Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][N:4]([CH3:8])[C:3]1=[O:9].[CH3:10][C:11]([C:14]1[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:17]=[C:16]([CH:25]=[O:26])[N:15]=1)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.ClCCl.[Zn]>[CH3:13][C:11]([C:14]1[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:17]=[C:16]([CH:25]([OH:26])[CH:2]2[CH2:7][CH2:6][O:5][N:4]([CH3:8])[C:3]2=[O:9])[N:15]=1)([CH3:10])[CH3:12]
Reactant: CN1OCCC(Br)C1=O
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: [Zn]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1OCCC(C(O)c2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)C1=O
Yield: 39.1 %

Procedure:
A mixture of 1.1 g (5.7 mmol) of 4-bromo tetrahydro-2-methyl 2H 1,2-oxazin-3-one, Example 1, 1.2 g (5.1 mmol) of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinecarboxaldehyde, Example 6, and 0.75 g (11 mmol) of zinc dust in 30 mL of toluene was stirred at reflux for 18 hours. The cooled reaction mixture was diluted with dichloromethane and vigorously stirred. The zinc was filtered and washed with dichloromethane. The combined filtrates were evaporated to a foam. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane elution) to give 0.70 g (39%) of the title compound as an oil mixture of diastereomers; MS m/e 352 (M+ 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].Cl.[NH2:14][OH:15].C(O)C.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=[N:14][OH:15])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C=O)[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(C=NO)[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (as prepared in the previous step, 300 mg, 1.80 mmol), hydroxylamine hydrochloride (560 mg, 8.10 mmol), ethanol (10 mL), sodium acetate (1.10 g, 13.4 mmol) and water (10 mL) was stirred at 90° C. for 30 min. The solvents were removed in vacuo and the solid was collected on a Buchner funnel and washed with water (10 mL) to yield 226 mg (69%) of the title compound as a white solid: LC-MS (ESI, m/z): Calcd. for C8H11N2O3, 183.1 (M+H); found: 183.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[CH:10]=3)=[CH:7][C:6]=1[F:23])(=[O:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3[Br:24])=[CH:7][C:6]=1[F:23])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(NC(C)=O)cc1C2
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)cc1C2
Reaction time: 1 h
Yield: 122.3 %

Procedure:
The product from step 1 (1.1 g, approx. 3.5 mmol) was dissolved in anhydrous CH2Cl2 (11 mL) and the solution was purged with N2, cooled in an ice bath, and treated with N-bromosuccinimide (0.498 g, 2.8 mmol). After stirring at 0–5° C. for one hour, the reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic portion was washed with aqueous 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to provide crude 7-(acetylamino)-4-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.35 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(Cl)Cl.[Cl:64][C:65]1[CH:66]=[C:67]([CH:70]=[CH:71][C:72]=1[Cl:73])[CH2:68][NH2:69]>>[Cl:64][C:65]1[CH:66]=[C:67]([CH:70]=[CH:71][C:72]=1[Cl:73])[CH2:68][NH:69][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:8])=[O:9])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
4-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 99, 1.30E3 mg, 0.00300 mol), HBTU (1400.8 mg, 0.0031671 mol) and Et3N (1.07 mL, 0.00766 mol) were mixed in methylene chloride (10 mL, 0.2 mol). 3,4-dichlorobenzylamine (457.3 mg, 0.002598 mol) was added and the reaction stirred overnight. The reaction was washed with saturated sodium bicarbonate (aq). The organic phase was separated and dried over magnesium sulfate, the solvent was removed in vacuo to give an oily residue. The residue was purified by column chromatography (40 g silica gel column, hexanes to 50% ethyl acetate-hexanes gradient elution). Product fractions were combined and evaporated to give 1.13 g of the protected benzamide intermediate. The residue was dissolved in DCM and TFA was added dropwise until wet pH paper turned acidic when held above the reaction. After 30 minutes of stirring at room temperature, the solid precipitate was collected by filtration. The solid was rinsed with DCM, then ethyl ether. The solid was dissolved in 0.5N NaOH (5 mL) and filtered. The filtrate was washed 2× with ethyl ether, then treated with activated carbon and filtered through Celite. The pale yellow filtrate was acidified to pH 2 with 6N HCl. The white precipitate was collected by filtration and rinsed with water then ethyl ether. Vacuum drying yielded 446 mg of product as a white powder.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CO>[CH2:9]([N:8]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Yield: 98.8 %

Procedure:
A! Starting from dibenzylamine (48.7 ml, 0.25 mole) and methyl acrilate (112.5 ml, 1.25 moles) in 259 ml of methanol, and following the procedure of Example 15,A!, there were obtained 70 g (yield: 99%) of methyl 3-(N,N-dibenzylamino)-propanoate which was used as such in the next step.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13]Cl)[CH:7]=1)[C:3]([OH:5])=[O:4].[S-:15][C:16]#[N:17].[K+]>CO>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][S:15][C:16]#[N:17])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: N#C[S-]
Reactant: NC(C(=O)O)c1ccc(O)c(CCl)c1
Agent: [K+]
Solvent: CO
Product: N#CSCc1cc(C(N)C(=O)O)ccc1O
Yield: 78 %

Procedure:
A solution of (-)-α-amino-3-(chloromethyl)-4-hydroxybenzeneacetic acid (0.5 g, 1.98 mmole) and potassium thiocyanate (0.4 g, 4.12 mmole) in 10 ml of methanol is stirred at room temperature for 16 hours. The reaction mixture is filtered to remove the potassium chloride, the filtrate is evaporated and to the residue is added saturated aqueous sodium bicarbonate until the pH is 7. The title compound precipitates as a white powder which is filtered and dried. (1.83 g, 78% yield), NMR (TFA-D+D2O) ppm (δ) 4.1 (s,2), 5.08 (s,1), 6.9-7.3 (m,3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]3[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=3[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCCOCCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOCCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 55.5 %

Procedure:
A mixture of 1.73 g of [[8-acetyl-7-[3-(3-bromopropoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 0.89 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.79 g of anhydrous potassium carbonate in 33 ml of anhydrous acetone and 11 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated in vacuo to an oil. Purification by high pressure liquid chromatography (10% ethyl acetate-toluene) gave 1.2 g (56%) of [[8-acetyl-7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[CH:16])[C:5](OC)=[O:6].[CH3:17][NH2:18]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[CH:16])[C:5]([NH:18][CH3:17])=[O:6]
Reactant: C#Cc1ccccc1C(=NOC)C(=O)OC
Reactant: CN
Product: C#Cc1ccccc1C(=NOC)C(=O)NC
Reaction time: 0.75 h

Procedure:
1 g (4.6 mmol) of the acetylene compound prepared in Example 1 is added to 20 ml of a 40% strength methylamine solution, and the mixture is stirred for 45 minutes at 40°-50° C. The solution is extracted with methyl tert-butyl ether, dried and evaporated down. 700 mg (70%) of the compound remain as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:23][CH2:24]4)[S:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nsc(N4CCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nsc(N4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 65 mg (0.16 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-thiadiazol-5-yl]piperazine and 36 μl (0.25 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1Br)[CH:12]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:11][CH2:10]2)=[O:5].[Cu][C:32]#[N:33].N>CN1C(=O)CCC1>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:32]#[N:33])[CH:12]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:11][CH2:10]2)=[O:5]
Reactant: N#C[Cu]
Reactant: COCC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Agent: N
Solvent: CN1CCCC1=O
Product: COCC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[N-(5-methoxyacetamido-6-bromoindan-1-yl)amino]benzoate (0.714 g, 1.50 mol) in NMP (8 ml) [1-methyl-2-pyrrolidone] was added copper (I) cyanide (0.230 g, 2.55 mmol). The reaction mixture was placed in an oil-bath preheated to 140° C. and stirred at this temperature for 2 h. More copper (I) cyanide (0.100 g, 1.10 mmol) was then added and stirring was continued for a longer 3 hours. The reaction mixture was allowed to cool to room temperature, then poured into a mixture of aqueous ammonia (d=0.88, 7 ml) and ice (˜20 ml) and the resulting brown mixture was stirred at room temperature for ˜5 min. The brown solid was collected by filtration washed with plenty of water, then suspended in dichloromethane (100 ml). The mixture was stirred at room temperature for 10 min, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 35% ethyl acetate in hexane, afforded an off white solid that was reprecipitated from dichloromethane-ethyl acetate/hexane: 0.328 g, (52%) m.p. 163-164° C. 1H-NMR (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(CH3)3), 1.85, 2.58 (2×m, 2H, indanyl 2-H), 2.89 (m, 2H, indanyl 3-H), 3.41 (s, 3H, OCH3), 4.05 (s, 2H, CH2OMe), 5.06 (m, 1H, indanyl 1-H), 6.73 (d, J=8.82 Hz, 2H, 3,5-H), 6.82 (d, J=8.37 Hz, 1H, N10—H), 7.59, 7.57 (2×s, each 1H, indanyl 4-H, 7-H), 7.66 (d, J=8.77 Hz, 2,6-H), 9.88 (s, 1H, CONH), MS (ESI, m/z) 444 {(M+Na)+, 100%}; Found: C, 68.21; H, 6.47; N, 9.81; C24H27N3O4 requires C, 68.39; H, 6.46; N, 9.97%.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:29]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH2:43])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1COCC1>[C:32]([O:31][C:29](=[O:30])[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:14]([C:12]1[S:13][C:9]([CH2:8][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH:6]=[CH2:7])=[CH:10][CH:11]=1)=[O:16])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: C=CCN(CC=C)Cc1ccc(C(=O)O)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
To a solution of 2.70 g (11.38 mmol) 5-diallylaminomethyl-thiophene-2-carboxylic acid in 50 ml THF was added 2.03 g (12.51 mmol) carbonyldiimidazol. After 45 min at rt, 2.48 g (11.95 mmol) mono-boc-ortho-phenylenediamine were added to the reaction mixture, and it was stirred for 3 h at rt. The solvent was evaporated and the residue dissolved in ethyl acetate. The organic phase was washed twice with sat. NaHCO3, once with water and dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/heptane 2:8) to yield 4.10 g (9.59 mmol) {2-[(5-Diallylaminomethyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester; exact MW [M+H] calc'd: 428.20; MW found [M+H]: 428.3.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C)C=O>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
4.80 g of sodium hydride (55% oil dispersion) was suspended in 50 ml of N,N-dimethylformamide. Into this, 17.60 g of diethyl malonate was added dropwise over a period of about 0.5 hours at room temperature under a nitrogen atmosphere. The mixture was stirred further for 0.5 hours at the same temperature, then, to the mixture was added 5.73 g of 2-chloropyrimidine. The mixture was stirred for 3 hours at 100° C. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 18.84 g of the resultant residue was subjected to silica gel column chromatography, to obtain 5.09 g of diethyl (2-pyrimidinyl)malonate.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:22]>>[ClH:22].[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C@H:9]1[CH2:10][S:7][C:6]([NH2:5])=[N:8]1)([O-:21])=[O:20]
Reactant: CC(C)(C)NC(=S)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: NC1=N[C@@H](Cc2cccc([N+](=O)[O-])c2)CS1
Reaction time: 7 h

Procedure:
The process is performed as in Example 2, starting with N-(tert-butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea in 80 cm3 of aqueous 6N hydrochloric acid. The heating time is 7 hours. The product is isolated in an identical manner and then purified by chromatography under an argon pressure of 80 kPa, on a column of silica gel (particle size 40-63μ; diameter 3.5 cm; height 30 cm), eluting with a dichloromethane/methanol mixture (95/5 by volume). The fractions corresponding to the expected product are collected. These fractions are combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 3.90 g of (−)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride are obtained in the form of a white solid melting at 220° C. (αD20=−18.4±0.05 at a concentration of 0.5% in methanol).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)(=O)C>[NH2:21][CH2:20][CH2:19][NH:22][CH:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCN
Reactant: CCN(CC)C(=O)COc1ccc(C(C)=O)cc1
Solvent: CC(=O)O
Product: CCN(CC)C(=O)COc1ccc(C(C)NCCN)cc1

Procedure:
By using 2-(4-acetylphenoxy)-N,N-diethylacetamide (250 mg), ethylenediamine (400 μl) and acetic acid (700 μl) as starting materials, the title compound (52.9 mg) was obtained in the same manner as that of Reference Example 64, (1).
Reaction SMILES: [CH2:1]([C:3]([CH2:22][CH3:23])([P:18]([OH:21])([OH:20])=[O:19])[C@H:4]1[CH2:13][CH2:12][C@@H:11]2[C@@H:6]([CH2:7][CH2:8][N:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)[CH2:5]1)[CH3:2].[CH3:24][OH:25]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.C([N+](CC)(CC)CC)C>[CH2:22]([C:3]([CH2:1][CH3:2])([P:18]([OH:20])([OH:21])=[O:19])[CH:4]1[CH2:13][CH2:12][CH:11]2[CH:6]([CH2:7][CH:8]([O:25][CH3:24])[N:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)[CH2:5]1)[CH3:23]
Reactant: CCC(CC)([C@H]1CC[C@H]2CN(C(=O)OC)CC[C@H]2C1)P(=O)(O)O
Reactant: CO
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCC(CC)(C1CCC2CN(C(=O)OC)C(OC)CC2C1)P(=O)(O)O

Procedure:
Four carbon plate electrodes were immersed into a solution containing the compound from Example 1 (250 mg), tetraethylammonium p-toluenesulfonate (21 mg), in methanol (10 ml). A constant current of 0.5 A was applied to the electrodes. Additional methanol (7.8 ml) was added to the reaction to replace methanol which was lost due to evaporation. After 550 coulombs of current had passed, the electrodes were removed and the solution was added to 10% brine. This mixture was extracted with ether (3×15 ml). The combined ether extracts were washed with water and with brine, dried over magnesium sulfate, and concentrated in vacuo at room temperature to give 237 ml of the title compound as an oil. The material was stored in the refrigerator and used in the next step without further purification.
Reaction SMILES: C([O:4][C:5](=[O:26])[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH2:23][CH2:24][Cl:25])[CH2:20][CH2:21][Cl:22])=[CH:18][C:11]=2[N:10]=1)(C)C.[ClH:27]>O>[CH3:14][N:13]1[C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:26])=[O:4])=[N:10][C:11]2[CH:18]=[C:17]([N:19]([CH2:20][CH2:21][Cl:22])[CH2:23][CH2:24][Cl:25])[CH:16]=[CH:15][C:12]1=2.[ClH:27]
Reactant: CC(C)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Agent: Cl
Solvent: O
Product: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
4-{5-[Bis-(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid isopropyl ester (3 g) is charged into a round bottom flask and 50% hydrochloric acid solution (21 mL) is slowly added. The mixture is heated to 35-40° C., maintained for about 90 minutes, and concentrated under vacuum at about 55-58° C., to give a viscous mass. Warm water (12 mL, 55-60° C.) is added and the mixture is stirred for about 1 hour. The obtained solid is collected by filtration, washed with water (3 mL), and dried under vacuum at 45-50° C. for 4 hours to give bendamustine hydrochloride. Yield: 2.2 g (75%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:8]=1)[CH3:5].[Li+].[OH-].O1CCOCC1>>[N:13]1([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][CH:4]([CH3:5])[C:3]([OH:18])=[O:2])[CH:17]=[N:16][N:15]=[N:14]1
Reactant: COC(=O)C(C)Oc1cccc(-n2cnnn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Oc1cccc(-n2cnnn2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a 25 mL round-bottom flask equipped with a magnetic stir bar was added 2-(3-tetrazol-1-yl-phenoxy)-propionic acid methyl ester 30 (326 mg, 1.3 mmol, 1.0 eq.), 2N LiOH (2.6 mL, 2.6 mmol, 2.0 eq), and 1,4-dioxane (2.6 ml, 2.6 mmol, 2.0 eq). The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with water (5 mL), acidified with 1 N HCl (adjust pH=3.5), and then extracted with 3× EtOAc (25 mL each). The organic layer was dried with Na2SO4, concentrated, and dried under high vacuum to yield 2-(3-tetrazol-1-yl-phenoxy)-propionic acid 31 (230.3 mg, 98% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 235.0 (M+H)+1 1H-NMR, Varian 400 MHz (MeOH-d4) δ 9.76 (s, 1H), 7.52 (t, 1H), 7.45 (d, 2H), 7.08 (d, 1H), 4.93 (q, 1H), 1.62 (d, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8]>S(Cl)(Cl)=O>[C:7]([OH:9])(=[O:8])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][C:12]([OH:13])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)C=Cc1ccc(O)c(O)c1
Solvent: O=S(Cl)Cl
Product: O=C(O)/C=C/c1ccc(O)c(O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
3,4-Dihydroxycinnamic acid (1.13 g, 6.27 mmole) was dissolved in thionyl chloride (25 ml) and the solution was stirred for 5 hours at 40-60° C. The solvent was removed, the residue was dissolved in thoroughly dried ethyl acetate and the solution was slowly added to a solution of 5-methoxy tryptamine (1.2 g) in benzene, which contained also ethylamine (1 ml). The mixture was stirred overnight, water (10 ml) was added and the mixture again stirred for 15 minutes. The solvents were removed, the residue was dissolved in ethyl acetate and the solution was washed successively with water, saturated NaHCO3 solution, water and brine, and then dried over Na2SO4. The solvent was removed and the product was purified by column chromatography using 1:9 methanol/dichloromethane. The purification process was repeated three times to remove byproducts. The fraction identified as the caffeic acid 5-methoxytryptamide was further purified by recrystallization from ethyl acetate/hexane solution. The compound was obtained as white crystals (yield about 60%).
Reaction SMILES: [C:1]([NH:4][CH:5]([O:16]CC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(F)(F)F.CCOCC.O.C([O-])(O)=O.[Na+]>>[C:1]([NH:4][CH:5]([OH:16])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)NC(O)C(=O)NCc1ccccc1

Procedure:
Reacting 2-acetamido-N-benzyl-2-ethoxyacetamide (1.00 g, 4.0 mmol), BF3.Et2O (0.91 g, 6.4 mmol) and H2O (0.12 g, 6.7 mmol) followed by aqueous NaHCO3 workup gave an aqueous reaction mixture. The solution was then extracted with EtOAc (3×50 mL), and the combined EtOAc extracts were dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 gel (3% MeOH/CHCl3) to give the desired product as a white solid.