Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>O1CCCC1>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:34]=[O:35])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a 3 ml tetrahydrofuran solution of 150 mg (0.36 mmol) of the compound obtained in Example 15, 0.45 ml of n-butyl lithium (1.59M hexane solution 0.72 mmol) was added dropwise at −78° C. After the mixture was stirred at the same temperature for 30 minutes, 33.4 μl (0.43 mmol) of N,N-dimethylformamide was added dropwise to the reaction mixture, followed by stirring the mixture at −78° C. for 2 hours. Then, an aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 73 mg (55%) of the captioned compound.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].[C:7](=O)([O:11]CC)[O:8][CH2:9][CH3:10].[H-].[Na+].Cl>C1C=CC=CC=1.CO.CN(C)P(=O)(N(C)C)N(C)C>[CH2:9]([O:8][C:7](=[O:11])[CH2:6][C:4](=[O:5])[CH:1]([CH3:3])[CH3:2])[CH3:10]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)C(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
10 g of methyl isopropyl ketone were added to a solution of 400 cc of benzene, 850 cc of diethyl carbonate, 200 cc of hexamethyl phosphoric acid triamide and 60 g of sodium hydride (80% in paraffin oil), and the reaction mixture was heated to 70° to 80° C. After the reaction had started, the reaction mixture was cooled to approximately 30° C, and a solution of 76 g of methyl isopropyl ketone in 200 cc of benzene was added dropwise over a period of 2 hours at that temperature. After the reaction mixture had stood overnight, methanol was carefully added to it with cooling, followed by acidification with aqueous hydrochloric acid. The reaction mixture was then treated as described in Example 1.1. The yield was 81% of 3-keto-4-methyl valeric acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:38])[N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29]>CCOCC.CO.C1COCC1>[O:37]=[C:31]1[CH:30]([N:23]2[C:22](=[O:38])[C:21]3[C:25](=[CH:26][CH:27]=[CH:28][C:20]=3[NH:19][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[C:24]2=[O:29])[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCOCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a solution of ethoxyacetic acid (0.8 mL, 8.5 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.03 mL) at room temperature. After 3 h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-ethoxy-acetamide as a white solid (1.3 g, 87% yield): mp, 253-255° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7.0 Hz, 3H, CH3), 2.06-2.10 (m, 1H, CHH), 2.46-2.64 (m, 2H, CH2), 2.84-2.98 (m, 1H, CHH), 3.66 (q, J=7.0 Hz, 2H, CH2), 4.14 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.7 Hz, 1H, NCH), 7.62 (d, J=7.2 Hz, 1H, Ar), 7.87 (t, J=8.2 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.88, 21.93, 30.92, 48.98, 66.89, 69.49, 116.00, 118.28, 124.25, 131.31, 135.99, 136.53, 166.69, 168.31, 169.49, 169.73, 174.71; Anal Calcd for C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 56.82; H, 4.71; N, 11.60.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CN(C)C=O.[CH2:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]>O>[CH:1]([NH:4][CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])([CH3:3])[CH3:2]
Reactant: C=C(C(F)(F)F)C(F)(F)F
Reactant: CC(C)N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCC(C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of isopropylamine (5.65 g) and dimethylformamide (DMF, 5 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 25° C. for 15 h. The reaction mixture was poured into water (100 mL) and the bottom layer separated, washed with water (10 mL) and dried over sodium sulfate to provide N-isopropyl N-(2-trifluoromethyl-3,3,3-trifluoropropyl)amine (15 g): MS (m/e) 223 (M+, 1.2%), 208 (100%), 72 (7.8%); 1H NMR (CDCl3) 1.06 (d, J=6 Hz, 6H), 1.12 (m, 1H), 2.81 (m, 1H), 3.07 (m, 3H) ppm; 19F NMR −67.0 (d, J=9 Hz) ppm.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 46 %

Procedure:
A mixture of methyl 6-chloronicotinate (5.0 g), 1-benzyl-3-aminopyrrolidine (6.16 g) and K2CO3 (4.83 g) in DMF (20 ml) was stirred at 100°C. for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-[(1-benzylpyrrolidin-3-yl)amino]nicotinate (4.17 g)
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:8]2[NH:9][CH:10]=[C:11]([CH2:12][CH2:13][OH:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.O=[C:17]([CH2:23][CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1(C)C=CC=CC=1>[CH2:23]([C:17]1([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10]2[NH:9][C:8]3[C:7]([C:11]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:2][CH3:1])[CH3:24]
Reactant: CCc1cccc2c(CCO)c[nH]c12
Reactant: CCC(=O)CC(=O)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Reaction time: 7 h
Yield: 82.7 %

Procedure:
To a solution of 7-ethyltryptophol (12.0 g) in a mixture of methanolic hydrogen chloride (10% w/v, 50.0 ml) and toluene (50 ml), methyl 3-oxopentanoate (9.1 g, 0.07 mole) was added in one lot, at 25° C. The reaction mixture was stirred at 25-30° c for 7 hours. The reaction mixture concentrated to about 20 ml under reduced pressure. Methanol (50 ml) was added to the concentrate and the solution was extracted with hexane (100 ml). Hexane was concentrated to about 20 ml and methanol (10 ml) was added. The product was filtered, washed with methanol and dried to afford the title compound (15.8 g, 84%), m.p. 128-130° C., purity: 97.8%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][C:26](OC)=[CH:25][CH:24]=5)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[Cl:32]C1C=CC=CC=1C[Zn+].O1C2C=CC(C3(C(NC4C=CC=C(Br)N=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:32])[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(Cc2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cc1
Reactant: Clc1ccccc1C[Zn+]
Agent: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Product: O=C(Nc1cccc(Cc2ccccc2Cl)n1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-(2-chlorobenzyl)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(4-methoxybenzyl)pyridin-2-yl)cyclopropanecarboxamide by reacting (2-chlorobenzyl)zinc(II) chloride with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]1([CH2:15][OH:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH:15]=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2cc3ccccc3cc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc2cc3ccccc3cc12
Yield: 67.9 %

Procedure:
To a 2 L round bottom flask equipped with condenser and magnetic stirring bar was added (1-anthracenyl)methanol (15C, 21.0 g, 0.10 mol), CH2Cl2 (1200 mL) and pyridinium chlorochromate (PCC) (Aldrich, 32.33 g, 0.15 mol). The mixture was then refluxed for 5 h. The reaction was cooled and then filtered through a plug of silica gel (400 g) using PhCH3 as eluting solvent. The first 1 L of solution was collected and concentrated to give 16 g of crude product. This material was further purified by preparative HPLC using PhCH3 as eluting solvent. The solvent was removed and the resulting solid recrystallized (PhCH3 /hexane) to give 14.0 g (67%) of 1-anthracenecarbaldehyde mp 130°-131.5°, (C, H), (lit. mp 126.5°-127.5°, P. H. Gore J. Chem. Soc. 1616 (1959)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[C:5]([F:15])[CH:4]=1.[O:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C(=O)[N-]C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd+]>[F:15][C:5]1[CH:4]=[C:3]([CH2:2][C:18]2[CH:19]=[CH:20][O:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(Cc2ccoc2)cc1F
Yield: 57.9 %

Procedure:
Compound 20 (0.88 g, 3.2 mmol) and 3-furanboronic acid (0.54 g, 4.8 mmol) were dissolved in tetrahydrofuran (12 mL) and a 2 M-aqueous solution (4.0 mL) of sodium carbonate. To this solution, trans-bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) [trans-PdBr(N-Succ)(PPh3)2] (25.9 mg, 1.0 mol %) was added and treated in the same manner as in Example 11. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (20:1) solution followed by conventional hydrolysis with potassium hydroxide to give 0.46 g (55%) of compound (22a) of interest as white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:23]([CH3:22])[C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCN(C)C(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and N-methyl-n-butylamine were used to obtain N-n-Butyl-N-methyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[N:18][O:19][CH2:20][C:21]([NH:23][CH2:24][C@H:25]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32])[C:26]([O:28]C)=[O:27])=[O:22])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].[Li+].[OH-]>CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:8]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]=[N:18][O:19][CH2:20][C:21]([NH:23][CH2:24][C@H:25]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32])[C:26]([OH:28])=[O:27])=[O:22])=[CH:15][CH:16]=1)(=[NH:9])[NH2:10]
Reactant: CCCCOC(=O)N[C@@H](CNC(=O)CON=Cc1ccc(C(=N)N)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCOC(=O)N[C@@H](CNC(=O)CON=Cc1ccc(C(=N)N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
Methyl 3-[2-[[(4-amidinophenylmethylene)amino]oxy]-1-oxoethylamino]-2-(S)-[n-butyloxycarbonylamino]-propanoate TFA salt (91 mg, 0.17 mmol) was dissolved in 1.5 mL of methanol and 0.51 mL of 1M LiOH was added. After stirring at room temperature for 16 hours, the reaction mixture was evaporated in vacuo and the residue was dissolved in 2 mL of 1:1 CH2Cl2/TFA. This solution was evaporated in vacuo and the residue was purified by preparative HPLC (Dynamax-300A C18 reverse phase column; 21.4×250 mm; 10 ml/min flow rate; 254 nM; gradient: from 100% H2O with 0.05% TFA to 20% H2O and 80% CH3CN with 0.05% TFA in 50 minutes) to yield 63 mg of desired product as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.39 (bs, 2H), 9.2 (bs, 2H), 8.44 (s, 1H), 7.99 (t, 1H), 7.83 (m, 4H), 7.36 (d, 1H), 4.6 (s, 2H), 4.05 (m, 1H), 3.9 (m, 2H), 3.55 (m, 1H), 3.36 (m, 1H), 1.46 (m, 2H), 1.3 (m, 2H), 0.85 (t, 3H); MS (ESI): m/e 408.2 (M+H)+; HRMS (FAB), e/z Calc. for (M+H)+: 408.188309, Found: 408.189211.
Reaction SMILES: [C:1]1([CH:11]2[CH2:16][CH2:15][N:14](NC(=O)OCC)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BrH:23]>>[BrH:23].[C:1]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NN1CCC(c2cccc3ccccc23)CC1
Agent: Br
Product: c1ccc2c(C3CCNCC3)cccc2c1

Procedure:
10.5 g of the compound obtained in Stage A in 300 ml of a 48% hydrobromic acid solution, are refluxed for 20 hours. After evaporation and washing twice with ethanol, the residue is taken up in acetone and the mixture then filtered to give 4-(naphth-1-yl)piperidine hydrobromide.
Reaction SMILES: [H-].[Na+:2].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>CS(C)=O>[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:11]2[C:12]([C:13]([O-:15])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:5]1.[Na+:2]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN1CCC(O)C1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(Oc2ncccc2C(=O)[O-])C1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 6.4 g (0.13 mole) of 50% sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g (0.063 mole) of 1-methyl-3-pyrrolidinol. During addition, the temperature rose from 25° C. to 31° C. After 10 minutes, a solution of 10 g (0.063 mole) of 2-chloronicotinic acid in 50 ml of dimethylsulfoxide was added dropwise causing the temperature to rise. When the temperature reached 55° C., it was maintained there by the intermittent use of an ice bath until addition was complete. The mixture was then heated to 55°-60° C. for 1.5 hr., cooled and filtered. The filter cake was suspended in 100 ml of ethyl acetate and filtered. The solid was recrystallized from ethyl acetate-methanol. Yield of product was 5 g., dec. 240° C. The NMR analysis showed that the compound contained 1/3 mole of sodium acetate as impurity.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[CH2:14](O)[CH2:15][OH:16]>CC1C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Oc1ccc(C2OCCO2)c2cccnc12

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (A,Oakwood Products) in ethylene glycol, p-TsOH is added to form 5-(1,3-dioxolan-2-yl)quinolin-8-ol (B). After purification, 5-(1,3-dioxolan-2-yl)quinolin-8-ol is added to a solution of MeI and NaH in THF to give C. A solution of C in THF is added to 1 eq of the Grignard reagent formed from magnesium turnings and L-N-Boc-2-bromomethyl glycine allyl ester (Advanced Technology & Industrial Co., Ltd., Hong Kong) at 0° C.; the reaction mixture is monitored by TLC until allyl(S)-vinyl 2-(tert-butoxycarbonylamino)-3-(5-formyl-8-methoxyquinolin-2-yl)propanoate (D) is formed. The reaction mixture is quenched with aqueous acetic acid, and purified by flash chromatography. The O-methyl and N-t-BOC protecting groups are simultaneously removed by treatment of D with warm 48% HBr/HOAc. The freed aliphatic amino group is protected as a fluorenoxymethylenecarbonyl carbamate, followed by condensation of the benzaldehyde moiety with two equivalents of 4-fluororesorcinol in methanesulfonic acid at rt. The resulting pro-fluorophore G is isolated by precipitation from water and filtration, followed by dehydrogenative oxidation with p-choranil in methane/chloroform. The resulting dye H is purified by flash chromatography using methanol in chloroform as eluant, and then readied for peptide synthesis of allyl ester deprotection using sodium 2-ethylhexanoate and catalytic Pd(PPh3)4 in ethyl acetate and dichloromethane to give compound I.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:31][CH3:32])=[C:11]([C:13]2([F:30])[C:21]3[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[N:15]([CH2:26]SC)[C:14]2=[O:29])[CH:12]=1>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:31][CH3:32])=[C:11]([C:13]2([F:30])[C:21]3[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[N:15]([CH2:26][Cl:4])[C:14]2=[O:29])[CH:12]=1
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)N(CSC)c2cc(C(F)(F)F)ccc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
Alternate Method: Sulfuryl chloride (135 mg, 80.2 μL, 1 mmol) was added at room temperature to a dichloromethane (10 mL) solution of 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-methylsulfanylmethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one (420 mg, 1 mmol) in a round-bottomed flask equipped with nitrogen inlet and magnetic stirrer. After stirring the reaction mixture at room temperature for 20 minutes, the crude solution was concentrated in vacuo to afford 3-(5-chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one (425 mg, 100% crude yield) as a light yellow solution. Step C: Phosphoric acid mono-[3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indol-1-ylmethyl] ester, bis-[tris(hydroxymethyl)ammoniummethane] salt
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[2-methyl-4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (315 mg) in THF (dry) (10 mL) and MeOH (10 mL) and the mixture was stirred at room temperature under hydrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (206.1 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:9]2)=[CH:4][CH:3]=1.C([O:27][C:28](=[O:39])[C:29]1[CH:34]=[C:33]([CH2:35]Br)[CH:32]=[CH:31][C:30]=1[O:37][CH3:38])C>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:35][C:33]4[CH:32]=[CH:31][C:30]([O:37][CH3:38])=[C:29]([CH:34]=4)[C:28]([OH:39])=[O:27])[CH2:23][CH2:24]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccc(Cl)s1
Product: COc1ccc2c(c1)c(C1CCN(Cc3ccc(OC)c(C(=O)O)c3)CC1)cn2Cc1ccc(Cl)s1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.13 mmol) 1-(5-chloro-thiophen-2-ylmethyl)-5-methoxy-3-piperidin-4-yl-1H-indole and 0.05 g (0.18 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. The crude mixture was purified by HPLC-MS using a C-18 column, and 0.002 g (99% of purity) of the expected acid were isolated.
Reaction SMILES: COC1C=CC(C2SC3C=C(OC)C=CC=3C=2)=C(N)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.FC1C=[C:44](C=CC=1OCCN1CCCCC1)[CH2:45][NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[C:61]([O:64][CH3:65])[CH:62]=[CH:63][C:57]=2[CH:56]=1>>[CH2:45]([N:46]([CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[C:61]([O:64][CH3:65])[CH:62]=[CH:63][C:57]=2[CH:56]=1)[CH3:44]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: COc1ccc(-c2cc3ccc(OC)cc3s2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1-c1cc2ccc(OC)cc2s1

Procedure:
Synthesized from 5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenyl]amine (231 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxybenzo[b]thiophen-2-yl)phenyl]amine (195 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (170 mg).