Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH:14][C:15](=O)[C:16]1[CH:21]=[C:20]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[C:18]([CH2:27][CH3:28])[CH:17]=1)[CH:6]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH2:5]2.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:26][S:23]([NH:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([CH2:27][CH3:28])[CH:19]=1)[CH2:15][NH:14][CH2:13][CH2:12][N:7]1[CH:6]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8]1)(=[O:25])=[O:24]
Reactant: CCc1cc(NS(C)(=O)=O)cc(C(=O)NCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc(NS(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Under an argon atmosphere, 62 mg of N-[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl]-3-ethyl-5-methanesulfonylaminobenzamide was dissolved in 1 mL of THF, and a borane/THF complex (1 ml) was added thereto, followed by stirring at 60° C. overnight. The reaction liquid was cooled to room temperature, and 1 N hydrochloric acid was added thereto, followed by further stirring for 6 hours. After completion of the reaction, an aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 42 mg (yield 70%) of a title compound as a light yellow oily substance.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH2:7]([N:10]1[N:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[N:11]1)[CH2:8][CH3:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[OH:16][CH2:15][C:13]1[CH:12]=[N:11][N:10]([CH2:7][CH2:8][CH3:9])[N:14]=1
Reactant: CCCn1ncc(C(=O)OC)n1
Agent: O=S([O-])([O-])=S
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCn1ncc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a solution of aluminum lithium hydride (1.57 g) in THF (140 ml) was added dropwise methyl 2-propyl-1,2,3-triazole-4-carboxylate (7.0 g) in. THF (70 ml) at 0° C. The mixture was stirred for 1 hour at room temperature, and an aqueous solution of saturated sodium thiosulfate was added to the mixture at 0° C. The mixture was filtered with Celite, and washed with ethanol. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-hydroxymethyl-2-propyl-1,2,3-triazole (5.9 g). To 4-hydroxymethyl-2-propyl-1,2,3-triazole (4.0 g), thionyl chloride (32 ml) was added to the mixture at 0° C., and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, the solvent was removed under reduced pressure, to give 4-chloromethyl-2-propyl-1,2,3-triazole (4.2 g).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:40])[C:8]([N:10]([CH3:39])[C:11]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:20](=[O:38])[C:21]([O:29]C(C4C=CC=CC=4)=O)=[C:22]([C:24]([O:26]CC)=O)[N:23]=[C:12]32)=[O:9])[CH2:3]1.CNC.CO.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=1.C(N(CC)CC)C>C(O)C>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:24]([C:22]2[N:23]=[C:12]3[C:11]4([N:10]([C:8](=[O:9])[C:7]([N:4]5[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]5)=[O:40])[CH3:39])[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]4)[CH2:14][N:13]3[C:20](=[O:38])[C:21]=2[OH:29])=[O:26])=[CH:49][CH:48]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N(C)C(=O)C(=O)N2CC[C@@H](F)C2)CC1
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: CN(C(=O)C(=O)N1CC[C@@H](F)C1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 90 °C
Yield: 51 %

Procedure:
To a mixture of ethyl 10-((((3R)-3-fluoro-1-pyrrolidinyl)(oxo)acetyl)(methyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylat (35 mg, 0.063 mmol) in ethanol (2 mL) was added 2M dimethylamine in methanol (0.063 mL, 0.126 mmol) and the resulting mixture was heated at 50° C. for 1 h. (4-Fluorophenyl)methanamine (0.036 mL, 0.316 mmol) followed by triethylamine (0.044 mL, 0.316 mmol) were added and the mixture heated at 90° C. for 18 h. The reaction mixture was then cooled, concentrated and purified by preparative HPLC to afford the title compound (17 mg, 51% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 11.96 (1 H, brs), 9.45 (1 H, brs), 7.34-7.40 (2H, m), 6.97 (2 H, t, J=8.70 Hz), 5.32-5.39 (0.5 H, m), 5.20-5.29 (0.5 H, m), 4.76-4.86 (1 H, m), 4.56-4.67 (1 H, m), 4.40-4.52 (1 H, m), 3.86-3.93 (0.5 H, m), 3.74-3.82 (0.5 H, m), 3.34-3.71 (6 H, m), 3.03 (1.2 H, s), 3.02 (1.8 H, s), 2.49 (1 H, brs), 2.29-2.41 (1 H, m), 1.99-2.09 (4 H, m), 1.76-1.83 (2 H, m), 1.44-1.51 (1 H, m). LCMS (M+H)=530.61. HPLC purity: >95%.
Reaction SMILES: ClC1C=C(C2C=CC([C@H](N)C)=CC=2)C(OC)=NC=1.BrC1C=CC([C@H](NC(=O)O)C)=CC=1.ClC1C=CC(OC)=C(B(O)O)C=1.[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([O:60][CH3:61])=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=2)[CH:50]=1.[F:62][C:63]1[CH:64]=[C:65]([S:70](Cl)(=[O:72])=[O:71])[CH:66]=[CH:67][C:68]=1[F:69]>>[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([O:60][CH3:61])=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=2)[CH:50]=1.[Cl:44][C:45]1[CH:46]=[CH:47][C:48]([O:60][CH3:61])=[C:49]([C:51]2[CH:56]=[CH:55][C:54]([C@H:57]([NH:59][S:70]([C:65]3[CH:66]=[CH:67][C:68]([F:69])=[C:63]([F:62])[CH:64]=3)(=[O:72])=[O:71])[CH3:58])=[CH:53][CH:52]=2)[CH:50]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: COc1ccc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Agent: COc1ccc(Cl)cc1B(O)O
Agent: COc1ncc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Product: COc1ccc(Cl)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2ccc(F)c(F)c2)cc1

Procedure:
(R)-1-(5′-Chloro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to (R)-1-[4-(5-chloro-2-methoxypyridin-3-yl)-phenyl]ethylamine (Example 39) starting from (R)-[1-(4-bromophenyl)-ethyl]-carbamic acid and 5-chloro-2-methoxyphenylboronic acid. The title compound was prepared in a similar manner to (R)-1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid 1-{[4-(5-chloro-2-methoxypyridin-3-yl)-phenyl]-ethyl}-amide (Example 39) using (R)-1-(5′-chloro-2′-methoxy-biphenyl-4-yl)-ethylamine and 3,4-difluorobenzenesulfonyl chloride. 1H NMR (400 MHz, CDCl3): 7.52-7.42 (m, 2H), 7.35-7.08 (m, 7H), 6.90 (m, 1H), 4.80 (d, 1H), 4.60 (q, 1H), 3.79 (s, 3H), 1.51 (d, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:8]=[CH:7]2)([O-])=O.O.NN>CO.[Ni]>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCCC2)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2c(ccn2CCN2CCCCC2)c1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A suspension of compound 94 (250 mg, 0.915 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (0.33 mL, 10.7 mmol) and the resulting mixture was refluxed for 20 min. The dark green reaction was cooled to room temperature, filtered through a celite pad, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 95 (215 mg, 97%) as a yellow oil. 1H NMR (CDCl3) δ 7.16 (d, J=8.7 Hz, 1H), 7.05 (d, J=3.0 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.67 (dd, J=2.1, 8.7 Hz, 1H), 6.29 (d, J=3.0 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 2.45 (m, 4H), 1.59 (m, 4H); ESI-MS (m/z, %): 244 (M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[OH:23]>C(O)(=O)C>[Cl:1][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[OH:23])=[CH:12][C:11]([O:10][CH3:9])=[C:20]([O:21][CH3:22])[CH:19]=2
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COc1cc2ncc(Cl)c(O)c2cc1OC
Temperature: 20 °C

Procedure:
5.45 g of N-chlorosuccinimide were added to a solution of 6,7-dimethoxyquinolin-4-ol in 300 cm 3 of acetic acid, with stirring and at a temperature in the region of 20° C. The reaction mixture was heated at a temperature in the region of 50° C. for 6 hours. After cooling to about 20° C. and stirring for 18 hours at this same temperature, the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. One hundred cm3 of sodium hydrogen carbonate solution were added dropwise to the evaporation residue and the suspension was then stirred for 24 hours in the region of 20° C. The insoluble material was filtered off and then dried in an oven under reduced pressure (20 Pa). 5.39 g of 3-chloro-4-hydroxy-6,7-dimethoxyquinoline were obtained in the form of a dark green solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:4].[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O>[CH2:34]([O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:20][CH:21]=1)[N:5]([C:3](=[O:4])[C:2]([F:30])([F:1])[F:31])[CH2:14][CH2:13]2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
A solution of 2,2,2-trifluoro-1-{6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}ethanone (1.886 g, 4.3 mmol) in anhydrous DMF (50 ml) was added to a suspension of NaH (0.104 g, 4.3 mmol) in anhydrous DMF (100 ml) at rt under N2. After stirring at rt for 1 hr, a solution of benzyl bromide (0.782 g, 4.6 mmol) in anhydrous DMF (10 ml) was added and the reaction mixture was heated to 100° C. for 4 hr. The reaction mixture was cooled to rt, diluted with H2O (250 ml), and extracted with EtOAc (4×100 ml). The combined extracts were washed with H2O (2×100 ml), dried over MgSO4, and concentrated in vacuo to give 2.71 g of orange oil. Purification by flash chromatography, eluting with EtOAc:MeOH (7:3) gave 0.745 g (33% yield) of yellow oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>CCO>[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]
Reactant: O=Cc1cccc(OCC2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Yield: 63 %

Procedure:
A solution of 3-(oxiran-2-ylmethoxy)benzaldehyde (1.0 g, 5.61 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.49 g, 11.22 mmol) in EtOH (20 mL) was heated at 110° C. for 3 h. The solvent was then removed by concentration and the residue dissolved in ethyl acetate, washed with water and the separated organic layer dried and concentrated. The crude product was purified by column chromatography. (1.1 g, yield 63%.) MS (ESI) e/z: 312.3 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[C:8]1=[O:26])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][NH:19][C:18]=3[N:17]=2)[C:8]1=[O:26])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCc2ccc3cccnc3n2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 2-8 (400 mg, 0.86 mmol) and 10% Pd/carbon (1300 mg) in EtOH (10 mL) was stirred under a balloon of hydrogen for 6 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 2-9 as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6]C=1.[Cl-].[NH4+].CO.C1C[O:23][CH2:22]C1>>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:3]1([CH:4]=[CH:9][CH:8]=[CH:7][CH2:6]1)[CH2:22][OH:23]
Reactant: C1CCOC1
Reactant: O=C(c1ccccc1)c1cccs1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCC1(c2cccs2)C=CC=CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92 %

Procedure:
Sodium borohydride (0.37 g, 10 mmol) was added to 2-benzoylthiophene (1.88 g, 10 mmol) dissolved in methanol/THF mixture (1:10 ratio, 11 ml). This was stirred at room temperature for 10 h. The reaction mixture was decomposed by addition of saturated ammonium chloride solution (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over anhydrous MgSO4. Removal of the solvent gave 1-(2-thienyl)benzyl alcohol as a solid (1.75 g, 92% yield).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[CH3:7].ClCCCl.Cl>CCCCCC.O1CCCC1.CCOCC>[C:16]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=2)[CH2:2][CH2:1]1)#[N:17]
Reactant: CCOc1ccc(CC#N)cc1
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOc1ccc(C2(C#N)CC2)cc1
Reaction time: 1 h

Procedure:
To 7.5 ml (0.012 mol) of 1.7M n-butyllithium in hexane, at room temperature, under an atmosphere of nitrogen, is added rapidly 10 ml of anhydrous tetrahydrofuran, followed by a solution of 4-ethoxyphenyl acetonitrile (0.8 g 0.005 mol) in 4 ml of tetrahydrofuran, during 5 minutes. The reaction mixture is stirred magnetically for 1 hour then treated with 0.50 g (0.005 mol) of 1,2-dichloroethane in 10 ml of tetrahydrofuran, during a period of 40 minutes (slow addition is important). After 16 hours, the mixture is hydrolysed by 10 ml of 3N HCl and then taken up in ether, washed with water, sodium bicarbonate, water and dried over anhydrous sodium sulphate. The solvent is removed under reduced pressure. Yield: 0.64 g of a viscous semi-crystalline oil.
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27]C)[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:11](=[O:23])[CH2:10][S:9]1)(=O)C.O1CCCCC1CCC1N(CCCCCCC(OC)=O)C(=O)CS1>>[O:4]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:5]1[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:23])[CH2:10][S:9]1
Reactant: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)OC)OC(C)=O
Agent: COC(=O)CCCCCCN1C(=O)CSC1CCC1CCCCO1
Product: O=C(O)CCCCCCN1C(=O)CSC1CCC1CCCCO1

Procedure:
This compound is prepared essentially by the method as described in Example 1, Step B, except that the methyl 7-[2-(3-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]heptanoate is replaced by methyl 7-{2-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-4-oxo-3-thiazolidinyl}heptanoate. After chromatographic purification on silica gel, the title compound is obtained as a viscous, pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[C:2]21[CH2:16][CH2:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:8]2.[BH4-].[Na+].C[OH:20]>O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:16][CH2:15][C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:8]2[OH:20]
Reactant: CO
Reactant: O=C1CCCNC12CCc1ccccc1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OC1c2ccccc2CCC12CCCCN2
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 0.80 g of 3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-one and following addition of 0.15 g of sodium borohydride in small portions, the mixture was stirred for 30 minutes. The reaction mixture was then diluted with water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was distilled off. The solid group was recrystallized from methylene chloride-ether to provide 0.25 g of white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[C:11](#[N:14])[CH:12]=[CH2:13]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:13][CH2:12][C:11]#[N:14])([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: C=CC#N
Product: N#CCCCc1ccccc1[N+](=O)[O-]

Procedure:
reaction of ortho-nitrotoluene with acrylonitrile to give 4-(2-nitrophenyl)-butyronitrile,
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[C:22]([OH:23])=[C:21]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH:20]=[C:19]([OH:31])[C:11]=2[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[C:22](=[O:23])[C:21]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])=[CH:20][C:19](=[O:31])[C:11]=2[C:12]([O:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[O:13])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)c2c(O)c(C(=O)OCC(C)C)cc(O)c2C(=O)OCC(C)C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)C2=C(C(=O)OCC(C)C)C(=O)C=C(C(=O)OCC(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
One part of diisobutyl 2-p-toluenesulfonyl-3,6dihydroxyterephthalate, 3 parts of electrolytic manganese dioxide and 5 parts of benzene were mixed. After allowing the mixture to stand for 24 hours, it was agitated at its boiling point for 3 hours. The reaction mixture was hot-filtered, and a portion of the benzene was distilled off to concentrate the filtrate to about 1/3 of its initial volume. Upon addition of ligroin, a yellowish precipitate was caused to deposit. The mixture was allowed to cool overnight at room temperature and the solid matter was collected by filtration. Then, it was washed with ligroin and dried at room temperature in air, thereby obtaining light-yellowish crystals having a melting point of 112°-114° C. with a yield of about 70%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][O:16][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(C)C(=O)Cl
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)C(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added isobutyryl chloride (0.15 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-isobutyryloxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (380 mg, 66% yield): mp, 107-109° C.; 1H NMR (DMSO-d6) δ 0.86-0.89 (m, 4H, 2CH2), 1.10 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 1.73-1.81 (m, 1H, CH), 2.62-2.73 (m, 1H, CH), 3.02-3.05 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.96-4.05 (m, 2H, CH2), 4.19 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.19 (d, J=8 Hz, 1H, Ar), 7.50 (d, J=8 Hz, 1H, Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.54 (s, 1H, NH), 11.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.76, 14.69, 15.46, 18.65, 31.27, 34.64, 46.59, 51.07, 55.47, 63.80, 111.93, 112.09, 116.82, 117.32, 117.50, 119.27, 131.23, 132.77, 136.98, 142.25, 147.95, 148.58, 166.61, 168.04, 171.72, 174.29; Anal Calcd for C28H33N3O7+0.11H2O: C, 63.99; H, 6.37; N, 8.00; H2O, 0.38. Found: C, 63.64; H, 6.37; N, 7.70; H2O, 0.39.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH2:31][CH:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Fc1ccc(C2CCNCC2)nc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CCC(c2ccc(F)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 34.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-fluoro-2-piperidin-4-ylpyridine (4.7 g, 26.5 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (4.25 g, 26.5 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.45 g of the intended substance (yield 34.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([N:1]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1)[S:24]([CH3:23])(=[O:26])=[O:25])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cn2cc(N)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2n1
Temperature: 0 °C
Yield: 42.3 %

Procedure:
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2 g) was dissolved in THF (10 ml). Triethylamine (9.75 mmol, 0.986 g) was added and the mixture was cooled to 0° C. Methanesulfonyl chloride (9.75 mmol, 1.116 g) was slowly added and the mixture was allowed to cool to RT. The stirring continued at RT until the reaction was finished. The solvent was evaporated, DCM was added and washed with NaHCO3 solution and water. The organic phase was dried, filtered and evaporated. The crude product was purified with flash chromatography. 0.149 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.33 (t, 3H), 3.61 (s, 6H), 4.34 (q, 2H), 7.50 (dd, 1H), 7.69-7.74 (m, 1H), 8.54-8.56 (m, 1H), 9.00-9.02 (m, 1H).