Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[OH:1][CH2:2][C:3]1[O:8][C:7]([CH3:9])=[CH:6][C:5](=[O:10])[C:4]=1[O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: Cc1cc(=O)c(O)c(CO)o1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(CO)oc(C)cc2=O)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 5.9 g of 6-hydroxymethyl-5-hydroxy-2-methyl-4-pyrone in 60 ml of dimethylformamide were successively added 6.2 g of potassium carbonate and 6.2 ml of p-methoxybenzyl chloride. The mixture was stirred at 70° C. for 2 hours. The reaction liquid was concentrated and 200 ml of water and 400 ml of dichloromethane were added to the concentrate. The organic phase was then washed with 200 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was then separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (300 g) to give 5.9 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH:45](I)I>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: IC(I)COCCOCC(I)I
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCOCCOCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.4 ml of 1,2-bis(diiodoethoxy)ethane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C30H32F2INO5 (651) MS (ESI): M+−18
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.[C:36]([O:40][C:41](=[O:50])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH2:49])([CH3:39])([CH3:38])[CH3:37]>C(Cl)CCl.C(N(CC)CC)C.O>[C:36]([O:40][C:41](=[O:50])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:18](=[O:20])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:12]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.1 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 170 ml DMF and 1.3 g HOBt.H2O and 12.0 ml triethylamine is stirred for 0.5 h. Then 4.9 g EDC.HCL is added and the suspension is stirred again at ambient temperature for 0.5 h. After that 1.8 g (2-amino-phenyl)-carbamic acid tert-butyl ester are added and the mixture is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate. The title compound is isolated by flash chromatography.
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH3:6].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]1([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[CH:26][CH:25]=[CH:24][CH:23]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:29]([CH2:30][C:31]2([OH:37])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:18]=1)[CH2:5][CH3:6]
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1

Procedure:
Trimethylorthobutyrate (1.9 mL, 12.0 mmol) and pyridine hydrochloride (58 mg, 0.5 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (10.0 mmol) in toluene (50 mL). The reaction mixture was heated at reflux for 4 hours and then concentrated under reduced pressure. The residue was triturated with acetonitrile and the filtered to provide 4-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: CCOC(=O)c1cc(-c2ccc(N)c(C)c2)no1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3c(F)cccc3F)c(C)c2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
Ethyl 3-(4-amino-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), 2,6-difluoro phenyl isocyanate (1.2 equiv.) and tetrahydrofuran was taken in a round bottom flask and was stirred at room temperature for 48 hours. The solid precipitate was filtered and washed with minimum quantity of THF and dried in vacuo to afford the title compound as a white solid (91%); 1H NMR (300 MHz, DMSO-d6) δ: 1.29-1.34 (t, J=7.0 Hz, 3H), 2.31 (s, 3H), 4.33-4.40 (q, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 1H), 7.71-7.74 (dd, J=8.7 Hz, 1.8 Hz, 1H), 7.81 (s, 2H), 8.04-8.07 (d, J=8.7 Hz, 1H), 8.31 (s, 1H), 8.65 (s, 1H); IR (KBr) 3292, 3132, 2984, 1723, 1644, 1621, 1588, 1560 1471, 1449, 1288, 1235, 1125, 1006, 849, 768 cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:25]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17]([O:19][CH3:25])=[O:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1cnoc1-c1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
A mixture of 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionic acid (5.28 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionate (5.45 g, yield 98%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 118–119° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[C:16]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17].C(OC(=O)[C@@H](OC)CC1C=CC(C(OC(C)(C)C)=O)=CC=1OC)C>>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:22]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:26])([CH3:24])[CH3:23])[CH:7]=1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: CCOC(=O)[C@H](Cc1ccc(C(=O)OC(C)(C)C)cc1OC)OC
Product: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1)OC

Procedure:
The title compound was prepared from 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9, step 4) and 2-bromo-2-methyl-propionic acid tert-butyl ester via the same procedure used for the preparation of (2S)-3-(4-tert-butoxycarbonyl-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 1) to produce a yellow oil. 1H-NMR (CDCl3, 200.15 MHz): δ 7.13-7.09 (m, 1H), 6.84-6.69 (m, 3H), 3.95-3.89 (dd, 1H, J=6.5, 4.4), 3.7 (s, 3H), 3.34 (s, 3H), 2.94-2.90 (m, 2H), 1.50 (s, 6H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[N:8]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1

Procedure:
The title compound was prepared as described in the final step of Example 1 from 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea (0.022 g, 0.050 mmol), and p-tolylboronic acid (0.014 g, 0.1 mmol), using copper (II) acetate (0.014 g, 0.075 mmol), pyridine (0.01 mL, 0.1 mmol), molecular sieves (4 Å activated, 0.030 g) and methylene chloride (2 mL). The title compound was obtained as a yellow-white solid (0.013 g, 50%), mp 144-146° C.; 1H NMR (DMSO) δ 1.26(s, 9H), 2.36(s, 3H), 2.53(t, 4H) 2.82(t, 2H), 3.52(t, 4H), 4.23(t, 2H), 6.32(s, 1H), 6.94(d, 1H), 7.33(d, 1H), 7.42(d, 1H), 7.54(m, 3H), 7.90(d, 1H), 8.15(d, 1H), 8.18(d, 1H), 8.82(s, 1H), 8.96(s, 1H); MS (CI) 528(M++H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=1[OH:19]>C(O)(=O)C>[OH:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[CH:14][C:13]=1[N:12]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A solution of phthalic anhydride (14.81 g, 0.10 mole) and 6-amino-m-cresol (12.32 g, 0.10 mole) in 200 mL of acetic acid was stirred at ambient temperature for 30 minutes and then refluxed for 6 hours. The solution was cooled and poured into 500 mL ice-water with rapid stirring and the resultant solid was collected by suction filtration, washed with ice-cold water several times and air dried overnight to afford 24.1 g (95% yield) of product 1 as a light brown solid, mp 251-254° C. TLC (silica ; EtOAc), Rf =0.68.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)CC1
Temperature: 90 °C
Yield: 55 %

Procedure:
To a mixture of 2,6-dichloro-4-iodo-pyridine (1.0 g, 3.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (1.4 g; 4.4 mmol), potassium carbonate (1.0 g, 7.3 mmol), and Pd(dppf)Cl2 DCM (300 mg, 0.37 mmol) in 1,4-dioxane (12.0 mL) and water (3.0 mL) was capped in a large CEM microwave vial, de-gassed with N2, and heated in an oil-bath at 90° C. for overnight. It was diluted with water (100 mL), extracted with EtOAc (2×100 mL). The combined EtOAc was washed with brine, dried over MgSO4, filtered, and concentrated onto Celite. It was purified by column chromatography (ISCO0, 40 g column, eluded with 0-15% EtOAc/Heptane to give 670 mg (56%) of the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 6.32 (s, 1H), 4.12 (d, J=2.7 Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 2.45 (s, 2H), 1.49 (s, 9H). LC-MS: m/z=330 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])(O)[CH3:12])[CH:3]=1.OS(O)(=O)=O>>[CH3:12][C:11]1([CH3:14])[CH2:10][C:9]([CH3:16])([CH3:15])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[S:8]1
Reactant: CC(C)(O)CC(C)(C)c1cc(Br)ccc1S
Agent: O=S(=O)(O)O
Product: CC1(C)CC(C)(C)c2cc(Br)ccc2S1

Procedure:
A mixture of 500 mg (1.49 mmol) of 4-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 32) and 8 ml of 20 percent aqueous H2SO4 was heated at reflux for 24 h. The mixture was extracted with hexanes, the organic extracts were combined and washed successively with water, saturated NaHCO3, water again, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 1.35 (6H, s), 1.40 (6H, s), 1.93 (2H, s), 7.17 (1H, dd, J-8.4 Hz, 2.1 Hz), 7.23 (1H, d, J-8.4 Hz), 7.26 (1H, d, J-2.1 Hz). MS exact mass, m/e 284.0221 (calcd. for C13H17S Br, 284.0234).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([C:14]2[CH:23]=[C:22]([CH3:24])[C:17]3[NH:18][C:19](=[O:21])[O:20][C:16]=3[CH:15]=2)=[O:13])[CH:11]=1)[C:7]#[N:8].I[CH3:26]>CN(C=O)C>[CH3:26][N:18]1[C:17]2[C:22]([CH3:24])=[CH:23][C:14]([C:12]([C:10]3[CH:9]=[C:6]([CH:5]=[C:4]([F:3])[CH:11]=3)[C:7]#[N:8])=[O:13])=[CH:15][C:16]=2[O:20][C:19]1=[O:21]
Reactant: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.161 g (3.70 mmol) sodium hydride (55%, suspension in mineral oil) were added to 1.00 g (3.38 mmol) 3-fluoro-5-(4-methyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-benzonitrile in 5 mL DMF at RT and stirred for 30 min at RT. Then 0.317 mL (5.00 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then a further 0.1 mL iodomethane were added and stirring was continued at RT. After dilution with ice water the aqueous phase was extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and dried i. vac.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH2:12]([O:15][CH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[CH2:13][CH3:14].[OH-].[Na+]>O>[CH2:12]([O:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH2:23])=[CH:24][CH:25]=1)[CH2:13][CH3:14]
Reactant: CCCOCCc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOCCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103 %

Procedure:
To a mixture of lithium aluminum hydride (120 mg, 2.5 mmol) and tetrahydrofuran (3 mL) was added 4-(2-propoxy-ethyl)-benzonitrile described in Preparation Example 196 (120 mg, 0.62 mmol), the solution was stirred overnight at room temperature. The reaction solution was cooled to 0° C., tetrahydrofuran (30 mL), water (0.12 mL), an aqueous solution of 5N sodium hydroxide (0.12 mL) and water (0.36 mL) were sequentially added dropwise. After stirring for 1 hour at room temperature, this reaction mixture was filtered through a filter paper. This filtrate was concentrated in vacuao, the residue was filtered using NH-silica gel, and the title compound (123 mg, 0.64 mmol, 103%) was obtained as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C>[OH:24]/[C:18](=[C:13]1/[CH2:12][O:11][CH2:16][CH2:15][C:14]/1=[O:17])/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)/C(O)=C1\COCCC1=O
Temperature: -72 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide 1M solution (30.0 ml, 30.0 mmol) and diethyl ether (40 ml) were added into a flask under nitrogen atmosphere and cooled to −72° C. with dry ice/acetone-bath. Tetrahydro-4H-pyran-4-one (3 g, 30.0 mmol) was diluted with diethyl ether (10 ml) and added slowly to the previously cooled mixture. The resulting mixture was stirred at −70° C. for one hour. Diethyl oxalate (4.07 ml, 30.0 mmol) diluted with diethyl ether (10 ml) was added and the reaction mixture was allowed to warm to RT and stirred overnight. The formed yellow precipitate was filtered, washed with cold diethyl ether and dried with vacuum at 40° C. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 1.92 (t, 2H), 3.68 (t, 2H), 3.98 (q, 2H), 4.19 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2ccc(F)cc2c1Cl
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1sc2ccc(F)cc2c1Cl

Procedure:
Following the 12a synthetic method, using B1 (55.33 mg, 0.25 mmol) instead of A1 gave 12b as a white powder; (87.65 mg, 92.8%). [α]D25: +22.3 (c=0.29, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.11-8.06 (m, 1H), 7.81 (d, J=7.2, 1H), 7.61-7.57 (m, 1H), 7.46-7.22 (m, 6H), 5.03-4.97 (m, 1H), 3.40-3.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.50, 163.02, 159.80, 138.09, 136.66, 135.36, 133.46, 129.49, 128.39, 126.88, 125.29, 118.28, 116.80, 116.46, 108.25, 107.93, 54.14, 36.79; HRMS (ESI): calcd for: C18H13ClFNO3S [M−H]−=376.0216, obsd [M−H]−=376.0221.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].O.C1COCC1.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
An 18-mL vial was charged with methyl 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate (20 mg, 0.053 mmol, 1 eq.) and LiOH/H2O (47.4 mg, 1.13 mmol, 21 eq.). THF (1 ml), H2O (0.3 ml) and MeOH (0.2 ml) was added to the vial. The resulting mixture was stirred at room temperature overnight. 2 N HCl aq. (0.5 ml) was added and the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using 5% of methanol in dichloromethane as eluent to give 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoic acid (4.8 mg, 25% yield). MW=364.82. 1H NMR (DMSO-D6, 360 MHz) δ 8.65 (s, 1H), 7.96 (s, 1H), 7.86 (m, 3H), 7.42 (m, 3H), 7.25 (d, J=8.31 Hz, 2H), 2.92 (t, J=7.86, 2H), 2.82 (t, J=6.93, 2H), 2.06 (m, 2H).
Reaction SMILES: [Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][C:28]([CH2:30][OH:31])=[CH:29][C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](OC1C2CCC=C(CO)CC=2C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)[C:33]1C=CC=CC=1.[Zn](CC)CC.ICI.Cl>C(Cl)Cl>[Si:1]([O:18][C:19]1[C:24]2[CH2:25][CH2:26][CH2:27][C:28]3([CH2:30][OH:31])[CH2:33][CH:29]3[C:23]=2[CH:22]=[CH:21][CH:20]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C(CO)C2)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCCC(CO)=C2)(c1ccccc1)c1ccccc1
Agent: CC[Zn]CC
Agent: Cl
Solvent: ICI
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC1(CO)CC21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a mixture of [1-(tert-butyldiphenylsilyloxy)-8,9-dihydro-7H -benzocyclohepten-6-yl]methanol and [1-(tert-butyldiphenylsilyloxy)-8,9-dihydro-5H-benzocyclohepten-6-yl]methanol (891 mg) in CH2Cl2 (10 ml) were added Et2Zn (1.0M hexane solution, 6.24 ml) and diiodomethane (0.838 ml) at −10 to −30° C. The mixture was stirred at the same temperature for 30 minutes. Then after warming to room temperature, the mixture was stirred for 8 hours. After addition of 1N-hydrochloric acid at 5° C., the resultant was extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 3:1) to give [5-(tert-butyldiphenylsilyloxy)-1,1a,2,3,4,8b-hexahydrobenzo[a]cyclopropa[c]cyclohepten-1a-yl]methanol (646.7 mg) as an amorphous solid.
Reaction SMILES: ClC1C=[C:4]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]3)[C:9]2=[O:19])C=CC=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO>[NH2:26][CH:14]1[CH2:15][CH2:16][CH2:17][C:10]2([C:9](=[O:19])[N:8]([CH3:4])[CH2:12][CH2:11]2)[CH2:13]1
Reactant: O=C1CCCC2(CCN(c3cccc(Cl)c3)C2=O)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CN1CCC2(CCCC(N)C2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 142.2 %

Procedure:
To a round bottom flask was added 2-(3-chloro-phenyl)-2-aza-spiro[4.5]decane-1,7-dione of step 5 (0.38 g, 1.35 mmol), methanol (4.92 mL), and ammonium acetate (1.25 g, 16.2 mmol). The mixture was stirred at rt for 1 hr. Sodium cyanoborohydride (0.085 g, 1.35 mmol) was then added. After stirring at rt for 2 hrs, the reaction mixture was quenched with ice and diluted with ethyl acetate (60 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 0.35 g (94%) of the title compound, 7-amino-2-methyl-2-aza-spiro[4.5]decan-1-one, as a white solid. The title compound is a mixture of two diastereomers (trans/cis: 5/2; under LC-MS method C, the first peak with RT of 0.80 min was assigned as cis, and the second peak with RT of 0.83 min was assigned as trans.). ESI-MS m/z: 279 (M+H)+. It was used without further purification.