Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=34)=[N:16]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[O:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[N:15]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]2[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C1CCNCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a solution of 3-[2-(1-tert-butoxycarbonyl-4-oxopiperidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (500 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml) at room temperature, and stirred for 2 hours. Solvent was evaporated and removed by toluene azeotrope to give residue, which was chromatographed on silica gel eluting in turn with 5% and 10% methanol in dichloromethane. Fractions containing desired product were collected and concentrated in vacuo to give residue, which was dissolved in methanol and passed through Amberlite IRA-910 (10 ml) eluting with methanol. Solvent was removed under reduced pressure to give 3-[2-(4-oxopiperidin-3-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.3 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+]>CN(C=O)C>[O:2]=[C:3]1[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH:6]2[N:5]([CH2:9][CH2:8][CH2:7]2)[CH2:4]1
Reactant: CCOC(=O)CCC1CCCN1CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC2CCCN2CC1=O
Yield: 13.2 %

Procedure:
A solution of ethyl 3-(1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl)propanoate (2 g) and NaH (2 g, 60% weight) in DMF was stirred at 40° C. for 10 mins. The completion of reaction was monitored by TLC. After the suspension was quenched with water (30 mL), the solution was extracted with ethyl acetate (3×100 mL) and the combined organic layer was washed with brine, dried over Na2SO4. The desired product (230 mg) was obtained by column chromatography. MS (ESI): 212 (MH+).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].O1CCCC1.[NH3:16]>CCOCC>[C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(=[O:2])[NH2:16]
Reactant: O=C(O)Cn1nnnc1S
Reactant: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)Cn1nnnc1S
Reaction time: 2.5 h

Procedure:
1-Carboxymethyltetrazole-5-thiol and 1,1-carbonyldiimidazole were reacted as described in Example 4. To the reaction mixture was added tetrahydrofuran saturated with dry ammonia gas. The resulting suspension was stirred for 2.5 hours and the solid which formed was collected by filtration, washed with tetrahydrofuran and dissolved in methanol. Amberlite IR-120 ion-exchange resin (50 g.) was added and the suspension was stirred for 15 minutes. The resin was then removed and washed with absolute methanol. The methanol solution was concentrated to give a residue which was dissolved in ether and triturated with acetone to give 1-carbamoylmethyltetrazole-5-thiol, m.p. 200° (dec.).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2cc1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1
Temperature: 50 °C

Procedure:
A solution of 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-(1H)-one (4.00 g, 12.6 mmol) in methanol (500 mL) was degassed with argon, and 10% palladium on carbon (1.2 g) added. The reaction was placed under 1 atm hydrogen and heated to 50° C. for 5.5 h. The reaction was cooled and filtered through celite. Concentration provided the title compound, 2.7 g. MS 229 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.80 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 3.52 (t, J=12 Hz, 2H), 3.17 (dt, J=3, 13 Hz, 2H), 3.15 (m, overlaps with δ 3.17 peak, 1H), 2.18 (d, J=14 Hz, 2H), 1.91 (dq, J=3, 12 Hz, 2H).
Reaction SMILES: O=[C:2]1NCN[C@@H](C([O-])=O)C1.[CH2:11]([O:18][C:19](=[O:44])[C@H:20]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1COCOC1>ClCCl.S(=O)(=O)(O)O>[CH2:25]([N:24]1[C:22](=[O:23])[CH2:21][C@H:20]([C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:44])[N:32]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:2]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1C[C@H](C(=O)[O-])NCN1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(=O)NCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: C1OCOCO1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Benzyl 1-benzyl-3-1(4-methoxyphenyl)sulfonyl]-6oxo-hexahydro-pyrimidine-4(R)-carboxylate (1c): To the solution of N-benzyl-2(R)-[(4-methoxyphenyl)sulfonylamino]-succinamic acid benzyl ester as an oil (2.10 g, 4.4 mmol) in 200 mL of dichloromethane is added, with stirring, 1,3,5-trioxane (1.57 g, 17.4 mmol) followed by two drops of sulfuric acid. The reaction is heated at reflux for 3 hours at which time mass spectrometry (ES) indicates the reaction to be complete. The reaction is allowed to cool to room temperature, diluted with dichloromethane (250 mL), and washed with water (2x). The product is purified by flash silica gel chromatography (1:1 hexanes-ethyl acetate), to give benzyl 1-benyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine4(R)-carboxylate.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:5]2[N:6]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2>CN(C)C=O>[CH3:1][NH:2][C:4]1[C:5]2[N:6]([C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CN
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCc1nnc2c(NC)nc3ccccc3n12
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Monomethylamine gas was bubbled through a solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, in N,N-dimethylformamide (50 ml.) at 0° C. for 2 minutes. The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 2 hours, and then poured over ice and stirred another 20 minutes. The precipitate which formed was separated by filtration, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g. (88% yield) of 4-methylamino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 271°-273° C. Mass spectrum: m/e, 227 (P).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17](O)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:17][OH:18])[CH2:15][CH2:16]2)=[CH:12][CH:13]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Br)cc2)CC1
Reaction time: 0.75 h

Procedure:
LiAlH4 (2M in THF) (1.6 mL, 3.20 mmol) was added to a solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (480 mg, 1.991 mmol) in THF (12 ml) at 0° C. The reaction mixture was shirred at rt for 45 min, then quenched with water (3 mL) at 0° C. The mixture was diluted with EtOAc (30 mL) and 1N aqueous potassium sodium tartrate and stirred atrt for 2 h. The organic layer was removed. Aqueous layer was extracted with EtOAc. Combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound that was used without further purification. LC-MS calculated for C10H11BrO 226, No ionization. Rt: 2.85/5.5 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[C:14](OCC)=[O:15].OC[C@@H]1[C@@H](C)CCN1C(OC(C)(C)C)=O>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@@H:3]1[CH2:14][OH:15]
Reactant: CCOC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO

Procedure:
The title compound was prepared from 1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate using the methods used to prepare 1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.4 (s, 9H), 1.6 (m, 1H), 1.9 (m, 1H), 3.1 (m, 1H), 3.2 (m, 2H), 3.4 (m, 2H), 4.1 (m, 1H). ES+=218.24, 117.97 (-Boc).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:16].NCC1C=C(C=C(OC)C=1)C(OC)=O>>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)c1cccc(C#N)c1
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: CCOC(=O)C(C)c1cccc(CN)c1

Procedure:
Ethyl 2-(3-(aminomethyl)phenyl)propanoate hydrochloride was prepared from ethyl 2-(3-cyanophenyl)propanoate in an analogous manner to Intermediate 2.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]1([N:27]=[C:28]=[O:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc3ccccc23)cc1-c1c(Br)cnn1C
Yield: 69.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 1-naphthyl isocyanate (0.023 g, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 24 (0.039 g, 0.09 mmol, 68%) as a white powder. LCMS m/z (%)=451 (M+H79Br, 95), 453 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.58 (s, 1H), 8.32 (s, 1H), 8.16 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.3 Hz, 1H), 7.91 (d, J=9.4 Hz, 1H), 7.75 (dd, J=2.7, 9.0 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.44-7.57 (m, 5H), 7.14 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N+:7](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-:8]>CCOCC>[CH:1]1([C:4](=[O:5])[C:9](=[N+:7]=[N-:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(Cl)C1CC1
Solvent: CCOCC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
Cyclopropanecarbonyl chloride (36 g, 0.34 mol) was added dropwise to a stirred solution of ethyl diazoacetate (86.2 g, 0.76 mol) in dry ether (500 ml) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to room temperature then was stirred for 1 day, heated to gentle reflux for 2 days, then left to stand at room temperature for 5 days. Evaporation of the mixture followed by distillation afforded ethyl 3-cyclopropyl-2-diazo-3-oxo-propanoate (27.4 g, 44%) bp 85°-90° at 1 mm Hg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:6]1[CH:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([F:19])=[CH:9][C:7]=1[NH2:8])=O>C1(C)C=CC=CC=1>[Cl:27][C:23]1[CH:22]=[C:21]([CH2:20][N:5]2[C:6]3[CH:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([F:19])=[CH:9][C:7]=3[N:8]=[C:3]2[C:2]([F:29])([F:28])[F:1])[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)Nc1cc(N(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)c(N)cc1F
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1cc2c(cc1F)nc(C(F)(F)F)n2Cc1cccc(Cl)c1
Yield: 85.9 %

Procedure:
A stirred solution of 3.2 grams (0.007 mole) of 2-[(trifluoromethylcarbonyl)(3-chlorophenylmethyl)amino]-4-ethoxycarbonylamino-5-fluoroaniline in 100 mL of toluene was heated at reflux for about 4.5 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue, which was triturated with petroleum ether, and the resultant solid was collected by filtration, yielding 2.5 grams of 1-(3-chlorophenylmethyl)-2-trifluoromethyl-5-fluoro-6-ethoxycarbonylaminobenzimidazole, mp 144°-146° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2cnn(C)c(=O)c2Cl)CC1

Procedure:
A mixture of 4,5-dichloro-2-methylpyridazin-3(2H)-one [S.-F. Chen and R. P. Panzica, J. Org. Chem., 46, 2467-2473 (1981)] (8.95 g, 50 mmol) and 1-methylpiperazine (12.5 g, 125 mmol) in water (150 ml) was refluxed for 30 h. After cooling, about two thirds of the solvent was removed under reduced pressure and the mixture was adjusted to pH 7-8 by addition of aqueous NaHCO3. It was then extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by recrystallization from ethanol (95%).
Reaction SMILES: [N:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[N:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=O)=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[N:1]=[CH:2][CH:3]=[N:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc2nc3ccc4nccnc4c3nc12
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4nccnc4c3nc12

Procedure:
Pyrazino[2,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from pyrazino[3,2-α]phenazine-11-carboxylic acid (II.6) and N,N-dimethylethylenediamine
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].CS[C:21]1[S:25][CH:24]=[CH:23][S+:22]=1>>[Cl:14]([O-:18])(=[O:17])(=[O:16])=[O:15].[S:22]1[CH:23]=[CH:24][S:25][C:21]1=[N+:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: CSc1scc[s+]1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1ccc(CN2CC[N+](=c3sccs3)CC2)cc1
Yield: 68.6 %

Procedure:
2.2 g of N-benzylpiperazine and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from water-ethanol, whereby 2.6 g (yield: 68.9%) of 1-(1,3-dithiol-2-ylidene)-4-benzylpiperazinium perchlorate (Compound No. 33) was obtained as crystals having a melting point of from 224° to 226° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[CH3:22][O:23][CH:24]([O:28][CH3:29])[C:25](=[O:27])[CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:25]([OH:27])([CH3:26])[CH:24]([O:28][CH3:29])[O:23][CH3:22])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: COC(OC)C(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(OC)C(C)(O)c1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (1.00 g) in tetrahydrofuran (20 mL) was slowly added a 1.6M n-butyllithium hexane solution (4.5 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min, and 1,1-dimethoxypropan-2-one (1.50 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.58 g, yield 90%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 276 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:58])([CH3:59])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41])=[O:14]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COc2ccc(CC(NC(=O)c3cccc4c(Cl)cccc34)C(O)c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-chloronaphthalene-1-carboxylic acid (260 mg, 1.26 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (242 mg, 1.26 mmol) and 1-hydroxybenzotriazole monohydrate (193 mg, 1.26 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (0.40 g, 1.20 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-1-naphthamide (473 mg, 76%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].C(N(CC)C(C)C)(C)C.[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][N:6]([C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:7]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CNCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)N(C)CCCN(C)C

Procedure:
A mixture of 3.89 g. (0.0335 mol) of N,N,N'-trimethyl-1,3-propylenediamine and 4.33 g. (0.0335 mol) of N,N-diisopropylethylamine in 50 mL chloroform was added to 7.33 g. (0.0335 mol) of lauroyl chloride dropwise, on an icebath, and was then reacted for another two hours at room temperature. 75 mL of aqueous sodium bicarbonate was then added to this reaction mixture, and the chloroform layer was separated and washed with 125 mL aqueous sodium bicarbonate followed by 100 mL water. The chloroform layer was then dried (MgSO4) filtered and concentrated in vacuo.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH:19]([F:21])[F:20]>C(Cl)(Cl)Cl>[Cl:10][C:11]1[C:12]([O:18][CH:19]([F:20])[F:21])=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[C:15]([F:17])[CH:16]=1
Reactant: Fc1ccc(OC(F)F)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(OC(F)F)c(Cl)cc1F
Temperature: 60 °C
Yield: 89.5 %

Procedure:
To 21 g of conc. nitric acid was dropwise added 28 g of conc. sulfuric acid at 0° C., and the mixture was heated at 60° C. At intervals of 3 minutes, 10 g of 1-chloro-2-difluoromethoxy-5-fluorobenzene was added in 5 portions to the mixture, which was kept at 60° C. for half an hour. After cooling, the reaction mixture was poured on ice water and shaken with chloroform. The chloroform layer was washed with water, dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (100:15 v/v). The eluate was concentrated to give 11 g of the titled compound XII-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[N:8]([CH2:20][CH2:21][CH2:22][N:23]([CH3:34])[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9](=[O:19])[NH:10][C:11]=1[CH2:12][O:13][CH2:14][CH2:15][N:16]=[N+]=[N-])=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[N:8]([CH2:20][CH2:21][CH2:22][N:23]([CH3:34])[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9](=[O:19])[NH:10][C:11]=1[CH2:12][O:13][CH2:14][CH2:15][NH2:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(=O)N(CCCN(C)C(=O)CCc2ccccc2)C1c1ccccc1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=C(COCCN)NC(=O)N(CCCN(C)C(=O)CCc2ccccc2)C1c1ccccc1Cl
Reaction time: 3 h
Yield: 56.6 %

Procedure:
A solution of 6-(2-azido-ethoxymethyl)-4-(2-chloro-phenyl)-3-{3-[methyl-(3-phenyl-propionyl)-amino]-propyl}-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (27 mg, 0.046 mmol) in EtOH (5 mL) was hydrogenated in the presence of 5% palladium on calcium carbonate poisoned with lead (10 mg). After 3 h, the catalyst was removed using a filter syringe. The filtrate was concentrated in vacuo to afford 29 mg of thick, colorless oil as crude product (87% pure by analytical HPLC). The crude product was purified by preparative HPLC (from 30% B to 100% B for 10 min, Solvent A=90% H2O-10% MeOH-0.1% TFA Solvent B=10% MeOH-90% H2O-0.1% TFA, at 20 mL/min using column YMC ODS S5 20×100 mm). The desired fractions were combined and concentrated to remove most of the MeOH. The concentrate was taken up in EtOAc (50 mL) and basicified with saturated aqueous NaHCO3 solution. The EtOAc extract was washed with brine, dried (Na2SO4), filtered, concentrated and dried in vacuo to afford 14.5 mg (43%) of purified material as a thick, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:20](F)(F)[CH2:21][N+:22]([O-:24])=[O:23]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][C:20]2=[CH:21][N+:22]([O-:24])=[O:23])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])CC(F)(F)F
Reactant: NCCNCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
5 g (26.9 mmol) of N-(2-chloro-5-pyridylmethyl)ethylene-diamine and 11.7 g (84.6 mmol) of potassium carbonate are placed in 40 ml of methanol. A solution of 3.64 g (28.2 mmol) of 1,1,1-trifluoro-2-nitro-ethane in 20 ml of methanol is added dropwise at 5° C. to 10° C. within 30 minutes. After the addition is complete, the mixture is stirred for 5 hours at 20° C. The mixture is then concentrated by removal of the solvent by distillation in vacuo, and the residue is taken up in methylene chloride, washed with a small amount of water, dried, concentrated and recrystallized from methanol. 4.6 g (70.1% of theory) of 1-(2-chloro-5-pyridylmethyl)-2-(nitromethylene)-imidazoline of a melting point of 160° C. to 161° C. are obtained.