Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1.CO[C:19](OC)([CH3:21])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:20][C:19]1([CH3:21])[O:14][C@H:11]([CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)[CH2:12][O:13]1
Reactant: COC(C)(C)OC
Reactant: OCCCc1ccc(OC[C@@H](O)CO)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(CCCO)cc2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-[4-(3-hydroxy-propyl)-phenoxy]-propane-1,2-diol (6.5 g, 28.7 mmol) in anhydrous DMF (100 mL) is added 2,2-dimethoxypropane (15.0 mL, 122.0 mmol) and pyridinium p-toluenesulfonate (0.75 g, 2.98 mmol). The reaction mixture is stirred at RT for 16 h and then concentrated in vacuo. The residue is dissolved in EtOAc and the organic portion is washed with 10% aqueous NaHCO3 solution, water, brine and dried over Na2SO4. The solvent is removed in vacuo and the crude product is purified by column chromatography (SiO2, EtOAc in petroleum ether, gradient 0-30% EtOAc) to obtain the title compound as a colourless oil. [M+H]+ 267.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][CH2:23][OH:24].[CH3:25][OH:26].[C-]#N.[K+]>CCOCC.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][C:23]([O:26][CH3:25])=[O:24]
Reactant: CO
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#CCO
Agent: [Mn+4]
Agent: [C-]#N
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-(3-hydroxyprop-1-ynyl)pyrazole (250 mg, the compound of Example A6) in ether (10 ml) was added manganese dioxide (1 g) and the mixture stirred at room temperature for two hours. Methanol (2 ml) and potassium cyanide (250 mg) were then added and stirring continued for 15 minutes. The reaction mixture was filtered and evaporated to dryness. The residue was purified by chromatography on silica gel eluted with dichloromethane. Combination and evaporation of appropriate fractions provided the title compound as a light brown solid m.p. 201-2° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][CH:30]=O>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[C:29]1[CH:30]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: Cc1ccc(C)c(CC=O)c1
Product: Cc1ccc(C)c(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2,5-Dimethyl-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 394; HRMS: calcd for C24H18F3NO+H+, 394.14132; found (ESI, [M+H]+), 394.1402.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[N:26][C:27]#[N:28])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[S:38]([NH:41][C:42]1[C:43]([O:57][CH3:58])=[N:44][CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1)(=[O:40])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:27]([N:26]=[C:13]1[N:12]([CH3:29])[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([C:46]4[CH:47]=[C:42]([NH:41][S:38]([C:32]5[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=5[F:30])(=[O:40])=[O:39])[C:43]([O:57][CH3:58])=[N:44][CH:45]=4)=[CH:3][C:4]=3[C:5]=2[N:14]1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:24]#[N:25])([CH3:22])[CH3:23])=[CH:19][CH:20]=1)#[N:28]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)cc2)c(=NC#N)n4C)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 111 °C

Procedure:
To the stirred solution N-(8-bromo-1-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (0.211 mmol) in dry DMF (5 ml) was added 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.390 mmol) followed by catalyst palladium dichlorobis triphenylphosphine (0.021 mmol). Saturated solution of sodium carbonate (0.780 mmol) was added to it and the resulting solution was heated to 111° C. for 8 minutes in microwave. Solvent was removed and the crude material was extracted in EtOAc, washed with brine several times and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, CHCl3/MeOH as eluent) to obtain the title compound.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C.O.CCOC(C)=O.C([O-])(O)=O.[Na+].CCOCC>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:29][CH2:28][N:27]([CH3:37])[CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2CCNC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nnc(OCC2CCN(C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 154.6 %

Procedure:
To a solution of 4-(4-benzyloxy-phenyl)-3-butyl-6-(pyrrolidin-3-ylmethoxy)-pyridazine dihydrochloride (0.3 mmol, 147 mg) in dichloromethane (2 mL) was added formaldehyde solution in water (37%, 10 mmol, 1.0 mL), and 2 drops of acetic acid. Then sodium triacetoxyborohydride (10 mmol, 2.12 g) was added. And the mixture was stirred at room temperature for 0.5 hour then condensed. It was then diluted with water/EtOAc and neutralized with NaHCO3 powder. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (117 mg). LCMS: m/z 433 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.82 (1H, s), 7.45-7.55 (4H, m), 7.36-7.40 (2H, m), 7.31-7.35 (1H, m), 7.21-7.24 (2H, m), 5.20 (2H, s), 4.43 (2H, d), 3.57-3.62 (2H, m), 3.05-3.17 (3H, m), 2.87 (3H, s), 2.14-2.30 (2H, m),1.70-1.81 (2H, m), 1.45-1.53 (2H, m), 1.23-1.33 (2H, m), 0.81 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH2:20][CH3:21])[C:13](=O)[C:14]([O:16]CC)=[O:15]>>[CH2:20]([C:12]1[O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:13]=1[C:14]([OH:16])=[O:15])[CH3:21]
Reactant: CCOC(=O)C(=O)C(Br)CC
Reactant: NC(=O)c1ccc(F)cc1
Product: CCc1oc(-c2ccc(F)cc2)nc1C(=O)O

Procedure:
The title compound was prepared from 6.5 9 of 4-fluorobenzamide and 6.08 g of ethyl 3-bromo-2-oxo-pentanoate (as described in example 2B) to give 1.55 g (22%) of intermediate 3C as a solid: 1H NMR (CDCl3, 300 MHz) δ8.12-8.08 (m, 2H), 7.23-7.17 (m, 2H), 3.19 (q, 2H, J=7.5), 1.40 (t, 3H, J=7.5).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Oc1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
DIPEA (48.2 mL, 276.86 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (24.65 g, 110.74 mmol) and 4-(piperidin-4-yl)phenol (20.61 g, 116.28 mmol) in DMF (200 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, then evaporated to dryness and re-dissolved in DCM (1 L) and washed with water (2×1 L). The organic layer was washed with saturated brine (500 mL), then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether to afford 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (36.6 g, 91%) is as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:35]4[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCN1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(CCO)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and N-(2-hydroxyethyl)piperazine (57 mg, 0.436 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as an off white solid (78 mg, 40%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/DCM]. MS (ESI) m/z 493.3 (M+H)+ (method A).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=S)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(Br)C1C=CC=CC=1.[N:44]#[C:45][NH2:46]>C(#N)C.O.FC(F)(F)C(O)=O.CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:46][C:45]#[N:44])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Reactant: N#CN
Agent: BrCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#CN=C(NCc1ccc(OCc2ccccc2)cc1)c1ccc2ncccc2c1
Yield: 4.5 %

Procedure:
To a mixture of quinoline-6-carbothioic acid 4-benzyloxy-benzylamide described in Preparation Example E+-10 (57 mg, 0.15 mmol) and toluene (2 mL) was added benzyl bromide (0.089 mL, 0.74 mmol), which was then stirred under reflux for 90 minutes. After cooling, the solvent was evaporated in vacuo, and the residue was washed with diethyl ether twice. A mixture of a portion (16 mg) of the resulting crude product (72 mg), cyanamide (20 mg, 0.48 mmol) and N-methylpyrrolidinone (1 mL) was stirred for 2.5 hours at 120° C. After cooling, the reaction solution was filtered through a membrane filter, the filtrate was directly purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (0.76 mg, 0.0015 mmol, 4.5%) was obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1>COCCOC>[OH:18][C:17]1[C:16]2[CH:15]=[N:14][CH:13]=[CH:12][C:11]=2[O:3][C:2]=1[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CO
Reactant: CCOC(=O)c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1oc2ccncc2c1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Ethyl glycolate (7.26 g, 59.7 mmol) was added slowly into a suspension of sodium hydride (2.95 g of 60% dispersion in mineral oil, 73.8 mmol) in 85 mL of 1,2-dimethoxyethane (DME) at 0° C., and the mixture was stirred for another 30 min. A solution of ethyl 4-chloronicotinate (6.20 g, 33.4 mmol) in 20 mL of DME was added slowly into the reaction mixture at room temperature. The mixture was heated to 70° C. and maintained at that temperature overnight. The solvent was evaporated and the residue was dissolved in 100 mL of water, and washed with hexane 3 times. The pH of the water solution was adjusted to about 5 using acetic acid to pH 5, and a yellow precipitate was formed. The yellow precipitate was filtered, washed with a small amount of water (20 mL×3), and dried overnight in vacuo to give ethyl 3-hydroxyfuro[3,2-c]pyridine-2-carboxylate free base as a yellow solid (5.79 g) which was used for the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([Cl:8])Cl)#[N:2].[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10]>>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[P:6]([Cl:8])[O:5][CH2:4][CH2:3][C:1]#[N:2])([CH3:11])[CH3:10]
Reactant: CC(C)NC(C)C
Reactant: N#CCCOP(Cl)Cl
Product: CC(C)N(C(C)C)P(Cl)OCCC#N

Procedure:
Chemistry FIG. 11 illustrates the synthesis of diphosphitylating and triphosphitylating reagents (6 and 7). Phosphorus trichloride (21, 20 mmol) was reacted with 3-hydroxypropionitrile (22, 1 eq) to yield 2-cyanoethylphosphorodichloridite (23). The subsequent reaction of 23 with diisopropylamine (20 mmol, 1 eq) afforded 2-cyanoethyl diisopropylphosphoramidochloridite (24). Addition of water (1 eq) gave the intermediate 25 that was reacted with 24 (1 eq) or 23 (0.5 eq) to yield the diphosphitylating (26, 97%) and triphosphitylating (27, 94%) reagents, respectively. The chemical structures of 26 and 27 were determined by nuclear magnetic resonance spectra (1H NMR, 13C NMR, 31P NMR) and high-resolution time of flight electrospray mass spectrometry. Stability studies using spectroscopic methods showed that the compounds remained stable even after two weeks storage at −20° C.
Reaction SMILES: [CH3:1]N(N=O)C(N)=O.[OH-].[Na+].[C:10]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14].C(O)(=O)C>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]1([CH2:12][CH2:11][C:10]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:1][CH2:14]1
Reactant: C=CCCC(=O)OCc1ccccc1
Reactant: CN(N=O)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(CCC1CC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-Methyl-N-nitrosourea (6.4 g, 31 mmol) was added to an ice-cooled mixture of 10% aqueous NaOH (250 g, 625 mmol) and Et2O (300 mL), and the mixture was stirred vigorously with ice cooling for 10 minutes. The ether layer was decanted into a dry, 1 L Erlenmeyer flask, and stirred with ice cooling as a solution of the product from Example 114A (3.00 g, 15.8 mmol) in ether (60 mL) was added. The yellow solution was stirred with ice cooling as Pd(OAc)2 (30 mg, 0.134 mmol) was added. After 1 hour, acetic acid (0.5 mL) was added to consume any excess diazomethane, and the reaction mixture was concentrated under vacuum to a gray oil. The residue was dissolved in EtOAc (50 mL) and washed with saturated NaHCO3(aq) (25 mL). The organic phase was concentrated under vacuum and the residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc 100:0-90:10) to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm −0.02-0.06 (m, 2H) 0.40 (ddd, J=8.1, 5.8, 4.1 Hz, 2H) 0.62-0.78 (m, 1H) 1.51 (q, J=7.1 Hz, 2H) 2.45 (t, J=7.3 Hz, 2H) 5.11 (s, 2H) 7.24-7.40 (m, 5H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CCCCCC(=O)CC(=O)OC
Agent: [Ru]
Solvent: CO
Solvent: ClCCl
Product: CCCCC[C@H](O)CC(=O)OC
Yield: 95.9 %

Procedure:
Into a 100-ml autoclave (made of Hastelloy) were introduced 20 g of methyl 3-oxooctanoate (manufactured by Inoue Perfumery Mfg. Co., Ltd.) and 50 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 140 mg of Ru2Cl4 ((-)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 1.0 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 6 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 19.4 g of methyl (S)-3-hydroxyoctanoate. Yield, 96%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:29][CH3:30])[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]2[C:5](=[CH:6][C:7]([O:21][Si](C(C)(C)C)(C)C)=[CH:8][CH:9]=2)[O:4]1)[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.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]>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([OH:21])=[CH:8][CH:9]=3)[O:4][C:3]([CH2:1][CH3:2])([CH2:29][CH3:30])[CH:12]=2)=[CH:34][CH:33]=1
Reactant: CCC1(CC)C=C(OS(=O)(=O)C(F)(F)F)c2ccc(O[Si](C)(C)C(C)(C)C)cc2O1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCC1(CC)C=C(c2ccc(F)cc2)c2ccc(O)cc2O1

Procedure:
A mixture of the compound obtained in (3) described above (3.5 g), 4-fluorophenylboronic acid (1 g), cesium carbonate (12.7 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (350 mg, 10% wt) in dimethoxyethane/water (3/1; 60 mL) was heated under reflux under nitrogen atmosphere for 12 hours. The reaction solution was concentrated in vacuo, and the residue was extracted with ethyl acetate (40 ml×3). The combined organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent: petroleum ether/ethyl acetate=20/1) to give the titled compound (2 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13](Cl)=[C:12]2[C:7]=1[C:8](Cl)=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.Cl>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(Cl)c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)COc1cccc2nc(C)c(Cc3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [4,8-dichloro-3-(4-chlorobenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.13 g), palladium (5 wt. % on activated carbon, 0.010 g), ethanol (5.0 mL) and 1.0 M aqueous hydrochloric acid (1.0 mL) was stirred at room temperature for 17 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washing with ethanol and water and the solvent removed under reduced pressure to afford title compound, 0.11 g.
Reaction SMILES: N([N:3]([CH2:6][CH3:7])CC)=O.[CH2:8]1[CH:12]2C3C=C[CH:15]([CH:11]2[CH:10]=[CH:9]1)C3.C(#N)C=C>>[C:6]([C:7]12[CH2:15][CH:11]([CH2:12][CH2:8]1)[CH:10]=[CH:9]2)#[N:3]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: CCN(CC)N=O
Solvent: C=CC#N
Product: N#CC12C=CC(CC1)C2
Yield: 93 %

Procedure:
Example 1 was repeated except that N-nitrosodiethylamine was used in place of N-nitrosodiphenylamine. N-nitrosodiethylamine was added to a mixed solution of dicyclopentadiene and acrylonitrile in an amount of 0.005% by weight. As a result, cyanonorbornene was continuously obtained with an average yield of 93% by mole. In this example, the amount of the soluble polymer produced was 0.01% by weight at the beginning of the reaction, which did not change significantly in 60 days after the initiation of the reaction. In addition , the operation was stopped after 80 days from the initiation to inspect in detail the inlet for the raw material, the inner wall, the outlet for the reaction solution and the-stirrer of the autoclave. No insoluble polymer was found to adhere to those surfaces.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:23][CH2:22][CH2:21][C:20]=2[C:24](OCC)=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([Br:14])[C:11]([N:15]2[C:24](=[O:25])[C:20]3[CH2:21][CH2:22][CH2:23][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Br)CCC1
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Br)cc1Br

Procedure:
using isopropyl 2,4-dibromo-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-dibromo-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 223°-226° C.,
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:13]([NH:15][C@@H:16]([CH:29]([CH3:31])[CH3:30])[C@@H:17]([C:19]2[C:20](=[O:28])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:18])=[O:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:38])[CH3:37].Cl>C(Cl)Cl.C(N(CC)CC)C>[C:36]([O:18][C@H:17]([C:19]1[C:20](=[O:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:30])[CH3:31])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)OCC1CCCCC1)C(=O)N[C@@H](C(C)C)[C@H](O)c1c(-c2ccccc2)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](c1c(-c2ccccc2)c1=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OCC1CCCCC1)C(C)C
Yield: 45.1 %

Procedure:
To 5 ml of a methylene chloride solution of 149 mg of 2-[(1R,2S)-2-{(S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone obtained in Example 2 were added 81 mg of acetyl chloride and 102 mg of triethylamine. The resultant mixture was stirred at room temperature for 3 hours, mixed with diluted hydrochloric acid and shaken with methylene chloride. The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated brine in that order, dried over magnesium sulfate and filtered. The filtrate was concentrated and chromatographed on a column of silica gel, eluting with hexane:ethyl acetate (1:1) to give 73 mg of the titled product.