Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:32](Cl)=[O:33]>>[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([F:38])[CH:37]=1)[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1)=[O:33]
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: Cc1ccc(NC(=O)c2cc(F)cc(F)c2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described in Example 5, 3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one was reacted with 3,5-difluorobenzoyl chloride to give the title compound; NMR Spectrum: (DMSOd6) 1.84-1.96 (m, 2H), 2.05 (s, 3H), 2.25 (s, 3H), 2.42-2.5 (m, 2H), 2.62-2.64 (m, 2H), 3.53 (t, 2H), 3.58-3.64 (m, 2H), 7.24 (d, 1H), 7.38 (m, 1H), 7.40-7.44 (m, 1H), 7.48-7.54 (m, 1H), 7.58 (d, 1H), 7.64-7.67 (m, 2H), 7.75-7.78 (m, 2H), 7.96 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.Br[C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:45][CH2:44][CH2:43][N:42]2[CH3:46])=[CH:37][CH:36]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:46][N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[CH:39]=[CH:40][C:35]([NH2:6])=[CH:36][CH:37]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1CCCC1c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1CCCC1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LiHMDS (5.0 g, 30.0 mmol) is added to a 250 mL round bottom flask. Toluene (60 mL) is then added followed by addition of Pd2(dba)3.CHCl3 (390 mg, 0.39 mmol) and P(tBu)3.HBF4 (300 mg, 1.03 mmol) and 2-(4-Bromo-phenyl)-1-methyl-pyrrolidine (3.5 g, 14.5 mmol). The mixture is degassed. The resulting mixture is then stirred at room temperature overnight. After TLC suggested no starting bromide left, the reaction mixture is diluted with ether and poured into dilute HCl (aq). The ether layer is discarded, the aqueous layer is basified with NH4OH and extracted with CH2Cl2. The CH2Cl2 layer is dried and concentrated. The residue is judged by NMR to be 90% purity product (2.52 g, 90%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].Cl.[NH2:25][OH:26].[OH-].[Na+]>ClCCl>[OH:26]/[N:25]=[C:20](\[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])/[C:21]([OH:23])=[O:22]
Reactant: NO
Reactant: O=C(O)CCCCCCCCCO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCC/C(=N\O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of dimethyl sulfoxide (1.17 g, 15 mmol) in dichloromethane (50 mL) is cooled to −30° C. and treated with oxalyl chloride (1.92 g, 15 mmol). The reaction mixture is then treated with 10-hydroxydecanoic acid (2.06 g, 10 mmol) in dichloromethane (50 mL) and allowed to warm to room temperature over a period of 2 h. The reaction is then washed with water (2×50 mL). The organic layer is dried over sodium sulfate and then treated with hydroxylamine hydrochloride (1.03 g 15 mmol) and sodium hydroxide (0.6 g in 10 mL water) and stirred vigorously for 1 h. The organic phase is then separated dried over sodium sulfate and concentrated in vacuo to give 11[(E)-hydroxyimino-decanoic acid (1.8 g, 9.0 mmol).
Reaction SMILES: [C:1](=[O:19])(SCC)[O:2][O:3][CH:4]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[CH2:5][CH2:6][CH3:7].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][C:1]([O:2][O:3][CH:4]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[CH2:5][CH2:6][CH3:7])=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCC(OOC(=O)SCC)OC(=O)C1CCCC1
Solvent: ClCCl
Product: CCCC(OOC(=O)Cl)OC(=O)C1CCCC1

Procedure:
A solution of (67) (1.83 g, 6.34 mmol) in CH2Cl2 at 0° C. was treated with sulfuryl chloride (0.62 mL, 7.61 mmol) under N2 for 10 min, then the reaction mixture was concentrated to dryness in vacuo to afford crude (1-cyclopentanecarbonyloxy-butoxy) chloroformate in quantitative yield. The chloroformate was dissolved in CH2Cl2, and was added to a mixture of N-hydroxysuccinimide (1.09 g, 9.51 mmol) and pyridine (1.28 mL, 15.8 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then was washed with water, dilute HCl and brine and dried over Na2SO4. After removal of solvent in vacuo the title N-hydroxysuccinimidyl carbonate (68) was obtained in quantitative yield, and was used in the subsequent step without further purification.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[N:12]1([C:18]([S-:20])=[S:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[NH2+]1CCCCC1.C(=S)=S>CO>[N:12]1([C:18]([S:20][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: S=C([S-])N1CCCCC1
Agent: C1CC[NH2+]CC1
Solvent: CO
Solvent: S=C=S
Product: O=[N+]([O-])CC(SC(=S)N1CCCCC1)c1ccccc1
Temperature: 8 °C

Procedure:
β-Nitrostyrene (14.9 grams, 0.10 mole) was added in portions to a stirred mixture of piperidinium 1-piperidinecarbodithioate (24.6 grams, 0.10 mole), and carbon disulfide (7.6 grams, 0.10 mole) in methanol (200 ml.). During the addition, the reaction temperature was 25° - 29° C. After the addition of β-nitrostyrene, the reaction mixture was cooled to 8° C., and the precipitated product was filtered off, washed with water, and dried in air. The yield of product melting at 85° - 87° C. (prior sintering) was 29.0 grams (93%). Repeated recrystallizations without heating from methylene chloride-hexane and methylene chloride-methanol solutions gave pure α-(nitromethyl)benzyl 1-piperidinecarbodithioate melting at 86° - 90.5° C. (prior sintering).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.Cl[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:26])[C:16]([C:23]([OH:25])=[O:24])=[CH:17][N:18]2[CH2:21][CH3:22])=[CH:13][C:12]=1[F:27]>N1C=CC=CC=1>[CH2:21]([N:18]1[C:19]2[C:14](=[CH:13][C:12]([F:27])=[C:11]([N:8]3[CH2:7][CH2:6][NH:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:9]3)[CH:20]=2)[C:15](=[O:26])[C:16]([C:23]([OH:25])=[O:24])=[CH:17]1)[CH3:22]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: COCC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC)C3)cc21

Procedure:
A 1.7 g portion of 2-(methoxymethyl)piperazine was dissolved in 8 ml of pyridine. A 0.88 g portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon, at 120°-130° C. for 18 hours. The solvents were removed and the resulting gum evaporated three times from toluene. The residue was purified by column chromatography, eluting with chloroform:methanol saturated with water (90:10). The appropriate fractions were combined and evaporated, giving 550 mg of the desired product, mp 169°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[C:11]([Si](C)(C)C)#[CH:12].[OH-].[Na+]>CCN(CC)CC.C(OCC)(=O)C.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>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[CH:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#Cc1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (1.25 g, 6.34 mmol) and ethynyltrimethylsilane (2.42 g, 12.7 mmol) in dry Et3N (15 mL) was added under N2 Cu(I) (60 mg), Pd(PPh3)4 (360 mg) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was evaporated and the residue was dissolved in methanol (20 mL), treated with 1M aqueous NaOH solution (1.05 equiv.) and stirred at room temperature for 1 hour. Methanol was evaporated off and the aqueous residue was extracted with CH2Cl2, dried over MgSO4, and purified over silica gel (ethyl acetate/hexanes 75/25) to furnish the desired product in 93% yield as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.54 (s, 1H), 6.24 (br s, 2H), 6.76 (dd, J=0.8, 7.6 Hz, 1H), 6.82 (dd, J=0.8, 8.4 Hz, 1H), 7.28 (dd, J=7.6, 8.4 Hz, 1H). MS 143 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([O:13][C:14]2[C:15]3[C:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[O:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8]1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:21]1[O:20][C:16]2[N:17]=[CH:18][N:19]=[C:14]([O:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])[CH2:8]3)[C:15]=2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: COC(=O)CCCN1CCC[C@@H](Oc2ncnc3oc(-c4ccccc4F)c(-c4ccc(OC)cc4)c23)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(CCCC(=O)O)C4)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 113 mg (0.20 mmol) of 4-[(3R)-3-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]-pyrimidin-4-yl]oxy}piperidin-1-yl]butyric acid methyl ester in 3 ml of dioxane and add 0.8 ml of a 1 N sodium hydroxide solution. Stir at room temperature for 16 hours, then add 0.8 ml of 1 N hydrochloric acid and 10 ml of ethyl acetate. Remove the organic phase, dry over sodium sulphate, filter and concentrate. 95 mg (90% of theory) of the target compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[O:14][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)phenol (0.583 g, 2.82 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.850 g, 4.22 mmol), PPh3 (1.11 g, 4.22 mmol), DIAD (0.67 mL, 4.22 rnmol), and benzene (8.7 mL) was allowed to stir at rt until reaction was judged to be complete. The reaction mixture was concentrated. The resulting off-white solid was purified by column chromatography to give tert-butyl 4-(3-nitro-5-(trifluoromethyl) -phenoxy)piperidine-1-carboxylate (0.750 g, 66%). 1H NMR (400 MHz, CD3OD) δ: 8.05-7.97 (m, 2H), 7.64 (s, 1H), 4.84-4.78 (m, 1H), 3.75-3.69 (m, 2H), 3.42-3.35 (m, 2H), 2.03-1.96 (m, 2H), 1.77-1.69 (m, 2H), and 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH3:13])=[CH:4][C:3]=1[F:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:23]1(B(O)O)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH:23]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][C:9]=3[CH3:13])=[CH:4][C:3]=2[F:14])[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: Cc1ncoc1-c1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ncoc1-c1ccc(C2CC2)c(F)c1
Yield: 185.5 %

Procedure:
A mixture of Example 36A (870 mg, 3.40 mmol), Pd(OAc)2 (38.1 mg, 0.170 mmol), tricyclohexylphosphine (95 mg, 0.34 mmol), K3PO4 (2524 mg, 11.9 mmol), and cyclopropylboronic acid (379 mg, 4.42 mmol) in toluene (16 mL) and water (0.8 mL) was heated in a microwave reactor at 100° C. for 1.5 hr. A second, identical reaction was performed. The two reactions were combined, and then filtered, rinsed with EtOAc, and concentrated to an orange oil. The crude product was chromatographed on silica gel (Analogix® SF25-40G column, 0%-25% EtOAc/hexanes, 30 mL/min), which yielded 1.37 g (93%) of the title compound as yellow crystals. 1H NMR (300 MHz, CH3OH-d4) δ 8.13 (s, 1H), 7.35 (dd, J=8.1, 1.8 1H), 7.29 (dd, J=11.4, 1.8 1H), 7.06 (t, J=8.0, 1H), 2.39 (s, 3H), 2.17-2.05 (m, 1H), 1.03 (dd, J=8.5, 6.4, 4.3 2H), 0.81-0.73 (m, 2H). MS (DCI+) m/z 218 (M+H).
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3.C(#[N:13])C.S(=O)(=O)(O)O>O>[NH2:13][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:1]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Reactant: CC#N
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: -16 °C
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
Into a 300 ml four-neck flask, 10.0 g (75.8 mmol) of cis-(±)-1,2-epoxyindan (VI) and 40 ml of acetonitrile were introduced. This mixture was cooled to -16° C. in an ice/salt bath. To this mixture, 10.62 g (113.6 mmol) of fuming sulfuric acid (containing 25% of sulfuric anhydride) was dropwise added at -13° to -17° C. in a period of 1.5 hour. The mixture was left for 1.5 hour to return to room temperature. An HPLC analysis of the contents revealed that 21.2% of cis-oxazoline derivative (IV: R=CH3) had been generated while no trans-amide derivative (III': R=CH3, Y=OH) was detected. Then, 72 ml of water was added thereto. The resulting mixture was treated in the same manner as Example 8 to yield 5.62 g (yield: 49.8%) of cis-(±)-1-aminoindan-2-ol (V) as a white crystal. Its purity determined by an HPLC was 98.7%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[C:19](=[N:32][NH2:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]1([C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:32][NH:33][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a suspension of quinolin-6-yl trifluoromethanesulfonate (40 g, 0.14 mol), benzophenone hydrazone (35.6 g, 0.18 mol), cesium carbonate (74 g, 0.23 mol) and 1,1′-bis(diphenylphosphino)ferrocene (2.5 g, 4.5 mmol) in degassed toluene (1 L) was added palladium acetate (0.013 g, 0.058 mmol). The resultant mixture was heated to 90° C. under a nitrogen atmosphere. After 16 h, the mixture was concentrated in vacuo and the residue was purified via silica gel column chromatography (EtOAc/pet ether) to provide 1-(diphenylmethylene)-2-(quinolin-6-yl)hydrazine (32 g, 68.6% yield). 1H-NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.58 (t, J=1.8 Hz, 1H), 8.13 (d, J=3.6 Hz, 1H), 7.80 (d, J=3.6 Hz, 1H), 7.61 (d, J=3.9 Hz, 1H), 7.59-7.51 (m, 4H), 7.50 (d, J=3.6 Hz, 2H), 7.33-7.39 (m, 6H); MS (ESI) m/z: 324 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:12](=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].C1([N+](C)(C)C)C=CC=CC=1.C(#N)C>[CH3:12][O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cncc(O)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cncc(OC)c1
Temperature: 80 °C

Procedure:
A mixture of 0.5 g of methyl 5-hydroxynicotinate, 1.2 g (2 equiv) of phenyltrimethylammonium chloride, 4.8 g (3 equiv) of cesium carbonate, and 5 mL of anhydrous acetonitrile was heated to 80° C. for 6 h, cooled, filtered and concentrated under reduced pressure. The residue was taken up in 25 mL of ethyl acetate, filtered and concentrated. Purification by flash chromatography (0-50% ethyl acetate in hexane) gave the product as white crystalline solid: MS (m+1)=168.1; 1H NMR (400 MHz, CDCl3) 8.72 (s, 1H), 8.4 (s, 1H), 7.67 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH:11]([NH:13][CH:14]([C:20](=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]>C1COCC1>[CH:11]([NH:13][C@H:14]([C@H:20]([OH:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]
Reactant: CCCCCCCCCCCCCCCC(=O)C(NC=O)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](NC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.9 %

Procedure:
A dehydrated THF solution (0.5 ml) of triethylamine (131.7 mg, 1.30 mmol) and a dehydrated THF solution (0.5 ml) of formic acid (64.2 mg, 1.37 mmol) were added to a dehydrated THF solution (4.0 ml) of RuCl[(R,R)-TsDPEN](p-cymene) complex (19.6 mg, 0.03 mmol) and ethyl 2-formylamino-3-oxooctadecanoate (73.5 mg, 0.20 mmol) synthesized in the same method as Example 8. After the mixture was stirred for 3 days at room temperature, the reaction solvent was removed in reduced pressure. Water was added thereto and extraction with ethyl acetate was carried out three times. The organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, hexane:ethyl acetate=1:2) to obtain the title compound (64.6 mg, yield: 87%). The product was analyzed by HPLC to find that anti-form:syn-form was 95:5 and the optical purity of the anti-form was 96% ee.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[S:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.CCOCC>[OH:17][CH2:16][CH2:15][S:14][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCCSCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)CCc1ccc(OCCSCCO)cc1
Temperature: 22 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
A solution of methyl 3-[4-hydroxyphenyl)propionate (30.0 g, 0.166 mol), 2,2′-thiodiethanol (61.0 g, 0.50 mol) and triphenylphosphine (48.0 g, 0.183 mol) in dry benzene (450 ml) was treated at 22° C. with diethyl azodicarboxylate (33.2 g, 0.19 mol) added dropwise over 10 min and the resulting mixutre was stirred at 22° C. for 5 h. The reaction mixture was then diluted with ether (300 ml) washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate 85:15) to give 37.64 g (79%) of the starting material as a white solid: mp 47-48° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)C.Cl>O.C1COCC1>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:29])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCCCCc1ccc(NCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 128.6 %

Procedure:
2.5N aqueous NaOH (1.2 mL) was added to a solution of 4-[4-(4-tert-butoxycarbonylaminobutyl)phenylamino]butyric acid ethyl ester 420 (0.45 g, 1.18 mmol) dissolved in a mixture of water (25 mL) and THF (30 mL). The reaction was stirred for 2 h. 12 N HCl was added dropwise until pH 3. The solvent was evaporated in vacuo. The residue was cooled to 0° C. and a solution of TFA/dichloromethane (10 mL) was added. The reaction was stirred for 30 minutes. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1:0.1, chloroform/methanol/concentrated ammonium hydroxide, v/v) to provide 460 (0.38 g, 100%). 1H NMR (300 MHz, CD3OD) δ 1.61 (m, 4H), 1.82 (m, 2H), 2.29 (t, 2H), 2.50 (m, 2H), 2.88 (m, 2H), 3.09 (t, 2H), 6.58 (d, 2H), 6.92 (d, 2H). m/z (ESI) 251.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].C(N(CCC)CCC)CC.C[O-].[Na+:32]>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[O-:19])([CH3:4])([CH3:3])[CH3:2].[Na+:32]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCN(CCC)CCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1

Procedure:
66.9 g of 2,4,6-tri-t-butylphenol was dissolved or dispersed into 213.5 g of tri-n-propyl amin. To this solution was added 13.5 of sodium methoxide. The mixture was heated in flask until reflux occurred at about 150° C. When the reflux temperature dropped below 150° C., distillate was condensed and removed from the reaction mixture until the vapor temperature in the flask rose above 150° C. then the mixture was again refluxed. When the vapor temperature dropped below 150° C., distillate was condensed and removed from the reaction mixture until the vapor temperature rose above 150° C. This alternate process of reflux and condensation was repeated until 8.0 g of methyl alcohol, CH3OH had been distilled Away from the reaction mixture. Approximately 112 g of tri-n-propyl amine was stripped from the reaction mixture leaving about 71 g of sodium 2,4,6-tri-t-butyl phenolate in about 100 g of tri-n-propyl amine as a 40 weight percent slurry of the phenolate salt in the amine solvent.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:24][OH:25])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CCC[N+](CCC)(CCC)CCC.[O-]I(=O)(=O)=O>C(Cl)Cl>[C:20]([O:19][C:17]([N:24]1[C@H:4]2[CH2:5][CH2:6][C@:1]([CH2:7][CH2:8][O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH:2]=[CH:3]2)[O:25]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C1=CCCC(CCOCc2ccccc2)=C1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1O[C@@]2(CCOCc3ccccc3)C=C[C@@H]1CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2-Cyclohexa-1,3-dienyl-ethoxymethyl)-benzene (9) (6 g, 28 mmol) is dissolved in 280 ml of dry methylene chloride and cooled down to 0° C. After addition of molecular sieves (6 g, UOP Type 4A) and N—BOC-hydroxylamine (5.6 g, 42 mmol) in small portions, tetrapropylammonium(meta)periodate (10.8 g, 28 mmol) is added slowly in small portions the mixture was stirred for 1 h. Then the mixture is diluted with CH2C12 and cooled to −10° C. 2M Na2S2O5 solution is added slowly (exothermic!). The mixture is washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), silicagel).