)CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(=O)CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-Methyl 4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxybutanoate (54 mg, 0.13 mmol) in anhydrous CH2Cl2 (5 mL) was added Dess-Martin periodinane (65 mg, 0.15 mmol). After stirring for 1 hour at room temperature, 2% Na2S2O3 (6 mL) was added and the resulting mixture was stirred at room temperature for 30 minutes. The layers were separated and the organic layer was washed with H2O, dried over MgSO4, concentrated, and purified by flash chromatography (0-20% EtOAc/CH2Cl2) to give the title compound in 34 mg. MS: (−) m/z 418.24 (M−1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1N1CCOCC1
Temperature: 10 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
2,4,6-Trifluoronitrobenzene (4.95 g) and potassium carbonate (4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to 10° C. under argon. Morpholine (2.56 mL) was added and the reaction mixture was allowed to warm to 25° C. and stirred under argon for 16 hours. The reaction mixture was concentrated in vacuo, brine (50 mL) was added and the product was extracted with ethyl acetate (3×50 mL), the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography to furnish 3.69 g (54% yield) of the title compound as a yellow oil.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([O:57][C:58]1[CH:59]=[CH:60][C:61]([CH2:65][CH3:66])=[C:62]([OH:64])[CH:63]=1)[CH3:56]>C(Cl)(Cl)Cl>[Br:1][C:59]1[C:58]([O:57][CH2:55][CH3:56])=[CH:63][C:62]([OH:64])=[C:61]([CH2:65][CH3:66])[CH:60]=1
Reactant: [Br-]
Reactant: CCOc1ccc(CC)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCOc1cc(O)c(CC)cc1Br
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of tetrabutyl ammonium tribromide (9.9 g, 20.5 mmol) in CHCl3 (60 mL) was added to a stirred solution of 5-ethoxy-2-ethyl-phenol (3.1 g, 18.6 mmol) dissolved in CHCl3 (90 mL). The reaction mixture was stirred for 30 mins and then quenched with 5% solution of sodium thiosulfate (30 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 15% EtOAc in hexanes) gave the product as an oil (2.6 g, 58%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 1.44 (t, J=7.1 Hz, 3H), 2.53 (q, J=7.6 Hz, 2H), 4.03 (q, J=7.1 Hz, 2H), 4.85 (s, 1H), 6.41 (s, 1H), 7.25 (s, 1H).