Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][N:10]1[CH:18]=[C:17]2[C:12]([N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][N:10]1[C:18]([B:24]([OH:29])[OH:25])=[C:17]2[C:12]([N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH3:20])[C:16]2=[O:19])=[CH:11]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1c(=O)c2cn(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-ethyl]-carbamic acid tert-butyl ester (step 3) (1.8 g, 5.58 mmol) was dissolved in anhydrous THF (49 ml) at room temperature. The flask was then evacuated and backfilled with nitrogen (×3) and cooled to −78° C. (external). After 10 mins, LDA (0.731 M, 22.92 ml, 16.75 mmol in THF, freshly prepared by standard procedure from BuLi and diisopropylamine) was charged over 3 mins. After 15 mins at −78° C., triisopropyl borate (3.87 ml, 16.75 mmol) was charged drop wise over 2 mins and the reaction held for 2 hr at −78° C. The reaction was then quenched with saturated NH4Cl solution (10 mL) via syringe under nitrogen and diluted with water (60 mL) and EtOAc (40 mL). The layers were separated and the aqueous extracted with EtOAc (4×50 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and filtered under reduced pressure to afford a pale yellow solution. The solvent volume reduced by half under reduced pressure to afford a suspension of a white solid. The solid was recovered by reduced pressure filtration and dried in air, followed by heating to 50° C. under vacuum for 3 h. This afforded the title compound as a white crystalline solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]([C:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.CN(C)C(=O)C>O>[C:11]1([NH:10][C:17]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:21][CH2:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCNCC1
Reactant: BrCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 28.7 parts of (2-bromoethyl)benzene, 34.7 parts of ethyl 4-anilinoisonipecotate, 25 parts of N,N-diethylethanamine and 162 parts of N,N-dimethylacetamide is stirred for 2 h. 30 at 75°-80° C. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with 210 parts of 1,1'-oxybisethane. The combined extracts are washed twice with 200 parts of water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane, yielding ethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 65° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:9]=2)=[CH:4][N:3]=1.[CH3:26][N:27]([CH3:33])[C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[C:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[CH2:31][CH2:32][C@@H:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)=[N:3][CH:4]=2)=[N:9][C:10]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)=[N:11][CH:12]=1)#[N:15]
Reactant: N#Cc1cnc(Nc2ccc3[nH]ncc3c2)nc1-c1ccc(Cl)nc1
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(c2ccc(-c3nc(Nc4ccc5[nH]ncc5c4)ncc3C#N)cn2)C1

Procedure:
4-(2-Chloropyridin-5-yl)-5-cyano-N-(indazol-5-yl)pyrimidine-2-amine (522 mg, 1.5 mmol) and 3-(R)-dimethylaminopyrrolidine were heated together at 140° in a sealed flask for 2 h. On cooling the reaction mixture was triturated with water to give a brown solid which was collected and subjected to column chromatography (silica gel; 1% triethylamine-10% methanol-89% dichloromethane) to give the title compound (417 mg) as a yellow solid m.p.249-250°. δH (d6DMSO) 13.00 (1H, br s), 10.32 (1H, s), 8.81 (2H, d, J 9.2 Hz), 8.15-8.12 (2H, m), 8.04 (1H, s), 7.59 (1H, m), 7.52 (1H, d, J 9.8 Hz), 6.63 (1H, d, J 9.0 Hz), 3.77-3.67 (2H, m), 3.41-3.24 (2H, m), 2.82 (1H, br m), 2.22 (6H, s), 2.21 (1H, m) and 1.84 (1H, m).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH:25]([F:27])[F:26])=[C:19]([F:28])[CH:18]=2)[CH2:9][CH2:8]1>C1COCC1>[F:28][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][C@H:10]2[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]2)[CH:22]=[C:21]([F:23])[C:20]=1[O:24][CH:25]([F:27])[F:26]
Reactant: CCC[Mg]Br
Reactant: Fc1cc(CCCCC2CC[SiH](Cl)CC2)cc(F)c1OC(F)F
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CCCCc2cc(F)c(OC(F)F)c(F)c2)CC1

Procedure:
50 ml (0.13 mols) of a THF solution of 2.5M of propylmagnesium bromide was dropped in a mixed solution of 36.9 g (0.1 mol) of 1-chloro-4-(4-(3,5-difluoro-4-difluoromethoxyphenyl)butyl)-1-silacyclohexane and 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 32.1 g (yield: 85%) of the intended trans isomer product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]CC2C=CC=CC=2)=[CH:5][C:4]=1[CH3:21].[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][C:4]=1[CH3:21]
Reactant: [H][H]
Reactant: COc1c(C)cc(OCc2ccccc2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(C)cc(O)c2ccccc12

Procedure:
The 1-methoxy-2-methyl-4-benzyloxynaphthalene, in an amount of 925 milligrams, is added to a mixture of 286 milligrams of a 10 percent palladium/carbon catalyst in 20 milliliters of ethyl acetate. The resultant mixture is subjected to hydrogenolysis by contact with a mixture of hydrogen and nitrogen at atmospheric pressure for 38 hours. Subsequent to the hydrogenolysis, the catalyst is removed by centrifugation, and the crude product is obtained by solvent evaporation. Crystallization of the product from benzene/petroleum ether gives 4-methoxy-3-methyl-1-naphthol in an amount of 473 milligrams.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2.S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][C:3]1[S:2][CH:1]=[C:10]2[C:9](=[O:11])[NH:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[S:5][C:4]=12
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1Nc2ccccc2Sc2cscc21
Solvent: ClCCl
Product: O=C1Nc2ccccc2Sc2c1csc2Cl

Procedure:
A suspension of 1.16 g. of thieno[3,4-b][1,5]-benzothiazepin-10(9H)-one in 20 ml. of methylene chloride was treated with 0.81 g of sulfuryl chloride as in Example 12 to give 3-chlorothieno[3,4-b][1,5]benzothiazepin-10(9H)-one as a white crystal, m.p. 287°-288° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH:5]([CH3:7])[CH3:6].[OH-].[Li+].Cl>O1CCCC1>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]([NH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:20])=[O:2])=[O:19])=[CH:17][CH:16]=1
Reactant: COC(=O)C(NC(=O)CCc1ccc(O)cc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)CCc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
2-[3-(4-hydroxyphenyl)propionylamino]-3-methyl butyric acid methyl ester (200 mg), prepared in Example 9, was dissolved in tetrahydrofuran (10 mL) and treated with 2M lithium hydroxide (1 mL). The resulting mixture was stirred for 18 hours at room temperature. The reaction was neutralized with aqueous hydrochloric acid, extracted with ethylacetate (EtOAc) (100 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: EtOAc) to obtain 160 mg of the title compound. The yield was 84%. The results of analyses of the compound are as follows:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][NH:27][CH3:28]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:27]([CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH3:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCN(C)C
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CN(C)CCN(C)c1c(C=O)c2ccccc2n1-c1ccc(C(C)(C)C)cc1
Yield: 42 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with N,N,N′-trimethylethylenediamine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-[(2-dimethylaminoethyl)-methylamino]-1H-indole-3-carboxaldehyde (42% yield) as a light tan solid. TLC (silica gel, 7N NH3 in methanol/MeOH/Ethyl acetate (0.1:2:10 mL)) Rf=0.29. ESI/MS 378 (M+M); RT=3.43 min. NMR10.18 (1H, s); 8.10 (1H, d, J=9 Hz); 7.66 (2H, d); 7.48 (2H, d); 7.17 (1H, t); 7.08 (1H, t); 6.88 (1H, d, J=9 Hz); 3.21 (2H, t); 3.02 (3H, s); 2.18 (2H, t); 2.00 (6H, t); 1.36 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]1(=O)[CH:18]2[CH:13]([CH2:14][CH:15]=[CH:16][CH2:17]2)[C:12](=[O:19])[CH:11]=[CH:10]1.Cl.C([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[OH:19][C:12]1[CH:11]=[C:10]2[C:9]([NH:1][C:2]3[C:3]([S:8]2)=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:18]2[CH2:17][CH:16]=[CH:15][CH2:14][C:13]=12
Reactant: O=C1C=CC(=O)C2CC=CCC12
Reactant: Nc1ccccc1S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cc2c(c3c1CC=CC3)Nc1ccccc1S2
Reaction time: 1 h

Procedure:
A solution of 2-aminothiophenol (385 mg) in methanol (3 ml) was added to a solution of 4a, 5, 8, 8a-tetrahydro-1,4-naphtoquinone (Ref.: Ber. 62, 2361 (1929)) (500 mg) in methanol (10 ml) and stirred for 1 hour. Then conc. HCl (2 ml) was added and the mixture was stirred for another 2 hours. Ethyl acetate was added to the reaction mixture followed by a solution of NaHCO3. The organic layer was decanted, dried and evaporated to dryness. The resulting oily residue was chromatographed on silica gel (CH2Cl2) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=3)=[O:26])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Cc2cc(N)ncn2)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine, 4-ethyl-phenyl-isocyanate, and DMF as the solvent. The reaction mixture is stirred for 2 h. The title compound is obtained as a white solid: ES-MS: 348.0 [M+H]+; single peak at tR=6.94 min (System 2).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O>[CH2:19]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:13][CH3:14])([O:2][CH3:1])[C:4]1=[O:12])[CH:18]=[CH2:17]
Reactant: COC1(OC)C(=O)Nc2ccccc21
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(OC)(OC)c2ccccc21
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 3.86 g of 3,3-dimethoxyindolin-2-one in 30 ml of N,N-dimethylformamide was added dropwise to a suspension of 1.2 g of sodium hydride (60%) in 40 ml of N,N-dimethylformamide at 0° C. in a nitrogen stream. After the mixture was stirred at that temperature for 30 minutes, 2.60 ml of allyl bromide was added thereto. The resulting mixture was stirred for 1 hour and then concentrated. Chloroform was added to the residue, and the mixture was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform/hexane=1/1) to give 4.19 g (90%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[C:10]([N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:13]([O:12][C:10]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[CH3:9])[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(Br)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 71.1 %

Procedure:
To a mixture of 1-bromo-2,4-dimethylbenzene (1.85 g), 1-Boc-[1,4]diazepane (2 g), palladium(II) acetate (0.12 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.31 g) and sodium tert-butoxide (1.34 g) was added toluene (35 mL), and the mixture was stirred with heating under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g). The obtained 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g) was dissolved in chloroform (17 mL), 4N hydrogen chloride/ethyl acetate solution (6.9 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture to give the title compound (1.74 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(Oc1cc(Cl)ncn1)C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OC(C)C(C)(C)C)ncn1
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.06 g of sodium hydride (60% in oil), to which 0.3 ml of a solution containing 0.09 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.3 ml of a solution containing 0.24 g of 4-chloro-6-(1,2,2-trimethylpropyloxy)pyrimidine in tetrahydrofuran at room temperature, followed by stirring for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.25 g of 4-(2-butynyloxy)-6-(1,2,2-trimethylpropyloxy)pyrimidine (the present compound (3)).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:22])[C@@:10]([NH2:21])(C(OC(C)(C)C)=O)[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@H:10]([CH2:11][O:12][CH3:13])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: COC[C@@](N)(C(=O)NCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)—N-benzyl-2-Boc-amino-3-methoxypropanamide (9.8 g, 31.8 mmol) was dissolved in 15 mL of DCM and then 15 mL of TFA was added to the solution. The mixture was stirred at room temperature for two hours. The solvent and TFA was removed by evaporation and a white solid was obtained (12.4, 100%). Upon analysis, it was determined that on average each molecule contained 1.6 TFA. 1H NMR (500 MHz, DMSO) δ 3.30 (s, 3H), 3.69 (m, 2H), 4.05 (m, 1H), 4.35 (m, 2H), 7.25 (m, 3H), 7.35 (m, 2H), 8.23 (br., 2H), 8.95 (m, 1H). LC-MS (m/z) calcd. 208.1. Found 209.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([Cl:20])=[C:17]([Cl:19])[Cl:18])[CH:15]=1)[CH2:11][OH:12].C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O>[CH3:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([Cl:20])=[C:17]([Cl:18])[Cl:19])[CH:15]=1)[CH:11]=[O:12]
Reactant: Cc1cc(CO)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc(C(Cl)=C(Cl)Cl)c1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a cold (-60° C.) solution of oxalyl chloride (3.17 ml) in 65 ml of dry methylene chloride (CH2Cl2), dimethyl sulfoxide (DMSO) (5.37 ml) in 16 ml of CH2Cl2 was added followed by the addition of 7.86 g of 3-methyl-5-(trichlorovinyl)benzyl alcohol in 16 ml of CH2Cl2, to this cold mixture, triethylamine (22 ml) was slowly added. The reaction mixture was permitted to warm to room temperature over 1.5 hours. The reaction mixture was then added to 200 ml of water and the layers separated. The organic layer was repeatedly washed with water and then dried with magnesium sulfate. Concentration afforded 8.16 g of an oil which was chromatographed on silica gel (60:40 hexane:CH2Cl2) to give 7.82 g of pure aldehyde, m.p. 42°-43° C..
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:11]2[C:12]([CH3:20])=[N:13][N:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=23)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]=[CH2:30].O>CN(C)C=O.C(OCC)(=O)C>[CH3:20][C:12]1[C:11]([C:4]2[S:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([O:1][CH2:30][CH:29]=[CH2:28])[N:3]=2)=[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: C=CCBr
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1nc(-c2c(C)nn3ccccc23)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Methyl 4-hydroxy-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (1.0 g, 3.5 mmol) produced in Example 13-B(i) was dissolved in N,N-dimethylformamide (50 mL), potassium carbonate (3.2 g, 9.7 mmol) and 3-bromoprop-1-ene (2.8 g, 23 mmol) were added, and the mixture was stirred at room temperature for 2 hr. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with water (100 mL×3) and saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100) to give the title compound (760 mg, 67%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][N:5]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:31].Cl.[C:33](OCC)(=[O:35])[CH3:34]>>[C:33]([O:1][CH2:2][CH2:3][NH:4][N:5]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:31])(=[O:35])[CH3:34]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NCCO
Reactant: CCOC(C)=O
Agent: Cl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NCCOC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the compound obtained in Example 74 (210 mg) in ethyl acetate (10 ml) is added a 4M solution of hydrogen chloride in ethyl acetate (10 ml), and the mixture is stirred at room temperature for five hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. The solution is washed successively with a saturated aqueous sodium hydrogen carbonate solution and water, and dried. The solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1), and crystallized from diethyl ether to give 2-(2-acetoxyethylamino)-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH2:22][OH:23])([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][C:15]([CH2:22][OH:23])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(CO)(C(=O)O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 125.4 %

Procedure:
To a solution of methyl 1-(2-(tert-butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylate (2.5 g, 7.56 mmol, 1.0 equiv.) in THF (10 mL) and CH3OH (10 mL) was added aqueous LiOH (2N, 7.56 mL, 15.13 mmol, 2.0 equiv.). The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was neutralized with HCl (1 N) and was concentrated to dryness to give 1-(2-(tert-butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid (3.0 g), which was used without further purification. LRMS (M-Boc+H+) m/z 261.0.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:24]3[CH2:23][CH2:22][N:21]([CH2:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[C:17]([F:31])([F:32])[F:16])[CH2:26][CH2:25]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN1CCN(CCCc2cc(-c3ccccc3)no2)CC1
Yield: 46.6 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-[2-(trifluoromethyl)benyl]piperazine (10.4, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0.15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 2.1 hr and followed the same processes as in Example 1 to obtain 10 mg (46.6%) of the target compound.