Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[N:4][CH:3]=1.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][CH:38]=1.[CH3:45][OH:46].ClCCl>>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:5]2[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([F:17])([F:16])[F:18])=[O:11])[C:7](=[O:8])[C:2]([NH:1][C:45]([O:44][CH2:43][C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)=[O:46])=[CH:3][N:4]=2)=[CH:35][CH:34]=1
Reactant: OCc1ccncc1
Reactant: CO
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F

Procedure:
2-[5-Amino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide and 4-pyridylcarbinol were subjected to a procedure similar to that described in Example 3.a. Chromatography, with methanol:dichloromethane (5:95) as the eluent, gave 2-[2-(4-fluorophenyl)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a yellow solid; MS: m/z=666(M+1).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[NH:30][CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:30]([CH:1]=[O:3])[CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:9]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.22 ml) was added dropwise formic acid (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling, a solution of methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.35 g) in THF (15 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(3-ethoxypropoxy) phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.36 g) as colorless crystals.
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#N.Cl.[OH2:25]>C1(C)C=CC=CC=1.B(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:1][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:25]
Reactant: O
Reactant: N#Cc1ccccc1Cl
Reactant: CN1CCC(Nc2ccccc2)CC1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCC(Nc2ccccc2C(=O)c2ccccc2Cl)CC1
Temperature: 150 °C
Yield: 99 %

Procedure:
To a 2.03M solution of boron trichloride (25×1.2 mmol) in toluene (14.8 ml) is dropwise added a solution of 4-anilino-1-methylpiperidine (4.79 g, 25 mmol) in toluene (40 ml) under ice cooling and stirring, and the resultant mixture is refluxed under stirring over a period of 1 hour. The toluene is evaporated under atmospheric pressure from the reaction mixture, and the residue is mixed with 2-chlorobenzonitrile (6.88 g, 25×2 mmol) and heated at 150° C. (bath temp.) over a period of 15 hours under stirring. After cooling, the reaction mixture is mixed with 2N hydrochloric acid (15 ml) and water (30 ml) and heated at 100° C. under stirring over a period of 20 minutes. After cooling, the reaction mixture is washed with ether, and the aqueous layer is neutralized with conc. aqueous ammoniac solution and shaken with methylene chloride. The methylene chloride layer is dried over anhydrous potassium carbonate and concentrated in vacuo. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride. The eluate is concentrated, and the residue is crystallized from ether-petroleum ether to give 4-[2-(2-chlorobenzoyl)anilino]-1-methylpiperidine (8.15 g) as crystals melting at 128° to 129° C. The yield is 99%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH:5]([C:10]1([CH:16](O)[CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)[C:6]([F:9])([F:8])[F:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH:5]([C:10]1([CH:16]([N:44]2[C:43](=[O:45])[C:42]3=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]3[C:40]2=[O:50])[CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)[C:6]([F:9])([F:8])[F:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)C(C)C(C(F)(F)F)C1(C(C)O)SCCCS1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)C(C(F)(F)F)C1(C(C)N2C(=O)c3ccccc3C2=O)SCCCS1

Procedure:
A solution of 462 mg (2 mMole) of the product of Example 4 in 20 ml of tetrahydrofuran is treated with 524 mg (2 mMole) of triphenylphosphine, 268 mg (2 mMole) of phthalimide, and 350 mg (2 mMole) of diethyl azodicarboxylate for 48 hours at 25° C. The solvent is evaporated and the product isolated by chromatography on silica gel affording 3-[2-(1-phthalimidoethyl)-1,3-dithian-2-yl]-4,4,4-trifluoro-2-methylbutyric acid methyl ester.
Reaction SMILES: [C:1](=[O:11])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15].C1(C)C(S(O)(=O)=O)=[CH:20][CH:21]=[CH:22][CH:23]=1>CCCCCC>[CH2:4]([O:16][C:13](=[O:17])[CH:14]([O:15][CH2:23][CH2:22][CH2:21][CH3:20])[NH:2][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:11])[CH2:5][CH2:6][CH3:7]
Reactant: NC(=O)OCc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: O=CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OCCCC

Procedure:
A solution of 3.0 g. (0.02 mol.) of benzyl carbamate 1.8 g. (0.02 mol.) of glyoxylic acid hydrate and 0.1 g. of toluenesulfonic acid in 50 ml. of n-butanol was slowly distilled over a 1 hour period. The last of the solvent was removed in vacuo to give a residue which was dissolved in hexane and filtered to remove the p-toluenesulfonic acid. The filtrate was chromatographed on alumina (Woelm, activity II) and eluted with hexane. Concentration of the eluate in vacuo and molecular distillation of the residue at 130°/0.1 mm. gave the title compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[CH:14][C:13]2[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=2)[C:26]([OH:28])=[O:27])=[CH:23][CH:24]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture of acetic anhydride (80 mL), 4-(methylthio)benzaldehyde (9.81 g, 61.2 mmol), 4-chlorophenylacetic acid (12.03 g, 70.5 mmol), and triethylamine (7.49 g, 7.42 mmol) was heated to reflux for 7 hours. The reaction was cooled to 90° C., and water (100 mL) was added through an addition funnel. A yellow solid separated from the solution which was isolated by filtration and air dried to afford the desired acid. The acid was recrystallized from toluene (9.59 g, 51%): mp 185°-187° C. 1H NMR (CDCl3) 300 MHz 7.91 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.17-7.35 (m, 3H), 7.03 (d, 2H), 7.00 (d, J=8.7 Hz, 2H), 2.44 and 2.36 (s, 3H). Mass spectrum: M+H=305.
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:9]([Si:6]([CH2:7][CH3:8])([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[Si:4]([CH2:15][CH3:16])([CH2:17][CH3:18])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Reactant: [Li][Si](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC[Si](CC)([Si](C)(C)c1ccccc1)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 68 mg (0.20 mmol) of octaethylcyclotetrasilane was added 0.72 ml (0.20 mmol) of a tetrahydrofuran solution (0.26M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 71 mg (0.05 mmol) of hexadecasilane (6) obtained in Example 6 was treated with 15 mg (0.10 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to give 1,16-bis(trifluoromethanesulfonyloxy)hexadecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to afford a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C., and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column (hexane) chromatography to give 46 mg (36% yield) of hexacosasilane (7) as a colorless crystal.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH:9]1[NH:13][CH2:12][CH:11]([CH3:14])[O:10]1)[CH3:8].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[CH2:7]([CH:9]1[N:13]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:12][CH:11]([CH3:14])[O:10]1)[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1NCC(C)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1OC(C)CN1S(C)(=O)=O

Procedure:
A solution was formed containing 25 ml. of benzene and 6 g. of 2-ethyl-5-methyl oxazolidine suspended in 24 ml. of benzene. Then, 5.5 g. of triethylamine was added. The solution was cooled in an ice bath, wherein 5.8 g. of methane sulfonyl chloride was added dropwise with stirring to yield 6.4 g. of product, nD30 = 1.4778.
Reaction SMILES: [H-].[Na+].[C:3]([NH:5][C:6](=[N:8][CH3:9])[CH3:7])#[N:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N:12]=1>CN(C)C=O>[C:3]([N:5]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[N:12][CH:13]=1)[C:6](=[N:8][CH3:9])[CH3:7])#[N:4]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN=C(C)NC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN=C(C)N(C#N)Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
0.6 g of sodium hydride (purity 60%) was added to the solution of 1.3 g of N-cyano-N'-methylacetamidine in 20 ml of N,N-dimethylformamide at ice bath temperature. After stirring it at the same temperature for 1 hour, 2.2 g of 2-chloro-5-pyridylmethylchloride was added to the mixture, followed by stirring for 5 hours at room temperature. The reaction mixture was then poured into ice-water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to afford 1.5 g of compound No. 22 m.p. 101°-103° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1>C(O)C.ClCCl>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:15][CH2:16][CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19]3)[CH2:11][CH2:10]2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(CCC1CCNCC1)CC2
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)CC1CCC2(CC1)CCN(CCC1CCNCC1)CC2

Procedure:
0.35 g (1.0 mmol) of the compound from Example 24 were hydrolized in 15 ml ethanol containing 7 drops aqueous sodium hydroxide as described for Example 23. The title acid solidified upon stirring in dichloromethane. It was filtered and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12]CCl)=[CH:8][S:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[I:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12][O:29][C:26]2[CH:27]=[CH:28][C:23]([I:22])=[CH:24][CH:25]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)CCCl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(I)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester ([51486-30-7], 2.0 g, 8.6 mmol) in dimethylformamide (30 mL) was added potassium carbonate (1.77 g, 12.8 mmol) and 4-iodophenol (2.26 g, 10.3 mmol) and the reaction mixture was then stirred overnight at 90° C. To the reaction mixture was added ethyl acetate (approximately 30 mL). The solid was filtered and washed with ethyl acetate. The filtrate was then reduced in vacuo and dissolved in dichloromethane (approximately 50 mL). The solution was filtered again over charcoal and to the filtrate was added isopropylether. After reducing the solution slowly in vacuo the solid was filtered to yield the title compound (3.57 g, 79%).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:27][C:26]([C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:29][CH:28]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(OC)cc1
Yield: 35.8 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (105.2 g) and 4-nitrobenzylamine (76.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (55.1 g), which was dissolved in ethyl alcohol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid (40.3 g), melting point 205-208° C. (decomposition).
Reaction SMILES: [S:1]1[C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].ClC(OCC(C)C)=O.[CH3:34][S:35]([NH-:38])(=[O:37])=[O:36].[Na+].Cl>CN(C)P(N(C)C)(N(C)C)=O.C(N(CC)CC)C.CN(C)C=O>[CH3:34][S:35]([NH:38][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:1][C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10]1)(=[O:37])=[O:36]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Reactant: CS([NH-])(=O)=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)NS(C)(=O)=O)S[C@H]2C[C@H]1O
Reaction time: 0.42 h
Yield: 62.1 %

Procedure:
To a mixture of 100 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15- dihydroxyprost-13-enoic acid (prepared as described in Example 2), 1.5 ml of N,N-dimethylformamide and 37 μl of triethylamine was added 35 μl of isobutyl chloroformate at 0° C., and the mixture was stirred at that temperature for 25 minutes. To it was added a mixture of 128 mg of sodium methanesulphonylamide and 0.233 ml of hexamethylphosphoramide at room temperature, and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was acidified to pH 4-5 with dilute hydrochloric acid, extracted with ethyl acetate, the extract washed with water, and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 5% v/v solution of methanol in ethyl acetate as eluent to give 75 mg of the title compound having the following physical characteristics.
Reaction SMILES: [CH3:1][N:2]1[C:17]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:16][C:4]2[CH:5]=[C:6]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[CH:7]=[CH:8][C:3]1=2.[OH2:24].Cl.[CH2:26]1O[CH2:27]1.[OH2:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:26]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N:9]([CH2:13][CH2:14][OH:29])[CH2:10][CH2:11][OH:24])=[CH:5][C:4]=2[N:16]=1)[CH3:27]
Reactant: O
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: C1CO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCCc1nc2cc(N(CCO)CCO)ccc2n1C
Temperature: 20 °C

Procedure:
Li-Mei et al., in Zhongguo Xinyao Zazhi (2007), 16(23), 1960-1961, 1970 disclose a process for the preparation of bendamustine hydrochloride monohydrate, which involves reacting [1-methyl-2-(4′-ethyl butyrate)-5-amino]-1H-benzimidazole with ethylene oxide in the presence of water, sodium acetate and acetic acid, by maintaining at 5° C. for 5 hours and overnight at 20° C. to give (4-{5-[bis-(2-hydroxy-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid ethyl ester as a jelly mass, which on chlorination using thionyl chloride in chloroform and in situ hydrolysis with concentrated HCl at 90-95° C. gave bendamustine hydrochloride. It also discloses a process for the recrystallization of bendamustine hydrochloride from water and the product obtained is a monohydrate with a melting point of 148-151° C.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.ClC(O[C:37](=[O:43])OC(Cl)(Cl)Cl)(Cl)Cl.[C:44]1([NH:50][NH2:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.O>[C:44]1([NH:50][NH:51][C:37]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:43])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: NNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(NNc1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.2 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.34 mmol) in tetrahydrofuran (1 mL) were sequentially added diisopropylethylamine (0.15 mL) and bis(trichloromethyl)carbonate (0.10 g, 0.34 mmol), and the mixture was stirred at room temperature for 45 minutes. Next, phenylhydrazine (39 mg, 0.36 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from ethyl acetate-diisopropyl ether to obtain the title compound (44 mg, yield 30%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:48]1([C:54]2[CH:55]=[C:56]([CH:60]=[C:61]([C:63]3[NH:67][N:66]=[N:65][N:64]=3)[N:62]=2)[C:57](O)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:15][CH2:16][N:17]([C:57]([C:56]4[CH:60]=[C:61]([C:63]5[NH:67][N:66]=[N:65][N:64]=5)[N:62]=[C:54]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:55]=4)=[O:58])[CH2:18][CH2:19]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1
Reactant: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: O=C(O)c1cc(-c2ccccc2)nc(-c2nnn[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(-c4ccccc4)nc(-c4nnn[nH]4)c3)CC1)O2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6-[(1-Methyl-1H-pyrazol-5-ylamino)]spiro[chroman-2,4′-piperidin]-4-one hydrochloride (117 mg), 1-hydroxybenzotriazole monohydrate (53 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (68 mg), triethylamine (94 μL) and water (1 mL) were added in that order to a DMF (3 mL) solution of 2-phenyl-6-(tetrazol-5-yl)-isonicotinic acid (75 mg), and stirred at 60° C. for 1 hour. Water was added to the reaction liquid, and the resulting precipitate was taken out through filtration, washed with hexane/ethyl acetate=2/1, and dried to obtain the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.37 (2.0H, d, J=6.8 Hz), 8.17 (1.0H, s), 8.08 (1.0H, br s), 7.93 (1.0H, s), 7.61-7.50 (3.0H, m), 7.32 (1.0H, d, J=2.0 Hz), 7.18-7.12 (2.0H, m), 6.99 (1.0H, d, J=8.4 Hz), 5.89 (1.0H, s), 4.31-4.27 (1.0H, m), 3.60 (3.0H, s), 3.50-3.20 (3.0H, m), 2.82 (2.0H, s), 2.12-2.05 (1.0H, m), 1.90-1.78 (3.0H, m). MS [M−H]+=560.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16].C(N(C(C)C)C(C)C)C>C(O)C>[OH:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)CS1
Yield: 36 %

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (870 mg) in ethanol (30 mL) were added cis-2-aminocyclohexanol hydrochloride (1.00 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.32 mL), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate), and the obtained powder was washed with ethyl acetate to give the title compound (504 mg).