Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[OH:27]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[CH:24]=[C:23]4[C:19]([CH2:20][CH2:21][CH2:22]4)=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: [O-][n+]1nc(NCCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: CO
Product: [O-][n+]1nc(NCCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 3.6 mL, ca. 72 mmol) was added dropwise to a stirred solution of TFAA (10.2 mL, 72 mmol) in DCM (25 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 62 (2.48 g, 7.2 mmol) and TFA (2.8 mL, 36 mmol) in DCM (25 mL) at 0° C. The solution was stirred at 20° C. for 16 h, cooled to 0° C. and made basic with dilute aqueous NH3 solution and stirred vigorously for 30 min. The mixture was extracted with CHCl3 (4×50 mL), the combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 62 (981 mg, 40%) and (ii) 1,4-dioxide 63 (504 mg, 19%) as a red solid: mp (MeOH) 140-141° C.; 1H NMR δ 8.09 (s, 2H, H-5, H-9), 7.32 (br s, 1H, NH), 3.74 (br t, J=4.6 Hz, 4H, 2×CH2O), 3.57-3.63 (m, 2H, CH2N), 3.09 (br t, J=7.5 Hz, 2H, H-6), 3.05 (br t, J=7.5 Hz, 2H, H-8), 2.50-2.55 (m, 4H, 2×CH2N), 2.47 (br t, J=7.1 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.71-1.79 (m, 2H, CH2), 1.61-1.69 (m, 2H, CH2); 13C NMR δ 155.9, 149.5, 145.8, 137.9, 129.8, 115.7, 111.6, 66.6 (2), 58.1, 53.5 (2), 41.2, 33.4, 32.4, 27.1, 25.5, 23.4; HRMS (FAB+) calcd for C18H26N5O3 (MH+) m/z 360.2036, found 360.2039.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[BrH:14].[CH3:15]COC(C)=O>>[Br:14][CH2:15][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:12]
Reactant: CCOC(C)=O
Reactant: Br
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Yield: 60 %

Procedure:
This was prepared following the method of Example 3A. The intermediate diazoketone was prepared from 1-adamantane carboxylic acid chloride (2.98 g, 15 mmol) and CH2N2 (generated from Diazald® 8.7 g, 40 mmol) and subsequently treated with a saturated solution of HBr in EtOAc. Flash chromatography on silica gel (eluant EtOAc:hexane fr 8:92) afforded the title compound as a pale brown mobile oil (2.30 g, 60%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:22]1[CH2:24][CH:23]1[C:25](O)=[O:26])#[N:21]>>[C:20]([CH:22]1[CH2:24][CH:23]1[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])#[N:21]
Reactant: N#CC1CC1C(=O)O
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: N#CC1CC1C(=O)NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Yield: 29 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 2-cyanocyclopropanecarboxylic acid as described in example 8 step 6 (90 mg, yield 29%): 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.52-7.46 (m, 3H), 7.41-7.37 (m, 1H), 6.72 (t, J=5.3 Hz, 1H), 3.92-3.86 (m, 2H), 3.75-3.68 (m, 4H), 2.30-2.22 (dddd, J=13.2 Hz, 9.8 Hz, 6.5 Hz, 3.4 Hz, 2H), 1.99-1.89 (m, 4H), 1.52-1.47 (ddd, J=9.1 Hz, 5.8 Hz, 4.6 Hz, 1H), 1.38-1.33 (ddd, J=8.6 Hz, 6.1 Hz, 4.9 Hz, 1H). MS (ESI) m/z: Calculated for C20H21N3O2S: 367.14. found: 368.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C[N+]1([O-])CC[O:23]CC1.ClCCl.[OH2:30]>CC(C)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[OH:30][CH:10]([CH2:11][OH:23])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCCCCCCCCCN1CCCCC1=O
Reactant: O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1CCCCN1CCCCCCCCCC(O)CO
Reaction time: 72 h
Yield: 93 %

Procedure:
To a mixture of N-(10-Undecenyl)-2-piperidone (4.00 g, 16 mmol) and a 60% aqueous solution of N-methylmorpholine-N-oxide (5 mL, 29 mmol) in water (10 mL) and acetone (20 mL) was added potassium osmate dihydrate (12 mg, 0.03 mmol). After stirring for 3 days, the mixture was treated with sodium dithionite (100 mg). After 30 minutes, dichloromethane (50 mL) and water (30 mL) were added and the organic layer separated. The aqueous layer was extracted with dichloromethane/10% methanol (2×70 mL). The combined organic extracts were dried over sodium sulfate and the solvents evaporated under vacuum. The residue was purified by chromatography using silica and ethyl acetate/methanol in a 0-20% gradient to yield 4.21 g (93%) N-(10,11-Dihydroxyundecyl)-2-piperidone (inventive compound no. 1617) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.05 g, 10 mmol) were mixed in 1,2-dchloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: CC(OC([N:8]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9]1)=O)(C)C.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[NH:8]1[CH2:9][CH2:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C1CCCNC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(S)-Nip.(S)-CSA 1.1. (1S)-(+)-10-Camphorsulfonic acid (11.62 g, 0.05 mol) was added to a stirred solution of racemic nipecotic acid (6.46 g, 0.05 mol) in acetone (100 mL). The solution was heated to reflux, and H2O (15 mL) was added until all solids dissolved. The solution was cooled to room temperature and allowed to stir overnight. The precipitate that formed was isolated by filtration and recrystallized three times with acetone/H2O (6/1, v/v) to afford 1.99 g (11% yield) of the desired product as a white solid: m.p. 221-223° C.; {a}D+25.3° (c 1.0, MeOH). Boc-(S)-Nip-OH 1.2. (S)-Nip.(S)-CSA (1.90 g, 5.3 mmol) was dissolved in methanol (12 mL). Triethylamine (2.2 mL, 15.8 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.3 mmol) were added and the solution was stirred at 50° C. for 12 h. The solution was then concentrated, and the residue was dissolved in H2O. The aqueous solution was washed with diethyl ether, and the organic layer was discarded. The aqueous layer was acidified to pH 3 with 1 M HCl and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to afford 1.24 g (quantitative yield) of the desired product as a white solid: m.p. 166-168° C.; FAB-MS m/z (M+Na+) calcd for C11H19NO4Na 252.3, obsd 252.5. Boc-(S)-Nip-OBn 1.3. Boc-(S)-Nip-OH (0.70 g, 3.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (14 mL). Cs2CO3 (1.0 g, 3.1 mmol) and benzyl bromide (0.41 mL, 3.5 mmol) were added, and the solution was stirred at room temperature for 24 h. The solution was then concentrated, and the residue was dissolved in H2O. The aqueous solution was then extracted with CH2Cl2. The organic solution was dried over MgSO4 and concentrated to give an oil. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (1/3, v/v) to afford 0.81 g (82% yield) of the desired product as a white solid. 2. Oligomer Synthesis
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C@@H:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CO>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][O:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C@@H:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCN1CCO[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Yield: 89.4 %

Procedure:
A solution of 0.15 g (0.28 mmol) of 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-4-(methoxycarbonylpentyl)-3-(R)-phenylmorpholine (from Example 64) in 3 mL of MeOH was saponified by treating with 0.5 mL of 5N NaOH for 40 min at 65° C. The solution was cooled, concentrated and the residue was diluted with water. The aqueous solution was adjusted to pH 6 by adding 2N HCl and it was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue upon chromatography on a flash column with 50% EtOAc/hexane furnished 0.13g (89%) of the product
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][CH3:15])[CH:8]=[CH:7]2.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14][CH3:15])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc(O)ccc2n1
Reactant: BrCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(OCCCCCCCCBr)ccc2n1
Temperature: 0 °C

Procedure:
Sodium hydride (60% in oil, 40 mg) was suspended in DMF (2 ml), and was cooled to 0° C. in ice water bath. 6-Hydroxy-2-methoxyquinoline (171 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for an hour. 1,8-Dibromooctane (0.37 ml) was added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (225 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Reactant: O=C1CCC(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccc(S(=O)(=O)NC(=O)CCC(=O)O)cc2)nn1C(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (0.10 g, 0.25 mmol) and THF (10 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (0.28 mL, 1.0 M solution in THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then succinic anhydride (28 mg in 5 mL THF, 0.28 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. A few drops of acetic acid was added, then the mixture was concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/8:2) to afford the desired product (39 mg, 31%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (d, 2H), 7.63 (m, 1H), 7.42 (d, 2H), 7.15 (t, 2H), 2.41 (br s, 4H); MS (ESI) m/z: 493 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:34]I>CC#N.[Ag]=O>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:29])/[CH:21]([O:28][CH3:34])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:30][CH3:31])[C:15]([CH3:32])=[C:14]2[C:10]=1[C:11](=[O:33])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: CCOC(=O)CC(OC)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl (E)-6-(1,3-dihydro-4-tert -butyldimethylsilyloxy-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-4-methyl-4-hexenoate (974 mg) was dissolved in a 6:1 mixture of methyl iodide in CH3CN (25 ml). Silver oxide was then added (5.1 g) and the mixture heated at reflux for 24 hr. The mixture was cooled to room temperature and filtered through a bed of celite. The celite was washed with CH2Cl2 (80 ml) and ethyl acetate (80 ml). The combined organic layers were evaporated to dryness and the residue passed through a flash column (silica gel, hexanes-EtOAc 8:2) to afford 601 mg (60%) of ethyl (E)-6-(1,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -3-methoxy-4-methyl-4-hexenoate the product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Li+].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CN(C)C=O>[CH2:18]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][C:2]=1[OH:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Temperature: 50 °C
Reaction time: 14.5 h

Procedure:
To a solution of 3′,4′-dihydroxyacetophenone (2.00 g) in N,N-dimethylformamide (40 ml) were added lithium carbonate (2.44 g) and benzyl bromide (4.0 ml), and the mixture was stirred for 14.5 hours at 50° C. To the reaction mixture was added 1N hydrochloric acid, and the resulting mixture was extracted with a mixed solution of diethyl ether and ethyl acetate (3/1). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) gave 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g). To a stirred solution of the obtained 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine (2.2 ml) under ice-cooling, and the mixture was stirred for 10 minutes. Chloromethylmethyl ether (1.2 ml) was added to the mixture, and the resulting mixture was stirred for 5.5 hours at room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) gave 4′-benzyloxy-3′-methoxymethoxyacetophenone (2.28 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH2:4][CH:3]1[NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25].[C:27](=O)([O-])[O-].[K+].[K+].IC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:27][N:8]1[C:2](=[O:1])[CH:3]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH2:4][C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: O=C(CCc1ccc(Cl)cc1Cl)NC1CC(=O)c2ccccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)CCc2ccc(Cl)cc2Cl)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
A 100 mL round bottom flask was charged with N-(2,5-dioxo-3,4-dihydro-1H-benzo[b]azepin-3-yl)-3-(2,4-dichlorophenyl)-propionamide (2.5 g, 6.38 mmole), potassium carbonate (1.76 g, 12.7 mmole), DMF (20 mL), and iodomethane (3.55 g, 25 mmole). The reaction mixture was stirred at room temperature for 5 hr. and then poured into saturated sodium bicarbonate (500 mL). The aqueous mixture was extracted with ethyl acetate (3×200 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting solid was swished with a minimum of warm ether and filtered to give 2.1 g (81%) of the product. mp 182°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:23])=O)=[CH:15][CH:14]=1.C[N:28]([CH:30]=O)C.CC([N:35](C)C)=O>>[N:28]1[N:35]=[C:21]([C:20]2[CH:19]=[C:18]([C:16]3[O:17][C:13]([CH:12]=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=5)[NH:7][C:6]4=[O:11])=[CH:14][CH:15]=3)[CH:26]=[CH:25][CH:24]=2)[NH:23][CH:30]=1
Reactant: CC(=O)N(C)C
Reactant: NC(=O)c1cccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)c1
Reactant: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2cccc(-c3nnc[nH]3)c2)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzamide (100 mg, 0.275 mmol) in 5 mL DMF/DMA was stirred at 80° C. during 2 hr. DMF was evaporated and AcOH (10 mL) added. Hydrazine (1 mL) was added dropwise, the mixture was stirred during 10 minutes at R.T., then 45 minutes at 80° C. Water was added and the solid formed isolated by filtration and dried under vacuum. The product was purified by preparative TLC (DCM/MeOH 1%). LCMS (M+1)=389.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=CC(Cl)=CC=1)=O.ClC1C=CC([C@@H](O)C)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Cl)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: C[C@H](O)c1ccc(Cl)cc1
Product: C[C@@H](O)c1ccc(Cl)cc1
Reaction time: 312 h
Yield: 58 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized buckwheat protein for the substrate (±)-1-(4-chlorophenyl)ethanol (200 mg) requires 13 days by going through bioconversion to 4-chloroacetophenone accompanying sterically selective oxidation of (S)-1-(4-chlorophenyl)ethanol to obtain 116 mg of (R)-1-(4-chlorophenyl)ethanol at a yield of 58%. Optical purity was obtained at 91% e.e.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:15]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.00 g, 13.8 mmol) in anhydrous DMF (6.5 mL) was added sodium hydride (827 mg of 60% dispersion in oil, 20.7 mmol). The mixture was stirred for 30 min at room temperature. Ethyl iodide (2.22 mL, 27.5 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, gradient elution of CH2Cl2 to 5% MeOH/CH2Cl2) gave the title compound (1-ethyl-1H-indole-4-carbaldehyde) (2.43 g, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.68-7.64 (m, 2H), 7.37-7.32 (m, 1H), 7.08 (d, J=3.0, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[C:12]1([N:18]2[C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:21](=[O:28])[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:25]1[CH2:24][CH2:23][C:22]2([N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][NH:20][C:21]2=[O:28])[CH2:27][CH2:26]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C1CCc2c(Cl)cccc21
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)cccc31)CC2

Procedure:
The title compound, white solid, m.p.>230° C. and MS: m/e=382.2 (M+H+) was prepared in accordance with the general method of example 34 from 4-chloro-indan-1-one and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([O:44]C)=[O:43])=[CH:40][C:39]=2[Cl:48])=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]2[CH:47]=[CH:46][C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]=2[Cl:48])=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3F)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccc(C(=O)O)cc2Cl)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a mixture of 330 mg of the crude methyl 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoate and 10 mL of THF-5.0 mL of methanol was added dropwise 5.0 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring overnight. It was neutralized by addition of 5.2 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 274 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoic acid as a pale yellow amorphous substance. ESI+: 660