Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1O)[CH3:3].[OH-:20].[Na+].[CH2:22](Br)[CH2:23][CH2:24][CH3:25]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1[CH2:25][CH2:24][CH2:23][CH2:22][O:20][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:10][C:9]=1[CH2:11][N:12]([CH3:14])[CH3:13])[CH3:3]
Reactant: CCCCBr
Reactant: [OH-]
Reactant: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)Cc1cc(CN(C)C)c(CCCCOCCCCc2c(CN(C)C)cc(CN(C)C)cc2CN(C)C)c(CN(C)C)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
53.1 g (0.2 mol) of 2,4,6-tris(dimethylaminomethyl)phenol and 6.8 g (0.02 mol) of tetrabutylammonium hydrogen sulfate are placed in 100 ml of toluene in a 350 ml sulfonating flask having an anchor mixer, thermometer, reflux condenser and dropping funnel and at RT 40 g (0.5 tool) of a 50% aqueous NaOH solution are added dropwise in the course of 30 minutes. The suspension is then stirred for 30 minutes at 80° C. and then at the same temperature 54.8 g (0.4 mol) of butyl bromide are added in the course of 45 minutes. After a subsequent reaction period of 3 hours the mixture is cooled and filtered, and the filtrate is washed once with 30 ml of H2O, dried over MgSO4, filtered and concentrated by evaporation, yielding 48 g of 2,4,6-tris(dimethylaminomethyl)phenylbutyl ether in the form of a brown liquid which no longer has an OH band in the IR spectrum and of which the NMR analysis is in agreement with the said structure.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10]CC)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19]O)[CH2:16][O:15]1.[H-].[Na+]>C1COCC1.[Cl-].[Na+].O>[CH3:13][C:14]1([CH3:21])[O:18][C@H:17]([CH2:19][O:1][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:16][O:15]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCOC(=O)c1cccc(O)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(C(=O)O)n2)O1
Temperature: 25 °C
Yield: 74 %

Procedure:
Ethyl 6-hydroxypicolinate (500 mg, 2.7 mmol), (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (1.11 mL, 3.0 eq) and NaH (60% dispersion in mineral oil, 385 mg, 3.3 eq) in THF was refluxed 18 hours. The reaction mixture was cooled to room temperature, acidified to pH=4, added to brine and extracted with ethyl acetate. The organic layer was dried, concentrated and recrystallized from pentane/ethylacetate to obtain (R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)picolinic acid (500 mg, 74% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]([CH3:17])([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[NH2:20][CH:21]([CH2:25][CH3:26])[C:22]([O-:24])=[O:23].[CH2:27](N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:12]([O:11][C:9](=[O:10])[C:8]([CH3:17])([CH3:16])[O:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][NH:20][CH:21]([CH2:25][CH3:26])[C:22]([O:24][CH3:27])=[O:23])=[CH:4][CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCC(N)C(=O)[O-]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCC(NCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)C(=O)OC
Temperature: 40 °C
Yield: 89 %

Procedure:
Similarly to the procedure of Example I-5, 1.20 g (4.54 mmol) of tert-butyl 2-(4-formylphenoxy)-2-methylpropionate (Example I-4) and 0.70 g (4.54 mmol) of methyl DL-2-aminobutyrate are reacted at room temperature with 0.92 g (9.08 mmol) of triethylamine and 1.44 g (6.81 mmol) of sodium triacetoxyborohydride in 10 ml of dichloroethane. A further 0.9 g (4.25 mmol) of sodium triacetoxyborohydride and 0.35 g (2.27 mmol) of methyl DL-2-aminobutyrate are added and the mixture is heated at 40° C. for 3 h, giving 1.47 g (89%) of methyl 2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyrate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:15][CH2:16][C:17](O)=[O:18]>C(Cl)(Cl)Cl.S(Cl)(Cl)=O>[N:1]1([C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:12]([O:11][CH3:10])[CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COc1ccc(OCC(=O)O)cc1OC
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCC(=O)n2nnc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
To a solution of 1H-benzo[d][1,2,3]triazole (11.2 g) in CHCl3 (120 ml), thionyl chloride (1.7 ml) was added and after stirring at room temperature for 30 minutes, 2-(3,4-dimethoxyphenoxy)acetic acid (5.00 g) was added and the mixture was stirred at room temperature for 1.5 hours. The precipitate was filtered off and the filtrate was washed with an aqueous solution of 2 N NaOH; thereafter, the organic layer was dried (MgSO4), filtered and concentrated to give the titled compound (8.06 g, colorless solid.)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]>ClCCl.C(=O)([O-])O.[Na+]>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][CH:28]=1)=[O:31]
Reactant: Nc1nc2ccccc2s1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3ccccc3s2)cc1)OCC
Reaction time: 10 h
Yield: 84.3 %

Procedure:
In 30 ml of dry dichloromethane were dissolved 3.0 g of 2-aminobenzothiazole and 10 ml of pyridine and while the resulting solution was stirred under ice-cooling, a solution of 5.8 g 4-[(diethoxyphosphoryl)methyl]benzoyl chloride in 10 ml dry dichloromethane was slowly added dropwise. The stirring was continued at room temperature for 10 hours, after which the reaction mixture was diluted with 30 ml of 10% aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed serially with 30 ml of 10% hydrochloric acid and 30 ml of water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform-ethyl acetate=1:1) and the resulting crude crystals were recrystallized from ethanol to provide 6.8 g of the title compound as colorless crystals. The structure and melting point of the compound thus obtained are shown in Table 1.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([C:8]2[C:9]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:12][CH:13]=2)=[N:5][N:4]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>ClCCl>[CH3:51][N:52]1[CH2:57][CH2:56][N:55]([CH2:2][C:3]2[O:7][C:6]([C:8]3[C:9]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[N:10][C:11]([NH:14][CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:12][CH:13]=3)=[N:5][N:4]=2)[CH2:54][CH2:53]1
Reactant: CN1CCNCC1
Reactant: C[Si](C)(C)CCOc1nc(NCCc2ccncc2)ncc1-c1nnc(CO)o1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(Cc2nnc(-c3cnc(NCCc4ccncc4)nc3OCC[Si](C)(C)C)o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 mL of dichloromethane, 5-(5-hydroxymethyl[1,3,4]oxadiazol-2-yl)-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine (0.76 g, 1.83 mmol) obtained in Step 2 was dissolved, then methanesulfonic anhydride (0.48 g, 2.75 mmol) and triethylamine (0.37 g, 3.66 mmol) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, saturated aqueous sodium hydrogen carbonate solution was added and the reaction mixture was separated. Further, an aqueous layer was extracted with dichloromethane and those organic layers were combined. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), then 1-methylpiperazine (403 mg, 4.03 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, the mixture was treated as described above. The residue was purified by silica gel chromatography (chloroform/methanol) to give 5-[5-(4-methylpiperazinyl)methyl[1,3,4]oxadiazol-2-yl]-2-[2-(4-pyridyl)ethylamino]-4-(2-trimethylsilylethoxy)pyrimidine [Compound (IH) in which R2B is 2-(4-pyridyl)ethylamino and —X—Y—Z— is
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:42])[C:18]([N:20]([CH2:24][CH2:25][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]#[C:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:21]([CH3:23])[CH3:22])=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:43][CH3:44].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:42])[C:18]([N:20]([CH2:24][CH2:25][N:26]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]#[C:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH:21]([CH3:22])[CH3:23])=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:43][CH3:44]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C)CC2
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A solution of 250 mg of 10j in 6 ml of dioxane was mixed with a solution of 120 mg of KOH in 1 ml of water and the reaction mixture was stirred for 5 h at 45° C. The mixture was diluted with 20 ml of water and acidified to pH3 with 0.5N HCl. The product was extracted into ethyl acetate. The organic layer was washed twice with water, dried and concentrated, to give 220 mg of amorphous 10k.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3]1.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: N#Cc1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 20.7 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carbonitrile (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (37 mg, 0.39 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carbonitrile as a yellow solid. MS(ES): m/e 242 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Br[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:11][CH2:12][CH3:13])[CH:7]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
A mixture 5-Bromo-2-fluoro-phenol (prepared by the method of Elliott, M. et al. GB2187731) (500 mg, 2.62 mmol, 1 eq.), 1-bromopropane (322 mg, 2.62 mmol, 1 eq.), and K2CO3 (434 mg, 3.14 mmol, 1.2 eq.) in acetone (20 mL) is heated at 65° C. for 24 h. After cooling to room temperature, the reaction is concentrated, diluted with EtOAc and sequentially washed with 1 N aqueous NaOH and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (3:1 hexanes/EtOAc) to give 4-Bromo-1-fluoro-2-propoxy-benzene as a yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH2:32][C:33]1[N:38]=[C:37]([CH2:39][CH2:40]O)[CH:36]=[CH:35][CH:34]=1.[C:42]([OH:45])(=[S:44])[CH3:43]>O1CCCC1>[C:42]([S:44][CH2:40][CH2:39][C:37]1[N:38]=[C:33]([NH2:32])[CH:34]=[CH:35][CH:36]=1)(=[O:45])[CH3:43]
Reactant: Nc1cccc(CCO)n1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCc1cccc(N)n1
Reaction time: 0.08 h

Procedure:
Triphenyl phosphine (2.36 g) was dissolved in tetrahydrofuran (40 ml). To the solution was added, at −20° C., diethyl azodicarboxylate (1.56 g). The mixture was stirred for 5 minutes, to which was added a solution of 2-(6-amino-2-pyridyl)ethanol (0.62 g) in tetrahydrofuran (2 ml). The mixture was stirred for one minutes, to which was added thioacetic acid (0.64 ml), followed by stirring for 4 hours at 25° C. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 120 g, developing solvent: ethyl acetate-hexane, 2:1) to give the title compound (0.56 g), m.p.55-59° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20]O>>[ClH:3].[CH3:20][O:18][C:17](=[O:19])[CH2:16][NH:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)CNc1ccc2ccccc2c1
Product: COC(=O)CNc1ccc2ccccc2c1
Product: Cl
Reaction time: 3 h
Yield: 94 %

Procedure:
33 mL of thionyl chloride was added dropwise to a mixture of 50.3 g of 2-naphthylglycine (racemic body) and 200 mL of methanol (dehydrated) at an inner temperature of 35° C. inner temperature over 1 hour and the mixture was stirred at the same temperature for 3 hours to effect reaction. The reaction mixture was concentrated and the resulting concentrated residue was mixed with 200 mL of diethyl ether. Then, the crystals produced were recovered by filtration and washed with 50 mL of diethyl ether. The crystals recovered by filtration were dried at an inner temperature of 50° C. under reduced pressure to obtain 59.0 g of white 2-naphthylglycine methyl ester hydrochloride (yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[CH:36]1([NH:42][NH2:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:43][NH:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: NNC1CCCCC1
Reactant: S=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NNC4CCCCC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 13 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (52 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 1.5 hr. Next, cyclohexylhydrazine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 7 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (10 mg, yield 13%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH3:12])=S)=[CH:4][CH:3]=1.[N:13]#[C:14]N.C1([N:22]=C=NC2CCCCC2)CCCCC1>C(N(C(C)C)C(C)C)C.C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([NH:13][CH3:14])=[N:11][C:12]#[N:22])=[CH:4][CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N#CN
Reactant: CNC(=S)Nc1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=NC#N)Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 34 h
Yield: 29 %

Procedure:
A mixture of 1.03 g of 1-(6-chloro-3-pyridyl)-3-methylthiourea, 0.32 g of cyanamide, 1.58 g of dicyclohexylcarbodiimide, 3 drops of ethyl diisopropylamine and 10 ml of acetonitrile was stirred for 34 hours at room temperature and filtered to collect an insoluble substance. The insoluble substance was recrystallized from a mixed solvent of acetonitrile and methanol, and then from acetonitrile to obtain 0.31 g of 1-(6-chloro-3-pyridyl)-2-cyano-3-methylguanidine (Compound No. 24).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[CH:16](I)([CH3:18])[CH3:17].Cl>CO>[O:13]=[C:9]([CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(C(=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 36 h
Yield: 48 %

Procedure:
p-Chlorophenylpyruvic acid (1.98 g, 10.0 mmoles) was dissolved in 20 ml of methanol, and a 3N aqueous solution of sodium hydroxide (8.0 ml, 24 mmoles) was added to form a solution. Then, 2.0 ml of isopropyl iodide was added, and the mixture was stirred at 35° C. for 36 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate and concentrated under reduced pressure. The resulting pale yellowish white oil was purified by silica gel column chromatography (ethyl acetate:hexane=1:7) to obtain pure 2-oxo-3-(p-chlorophenyl)-4-methylpentanoic acid as an oil in a yield of 48 %. This product was treated with an aqueous solution of sodium hydroxide, and isolated as a pure sodium salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[O:18][N:17]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:19]2[O:18][N:17]=[C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:20]=2)=[O:23])[CH2:57][CH2:58]1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)on1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-isoxazole-5-carboxylic acid (40 mg, 0.13 mmol) and TBTU (64.6 mg, 0.20 mmol) in DMF (2.0 mL) was added DIPEA (106.9 μL, 0.63 mmol). Then 4-aminotetrahydropyran (14 mg, 0.14 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (35 mg, 70%) as a white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@@H:33]1[CH2:38][NH:37][CH2:36][C@H:35]([CH3:39])[NH:34]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:37]3[CH2:36][C@@H:35]([CH3:39])[NH:34][C@@H:33]([CH3:32])[CH2:38]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3C[C@@H](C)N[C@@H](C)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using the product of Example 75 step i) and (2R,6S)-2,6-dimethyl-piperazine, and the product purified by SiO2 chromatography (eluting with 5% methanol in dichloromethane followed by 5% of 7M methanolic ammonia in dichloromethane).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[OH:1][CH:2]([CH2:8][CH:9]([OH:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC=CC=CC(=O)CC(O)CC(=O)OC
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC=CC=CC(O)CC(O)CC(=O)OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 42.7 %

Procedure:
To a cold (-15° C.) solution of methyl 3-hydroxy-5-oxo-6,8-decadienoate (18.5 g, 86.9 mmol) in THF (300 mL) was added triethylborane (1M in THF, 113 mL, 113 mmol) and the solution was stirred for 20 minutes. After the mixture was cooled to -78° C., NaBH4 (6 g, 159 mmol) and methanol (37.5 mL) were added. The solution was vigorously stirred for 30 minutes at -78° C. and at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (diethyl ether:hexane/3:1) to afford 7.95 g (42.7%) of the title compound as a yellow oil.
Reaction SMILES: [Na].[CH2:2]([CH:4]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][C:11](Cl)([Cl:13])[Cl:12])[C:5]([OH:7])=[O:6])[CH3:3].[Cl:17][C:18](Cl)([Cl:30])[CH2:19][CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C(O)C>[CH2:2]([CH:4]([C:8]([CH3:15])([CH3:16])[CH2:9][CH:10]=[C:11]([Cl:12])[Cl:13])[C:5]([OH:7])=[O:6])[CH3:3].[Cl:17][C:18]([Cl:30])=[CH:19][CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCC(C(=O)O)C(C)(C)CCC(Cl)(Cl)Cl
Reactant: CCOC(=O)CC(C)(C)CCC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCC(C(=O)O)C(C)(C)CC=C(Cl)Cl
Product: CCOC(=O)CC(C)(C)CC=C(Cl)Cl
Yield: 78.9 %

Procedure:
In 50 g of ethanol were dissolved 2.5 g of sodium metal and 20.0 g of the above ethyl β-(3,3,3-trichloropropyl)isovalerate were added to the solution. The mixture was refluxed for 8 hours. The reaction mixture was neutralized with a solution of hydrogen chloride in dry ethanol and concentrated to about one-twentieth of its original volume. To this concentrate were added 100 g of ice-water and the mixture was extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. By the above procedure there were obtained 13.7 g of ethyl β-(3,3-dichloroallyl)isovalerate (ethyl 6,6-dichloro-3,3-dimethyl-5-hexenoate), the NMR spectrum of which is given below (yield: 79%).