Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[N:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[O-:33][N+:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][OH:24])=[CH:21][CH:22]=3)=[N:9]2)=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCc1ccc(-c2nc3cnccc3cc2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2c1

Procedure:
To a solution of [4-(3-phenyl-1,7-naphthyridin-2-yl)phenyl]methanol (142 mg, 0.455 mmol) in chloroform (3 mL) was added a solution of m-chloroperbenzoic acid (85%, 105 mg, 0.47 mmol) in chloroform (2 mL). The reaction was stirred over night and then the solvent was removed in vacuo. The residue was digested with diethyl ether twice to remove the m-chlorobenzoic acid and give the title compound as a yellow solid. 1H-NMR (500 MHz, CDCl3): δ 9.07 (1H, s), 8.24 (1H, d, J=6.8 Hz), 8.09 (1H, s), 7.70 (1H, d, J=7.1 Hz), 7.41 (2H, d, J=8.1 Hz), 7.22-7.39 (7H, m), 4.71 (2H, s). m/e (m+1): 329.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH:15]=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:17])[C:14]=1[CH2:15][OH:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(C=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(F)c(CO)c(F)c1
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
To a stirred solution of tert-butyl 3,5-difluoro-4-formylbenzoate (21 g, 86.7 mmol) in MeOH was portionwise added NaBH4 (3.28 g, 86.7 mmol) at 0° C. After 20 min, the reaction mixture was evaporated in vacuo and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=4:1) to give tert-butyl 3,5-difluoro-4-(hydroxymethyl)benzoate (20.7 g, 97%) as a white solid.
Reaction SMILES: [CH:1]1([C:4](=[O:24])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]=2[Br:23])=[O:7])[CH2:3][CH2:2]1.[CH2:25]([O:27][CH:28](OCC)OCC)[CH3:26]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:24])[C:5](=[CH:28][O:27][CH2:25][CH3:26])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C:9]=2[Br:23])=[O:7])[CH2:3][CH2:2]1
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1Br
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)c(OCCOC)c1Br)C(=O)C1CC1
Yield: 100 %

Procedure:
A mixture of 3-cyclopropyl-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (7.5 g) and triethylorthoformate (10.3 g) in acetic anhydride was stirred and heated at reflux for 3 hours. It was evaporated to dryness and the residue was treated with xylene and re-evaporated to give crude 3-cyclopropyl-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]-2-ethoxymethylenepropan-1,3-dione (8.5 g) as a dark brown oil which was not purified further.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:16]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)=[O:14])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[BH4-].[Na+].O>CCO>[CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[N:16]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[N:19]=2)[OH:14])[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(CCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC1(CCCCCC(O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Reaction time: 1 h

Procedure:
To a solution of the ketone F1 in EtOH (0.04 M solution) at 0° C. was added NaBH4 (2.0 eq.) and the mixture was stirred for 1 hr. Water was slowly added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and solvents were removed under reduced pressure. The crude product was used without purification in the next step. MS (ES) C30H44N2O4Si requires: 525, found: 526 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:12]([C:22]3[CH2:27][CH2:26][CH:25]([O:28][Si](C(C)(C)C)(C)C)[CH2:24][CH:23]=3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]>CCO.Cl>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:12]([C:22]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH:23]=3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2c(n1)c(C1=CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCCCNc1ncc2c(n1)c(C1=CCC(O)CC1)cn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-butyl-7-(4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl)-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (0.12 g, 0.25 mmol) in EtOH (5 mL) was added 2 drops of concentrated HCl solution. The resulting reaction mixture was stirred at room temperature for 16 h and concentrated to give the desired product use as such. 1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 8.23 (s, 1H), 7.66-7.58 (m, 2H), 7.40-7.31 (m, 2H), 6.88 (s, 1H), 4.05-3.93 (m, 1H), 3.54 (t, J=7.2 Hz, 2H), 2.77-2.66 (m, 1H), 2.63-2.51 (m, 2H), 2.28-2.16 (m, 1H), 2.11-1.99 (m, 1H), 1.85-1.75 (m, 1H), 1.75-1.65 (m, 2H), 1.54-1.40 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); MS m/z 381.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=4)[CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3ccc(Br)cc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Cn2ccc3ccc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1
Yield: 61.4 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (0.488 g, 1.43 mmol) was coupled to 4-trifluoromethoxybenzene boronic acid (0.329 g, 1.60 mmol), using tetrakis(triphenylphosphine)palladium (0.0574 g, 0.0496 mmol) and sodium carbonate (0.617 g, 5.82 mmol) in water (2.8 mL), ethanol (1.4 mL) and toluene (10 mL). Purification by flash chromatography using hexane as an eluant yielded 1-[4-(tert-butyl)benzyl]-6-[4-(trifluoromethoxy)phenyl]-1H-indole as a white solid (0.372 g, 61%), mp 100-102° C. 1HNMR (200 MHz, DMSO-d6): δ 7.8 (d, 3H, J=8.5 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=3.5 Hz), 7.3-7.5 (m, 5H), 7.15 (d, 2H, J=7.5 Hz), 6.5 (d, 1H, J=3.5 Hz), 5.45 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([O:38]C)=[CH:37][C:30]=3[N:29]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:30]=3[N:29]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1nc2cc(OC)ccc2n1C)[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1nc2cc(O)ccc2n1C)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)(5-methoxy-1-methyl-1H-benzimidazol-2-yl)amino]indane-5-carboxylate (0.40 g, 0.75 mmol) in 20 mL of anhydrous dichloromethane at −78° C. was slowly added BBr3 (1.0 M solution in CH2Cl2, 3.8 mL, 3.8 mmol) over 10 min. The reaction mixture was stirred at −78° C. for 30 min and then the cold bath was removed. The reaction was quenched after 20 min with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, dried over Na2SO4 and concentrated. Chromatography afforded butyl 1-[(trans-4-tert-butylcyclohexyl)(5-hydroxy-1-methyl-1H-benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC/MS: m/z=518.4 (M+1), Rt=2.45 min.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>ClCCl.C(N(CC)CC)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.7 %

Procedure:
To N—BOC-piperazine (500 mg) in dichloromethane (5 mL) and triethylamine (0.41 ml) was added 4-nitrophenyl chloroformate (541 mg). After 1 hour the reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (940 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1)=[O:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2C=O)cc1F

Procedure:
4-(2′-N,N-Dimethylaminomethylphenyl)-2-fluoroaniline: To a solution of 2-formylphenylboronic acid (5 g, 33 mmol) in THF (80 mL) was added 4-bromo-2-fluoroaniline (4.2 g, 22 mmol) and sodium carbonate (2 M, 80 mL) and then was bubbled with nitrogen for 10 min. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 h. The THF layer was separated and filtered through a pad of silica gel. The pad was washed with THF to give an 80 mL solution of 4(2′-formylphenyl)-2-fluoroaniline in THF. To the filtrate (15 mL from total 80 mL) was added Me2NH·HCl (0.68 g, 8.3 mmol) and the resulting mixture was refluxed for 2 h. The mixture was cooled to rt and MeOH (5 mL) was added followed by NaBH4 (0.32 g, 8.3 mmoL). After being stirred at 50° C. for 1 hour, the mixture was cooled to rt and quenched with 1 N HCl to pH 1. The aqueous layer was separated, neutralized with 50% NaOH to pH 12, and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated, and purified by SiO2 chromatography eluted with EtOAc to give 54a (0.89 g, 88% yield); [M+H]+=245.2; 1H NMR (CDCl3) δ 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.31-7.21 (m, 3H), 7.14 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 6.80 (t, J=8.8 Hz, 1H), 3.76 (bs, 2H), 3.34 (s, 2H), 2.17 (s, 6H); 19F NMR (CDCl3) δ −136.19. This material was converted to the bis-HCl salt by dissolving a sample in a minimum volume of methanol and adding 2.2 equivalents of 1.0 M HCl in diethyl ether followed by removal of the solvent under reduced pressure.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH2:17]([O:16][C:14]([NH:13][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:15])[CH3:18]
Reactant: CCOC(N)=O
Reactant: CCOC(=O)C1CCCCC1=O
Product: CCOC(=O)NC1=C(C(=O)OCC)CCCC1

Procedure:
Using the method of Example 1 Part A, ethyl 2-oxocyclohexanecarboxylate (201 g, 1.18 mole) was reacted with urethane to provide 135 g of ethyl 2-[(ethoxycarbonyl)amino]-1-cyclohexene-1-carboxylate as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C([O-])(=O)C.[NH2+]1CCCCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:9](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Reactant: COc1ccc(C=O)cc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C(/C(=O)OC(C)(C)C)C(=O)c2ccccc2O)cc1
Temperature: 22 °C
Reaction time: 168 h
Yield: 70.5 %

Procedure:
Prepared according to general procedure B using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (236 mg, 1.0 mmol), p-anisaldehyde (115 μL, 1.0 mmol), 12.0 mL toluene, piperidinium acetate (0.3 mL, 0.025 M in toluene) and sodium sulfate (2.0 g), stirred at 22° C. for 7 d. Purified via recrystallization from hexanes/CH2Cl2, yielding 250 mg (71%) of white crystals. mp=129-132° C.; IR (film) 2982.5; 1708.9; 1603.8; 1246.8; 1155.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.97 (bs, 1H); 7.80 (s, 1H); 7.56 (d, J=8.0 Hz, 1H); 7.48 (t, J=7.4 Hz, 1H); 7.32-6.79 (AA′BB′, 4H), 7.04 (t, J=8.6 Hz, 1H), 6.82 (m, 1H), 3.78 (s, 3H); 1.40 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 202.3, 164.1, 162.9, 161.6, 142.0, 137.1, 132.4, 132.0, 128.9, 125.3, 120.2, 119.5, 118.5, 114.7, 82.5, 55.6, 28.1; LRMS (electrospray): Mass calculated for C21H22O5 [M]+, 354.14. Found [M+23]+, 377.5. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1C=CC=CC=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:21])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(Cl)cc1C(=O)Cl
Yield: 72 %

Procedure:
5-Chloro-2-methoxybenzoic acid (19 g.) was heated in thionyl chloride 64 ml.) under reflux for 1 hour. Benzene (100 ml.) was then added, and evaporated off under reduced pressure. The solid residue was recrystallized from hexane to give the required product (15 g., 72%) m.p. 59°-60°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[B:23](OC)([O:26]C)[O:24]C.Cl>CCCCCC.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:23]([OH:26])[OH:24])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of n-butylithium (50.97 cm3, 0.1274 mol, 2.5M in hexane) was added dropwise to a cooled (−78° C.) stirred solution of 4-bromo-4′-octyloxybiphenyl (40.00 g, 0.1108 mol) in THF (400 cm3). After 1 h, trimethyl borate (23.05 g, 0.2216 mol) was added dropwise to the reaction mixture maintaining a temperature of −78° C. The reaction mixture was allowed to warm to room temperature overnight. 20% hydrochloric acid (350 cm3) was added and the resultant mixture stirred for 1 h. The product was extracted into diethyl ether (3×300 cm3). The combined organic layers were washed with water (300 cm3), dried (MgSO4), filtered and the filtrate evaporated down under partially reduced pressure. The crude product was stirred with hexane for 30 minutes and filtered off to yield a white powder (26.20 g, 73%, m.pt. 134-136° C.).
Reaction SMILES: CO[C:3]1[C:11]([CH2:12][CH:13]([NH:27][C:28](=[O:40])[CH2:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][N:34]([CH3:39])[CH2:33]3)[B:14]2[O:22]C3C(C)(C4CC(C3)C4(C)C)[O:15]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl>O1CCOCC1>[OH:15][B:14]1[C@@H:13]([NH:27][C:28](=[O:40])[CH2:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][N:34]([CH3:39])[CH2:33]3)[CH2:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=2[O:22]1
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CN1Cc2ccc(CC(=O)N[C@H]3Cc4cccc(C(=O)O)c4OB3O)cc2C1
Temperature: 100 °C

Procedure:
To a mixture of 2-Methoxy-3-[2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid (0.113 g, 0.207 mmol) and 1,4-dioxane (2.0 mL) was added 3N HCl (1.7 mL, 5.10 mmol) and the reaction was heated at 100° C. for 1 hr. The reaction was cooled to room temperature and extracted with diethyl ether (3×). The product remained in the aqueous layer and was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 381 (MH)+.
Reaction SMILES: [CH:1]([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[CH2:28]([O:30][C:31]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31](/[CH:33]=[CH:1]/[C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:32])[CH3:29]
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/[C@]1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 1.25 h

Procedure:
500 mg (1.30 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 20 ml of THF under argon and treated with 500 mg (1.40 mmol) of ethoxycarbonylmethylene-triphenylphosphorane. The yellow solution was stirred at 50° C. for 75 minutes and subsequently concentrated. The residue remaining behind was chromatographed over silica gel (0.040-0.063 mm particle size) with ethyl acetate:hexane (9:16) as the eluent.
Reaction SMILES: N1CCCCC1.C1C2C([CH2:20][O:21][C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][O:31][CH3:32])[C:26]([OH:28])=[O:27])=[O:23])C3C(=CC=CC=3)C=2C=CC=1.C([O-])([O-])=O.[Na+].[Na+].ClC(OC)=O.Cl>CN(C=O)C>[CH3:32][O:31][CH2:30][CH2:29][C@H:25]([NH:24][C:22]([O:21][CH3:20])=[O:23])[C:26]([OH:28])=[O:27]
Reactant: COCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COCC[C@H](NC(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
Piperidine (1.0 mL, 10 mmol) was added to a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxybutanoic acid (0.355 g, 1 mmol) in DMF (3 mL), and the mixture was stirred at rt for 3 h. The volatiles were removed and the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL). The aqueous layer was further washed with EtOAc and Et2O. To the aqueous solution was added Na2CO3 (212 mg, 2.0 mmol) followed by methyl chloroformate (0.16 mL, 2.0 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with 1 N HCl (aq.) until pH <7 and then extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%) to yield (S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (Cap-194) (91.5 mg) as viscous colorless oil. LC-MS retention time=0.61 min; m/z 214 [M+Na]+. (Column: PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, chloroform-d) δ ppm 7.41 (br. s., 1H), 5.74-6.02 (m, 1H), 4.32-4.56 (m, 1H), 3.70 (s, 3H), 3.54 (t, J=5.0 Hz, 2H), 3.34 (s, 3H), 1.99-2.23 (m, 2H).
Reaction SMILES: C1(CCCC[OH:11])C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1.[CH2:23]1[CH2:30][CH:29]2[N:31]([O])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH2:23]1[CH:30]2[CH:29]3[NH+:31]([O-:11])[CH:25]([CH2:24]2)[CH2:26][CH:27]1[CH2:28]3
Reactant: OCCCCc1ccccc1
Reactant: [O]N1C2CCCC1CCC2
Agent: CC1(C)CCCC(C)(C)N1[O]
Product: [O-][NH+]1C2CC3CC(C2)C1C3

Procedure:
In the oxidation of 4-phenylbutanol (entry 1), which is a primary alcohol, when the catalyst amount was 1 mol %, all the catalyst compounds gave the objective substance in a high yield, but when the catalyst amount was reduced, marked differences was observed in the catalytic activity. Specifically, in the case of using TEMPO, when the catalyst amount was reduced to 0.01 mol %, marked decrease of the yield was observed, and in the case of ABNO, when the catalyst amount was reduced to 0.003 mol %, the yield decreased to about 60%. In contrast, Nor-AZADO gave the objective substance in a high yield even when the catalyst amount was reduced to 0.003 mol %.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]([CH2:7][Br:8])=[CH2:6])=[CH2:4].[CH2:9](NC(OCC)=O)[NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClC(Cl)C.B(F)(F)F.CCOCC>[C:11]([N:10]1[CH2:4][C:3]([CH2:2][Br:1])=[C:5]([CH2:7][Br:8])[CH2:6][CH2:9]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=C(CBr)C(=C)CBr
Reactant: CCOC(=O)NCNC(=O)OCC
Agent: FB(F)F
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)N1CCC(CBr)=C(CBr)C1
Yield: 90 %

Procedure:
To a solution of 2,3-bis (bromomethyl)-1,3-butadiene (4.8 g) and methylenediurethane (3.9 g) in dichloroethane (40 ml), borontrifluoride etherate (0.3 ml) was added. The reaction mixture was refluxed for 10 hours and washed with 10% sodium bicarbonate solution (30 ml×3). The organic phase was filtered though silicagel and evaporation of the solvent to give 1-carboethoxy-4,5-bis(bromomethyl)-1,2,3,6-tetrahydropyridine (6.14 g, yield 90%) which was cyclized with 40% methylamine (1.8 ml) and potassium carbonate (15 g) in acetonitrile (50 ml) for 2 hours at room temperature. The solid was filtered off and the filtrate was purified by silicagel column chromatography to give 3-carboethoxy-8-methyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene (2.57 g, yield 68%). This amine was refluxed in 20% hydrochloric acid (50 ml) and evaporation gave the title compound (1.35 g, yield 80%).