Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42][CH2:43][CH2:44][CH2:45]O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:42][CH2:43][CH2:44][CH2:45][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: OCCCBr
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (29 g, 94.7 mmol), (prepared as described for the starting material in Example 12), in methylene chloride (280 ml) coiled at 5° C. was added triphenylphosphine (37.1 g, 141.6 mmol) followed by 3-bromo-1-propanol (12.8 ml, 141.6 mmol) and diethyl azodicarboxylate (2.4 ml, 141.6 mmol) dropwise. After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (98/2). The fractions containing the expected product were combined and evaporated and the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (37.22 g, 92%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:36])[CH3:35]
Reactant: O=C(N[C@@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A149) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N+:28]([O-])=O)=[C:15]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:16]=2)=[CH:8][CH:7]=1.CO.C(N(CC)CC)C>C(Cl)Cl>[NH2:28][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[S:10][C:6]([CH2:5][NH:4][CH2:3][CH2:2][OH:1])=[CH:7][CH:8]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(CNCCO)s3)ccc2[N+](=O)[O-])cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(CNCCO)s3)ccc2N)cc1
Yield: 46 %

Procedure:
Following the same procedure as described in Example 14, step 4 (scheme 14) but substituting compound 146 for compound 192, the title compound 193 was obtained after column chromatography (46% yield, eluent: 50% MeOH in DCM with 1% triethylamine).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:22][C:23]([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])=[O:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC(=O)Cl
Yield: 264.6 %

Procedure:
Phytanol (48.8 g, 163.5 mmol), and triphosgene (16.17 g, 54.66 mmol) were dissolve in 300 ml of dichloromethane, stirred and cooled on an ice bath. Anhydrous pyridine (12.93 g, 163.5 mmol) was added dropwise over a period of 1 hour. The reaction mixture was stirred for an additional 1 h at room temperature, and then quickly extracted with extra methylene chloride and ice water. The organic layer was pooled, dried over Na2SO4 and evaporated to dryness to yield 52.22 g (88.7%) of phytanyl chloroformate as yellow liquid. 1H NMR in CDCl3: δ0.83, 0.85, 0.86, 0.88, (4s, each 3H, CH3), 0.91 (d, 3H, J=6.0 Hz, CH3), 0.95-1.40 (m, 20H, CH2), 1.39-1.68 (m, 4H, CH), 1.68-1.88 (m, 1H, OH), 4.27-4.47 (m, 2H, CH2OH).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:7]([O:19][CH3:20])[CH:6]=1)[CH3:2].[CH:24]1[CH:25]=[CH:26][C:27](CCO)=[CH:28][CH:29]=1.S([O-])(O)(=O)=O.[K+].[CH2:39](O)[CH3:40]>C1(C)C=CC=CC=1>[C:40]1([CH2:23][CH2:22][O:21][CH:4]([O:3][CH2:1][CH2:2][C:29]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[C:7]([O:19][CH3:20])[CH:6]=2)[CH:39]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(OCC)c1ccc(OC(=O)OC(C)(C)C)c(OC)c1
Reactant: CCO
Reactant: OCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(C(OCCc2ccccc2)OCCc2ccccc2)ccc1OC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
An amount of 1.1 g (3.36 mmol) of 3-methoxy-4-tert.-butoxycarbonyloxy-benzaldehyde diethylacetal was dissolved in 40 ml of dried toluene. After the addition of 0.82 g (6.71 mmol) of phenylethanol and 16 mg of potassium hydrogen sulfate, the resulting mixture was stirred for 2 hours under reflux. The ethanol formed was then distilled off slowly, while more, toluene was added to the mixture. After complete removal of the ethanol, the mixture was cooled down and the potassium hydrogen sulfate was filtered off. The filtrate was concentrated in a rotary evaporator. This gave a yellowish, viscous oil, which was dried on an oil pump.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][C:26](OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.[CH3:38]C([O-])(C)C.[K+].BrCC1CC1.CN(C=O)C>C1COCC1.CCOC(C)=O>[CH:25]1([CH2:24][S:23][C:20]2[CH:19]=[C:18]([O:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[C:17]([NH:16][C:14]3[S:13][N:12]=[C:11]([C@H:2]4[CH2:3][O:4][C:5]5([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]5)[O:1]4)[N:15]=3)=[N:22][CH:21]=2)[CH2:38][CH2:26]1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
to a solution of (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)-pyridin-3-ylthio)propanate (0.428 g, 0.787 mmol) in THF (20 mL) was added potassium 2-methylpropan-2-olate (1M in THF, 236 ml, 2.36 mmol) and the reaction was stirred at ambient temperature for 5 minutes. (Bromomethyl)cyclopropane (0.106 g, 0.787 mmol) was added followed by DMF (5 mL) and the reaction was stirred for 1 hour at ambient temperature. The reaction was poured into EtOAc (500 mL) and the organic layer was washed with a 1:1 solution of water, 1N NaOH (100 mL total) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified over silica get (40% EtOAc/CH2Cl2) to afford (S)-N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)-pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (0.30 g, 0.586 mmol, 74.5% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)[CH3:16].S(=O)(O)[O-].[Na+].CC(N(C)C)=O>O>[CH2:15]([S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]1[NH:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:11]([F:12])([F:14])[F:13])[CH:4]=[N:3][C:2]=2[N:1]=1)[CH3:16]
Reactant: NC(=O)c1cc(C(F)(F)F)cnc1N
Reactant: CCSc1ccccc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCSc1ccccc1-c1nc2ncc(C(F)(F)F)cc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A mixture of 1.0 g of 2-amino-5-trifluoromethylpyridine-3-carboxylic acid amide, 810 mg of 2-ethylsulfanylbenzaldehyde, 1.01 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 12 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 975 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH3:15][O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20].C[O-].[Na+]>CO>[CH3:15][O:16][C:17]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)=[N:2][O:1][C:19]=1[NH2:20])=[O:21]
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(C(F)(F)F)c2)noc1N
Yield: 78 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethyl)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.14 g, 41.74 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (7.46 g, 26.06 mmol, 78%) was obtained.
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:35]=[CH:34][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:19])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:12]([C:14]1[CH:35]=[CH:34][C:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:19])=[CH:16][CH:15]=1)(=[NH:11])[NH2:13]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(C(=O)N2CCC[C@H]2CC(=O)NCCC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(C(=O)N2CCC[C@H]2CC(=O)NCCC(=O)O)cc1
Yield: 55.5 %

Procedure:
115 mg of N-[[(S)-1-[p-[N-[(benzyloxy)carbonyl]-amidino]benzoyl]-2-pyrrolidinyl]acetyl]-β-alanine and 50 mg of Pd/C were stirred under hydrogen for 4 hours in 2.5 ml of acetic acid. The catalyst was filtered off and the solution was evaporated. The residue was dissolved in water, evaporated again and chromatographed on silica gel using methanol. 46 mg of N-[[(S)-1-(p-amidino-benzoyl)-2-pyrrolidinyl]acetyl]-βalanine, m.p. >250° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]O)[CH:21]=2)[CH:19]=1)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Br:54][CH2:26][C:22]1[CH:21]=[C:20]([C:18]2[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[C:15]3[CH:30]=[N:29][N:28]([CH:31]([CH3:32])[CH3:33])[C:16]=3[N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(hydroxymethyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.1 g, 4.7 mmol) in DCM (35 mL), triphenyl phosphine (5 g, 19.06 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (6.2 g, 18.69 mmol) was added portion wise to it and resulting solution was stirred at room temperature for overnight. After completion of reaction, solid was filtered and dried to obtain the desired compound (1.2 g, 52.2%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:3]=1[O:4][CH2:5][C:6]([NH2:8])=O.B.CSC.[ClH:18]>O1CCCC1>[ClH:18].[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:3]=1[O:4][CH2:5][CH2:6][NH2:8]
Reactant: NC(=O)COc1c(Br)cccc1Br
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: NCCOc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 2-(2,6-dibromo-phenoxy)acetamide (9.3 g, 0.03 mol) in tetrahydrofuran (100 mL) was heated to reflux and borane-dimethylsulfide (4.5 mL, 0.045 mL) was added in drops over a period of 15 min. After 3 h, 20 mL of ethanolic hydrogen chloride (2M, 0.4 mol) was added. The solution was refluxed for 30 min. Upon cooling to ambient temperature a white solid precipitated which was filtered and washed with diethyl ether (20 mL) to give 2-(2,6-dibromo-phenoxy)ethylamine, hydrochloride salt (7.25 g, 73.3%). MS: MH+=294. M.p. 249.7-252.3° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[NH:26][CH:25]([C:27]([OH:29])=O)[CH2:24][S:23]2)[CH:17]=1.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:37][NH:38][C:27]([CH:25]1[CH2:24][S:23][CH:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[NH:26]1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NOCc1ccccc1)C1CSC(c2cccnc2)N1
Reaction time: 12 h

Procedure:
A solution of 490 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 500 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, mg of O-benzylhydroxylamine, 480 mg of 1-hydroxybenzotriazole, 240 mg of N-methylmorpholine and 15 ml of tetrahydrofuran with ice cooling, and the resultant mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent:ethyl acetate) gave 260 mg of N-benzyloxy-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1.5 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 240 mg of N-benzyloxy-2-(pyridin-3-yl)thiazolidine-4-carboxamide dihydrochloride. Melting point 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH:21](OCC)=[O:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:21]=[O:22])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CCOC=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Product: COC(=O)c1nc2n(c1C=O)C1CC(C1)c1ccc(Br)cc1-2
Yield: 74 %

Procedure:
Methyl 10-bromo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (4 g) was reacted with ethyl formate similarly to as described in example 8 with non-critical modifications to afford 3.2 g (74%) of methyl 10-bromo-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:19])[C@@H:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][OH:7].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:7][CH2:6][C@H:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH:4]([CH3:19])[CH3:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@H](CO)Nc1ccc(C(F)(F)F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](COCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydride (10 mg) and (2R)-3-methyl-2-{[4-(trifluoromethyl)phenyl]amino}butan-1-ol (30 mg), which is the compound obtained in Step 1 of Example 2, were dissolved in dimethylformamide (1 mL), and then benzyl bromide (0.052 mL) was added. The mixture was stirred at 50° C. for 3 hrs, and the title compound (37.5 mg) was obtained by purification step A.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:12](C)C)CN)=[CH:5][CH:4]=1.C([O:19]C1C(OC)=CC(C(O)=O)=CC=1OC)CCC.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:9]([NH2:12])(=[O:19])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Reactant: COc1ccc(C(CN)N(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(4-methoxyphenyl)-N,N-dimethylethane-1,2-diamine represented by Formula 115 (134.6 mg, 0.69 mmol, purchased from Enamine Co.) was slowly added to 4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (193.8 mg, 0.76 mmol) prepared in Preparative Example 2 and diisopropylethylamine (0.48 mL, 2.77 mmol) in DMF (6 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 289.76 mg, 0.76 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (15 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 23 as a desired product (VVZ-024; 242.4 mg, 81% yield).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[C:6]([F:15])[C:5]([F:16])=[C:4]([F:17])[C:3]=1[F:18].[CH3:19][Li]>CCOCC.O>[F:15][C:6]1[C:5]([F:16])=[C:4]([F:17])[C:3]([F:18])=[C:2]([CH3:19])[C:7]=1[C:8]1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=1
Reactant: [Li]C
Reactant: CC1(C)COC(c2c(F)c(F)c(F)c(F)c2F)=N1
Solvent: CCOCC
Solvent: O
Product: Cc1c(F)c(F)c(F)c(F)c1C1=NC(C)(C)CO1
Temperature: -20 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 21.2 g (80.0 mmol) of 2-(pentafluorophenyl)-4,4-dimethyl-2-oxazoline (Bull. Chem. Soc. Jpn., 57, 225 (1984)) in 300 mL of dry ether was cooled to -20° C. under argon and treated with 60 mL of 1.6M methyl lithium (96.0 mmol). The solution was stirred at -20° C. for 2 hours, then stirred at room temperature overnight. The mixture was diluted with water, and the organic layer was dried over magnesium sulfate and concentrated to give 20.8 g of the title compound as an orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@@H:14]1[CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]([CH2:23][C@@H:14]2[O:13][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][CH2:15]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@]1(C)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
A mixture of (S)-ethyl-3-methylpiperidine-3-carboxylate (7.23 g, 42.2 mmol), Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl ester (15.0 g, 44.3 mmol), potassium carbonate (6.42 g, 46.4 mmol) and N,N-dimethyl formamide (50 ml) was heated to 120° C. After 4 hours the reaction mixture was cooled down, water (35 ml) was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness. Toluene (35 ml) was added to the evaporation residue and the mixture was extracted twice with 1M HCl. The combined acidic water layers were made basic with aq NaOH. The basic water layer was extracted twice with ethyl acetate and the combined ethyl acetate layers were evaporated to dryness to yield 10.8 g (76%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([NH:30][C:31]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=S)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:37]([O:36][C:34]([NH:33][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([C:11]2[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:17]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2CO[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a suspension of 3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)aniline (364 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (385 mg) and diisopropylethylamine (0.465 ml) in dichloromethane (12 ml) was added 1-methyl-2-chloropyridinium iodide (385 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 35 g, 20% ethyl acetate in n-hexane) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)phenyl)guanidine (549 mg).