Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[O:1]([C:8]1[N:13]=[C:12]([C:14]([Cl:20])=[O:16])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccnc(Oc2ccccc2)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccnc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenoxy-pyrimidine-4-carboxylic acid, 17, (0.19 g, 0.89 mmol) in methylene chloride (10 mL) containing a few drops of DMF is added oxalyl chloride (0.1 mL). The solution is stirred for 2 hours at room temperature and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[C:11][CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([N:16]1[CH2:17][CH2:18][N:13]([C:10]#[C:11][CH3:12])[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#CN1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC#CN1CCN(C(=O)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
A solution of 5.6 g. of benzoyl chloride was added to a stirred solution of 1.96 g. of N-propynyl piperazine, 4.04 g. of triethylamine and 100 ml. of chloroform. The mixture was stirred 4 hours, filtered and the filtrate washed in sequence with 100 ml. of water, 100 ml. of 5% aqueous potassium carbonate and 100 ml. of water. The chloroform solution was then evaporated in vacuo to produce a white solid. Crystallization from cyclohexane produced the expected white crystals of N'-benzoyl-N-propynyl piperazine, m.p. 94°-5° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]1Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.O>[CH2:8]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:16]1[S:5][CH2:4][CH2:3][NH2:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reactant: NCCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1c(SCCN)n(Cc2ccccc2)c2ccccc12

Procedure:
2-Aminoethanethiol hydrochloride (0.419 g, 3.12 mmol) was added to a stirred suspension of sodium hydride (0.314 g, 50% in mineral oil, 6.56 mmol) in anhydrous dimethylformamide (30 ml) and after 1 hour, 1-benzyl-2-chloro-3-methylsulfonylindole (1.0 g, 3.29 mmol) was added. One half hour thereafter the solution was diluted with water, the product extracted with ether, the extract dried over sodium sulfate and evaporated in vacuo. The product was obtained as a solid, M.P.-95°-96°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2[CH:36]=[CH:37][CH:38]=CC=2N=N1.C1(CN)CC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([CH2:35][NH:31][C:17]([C:16]2[N:15]=[C:14]([C:20]([F:22])([F:23])[F:21])[N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C:10]=23)=[O:18])[CH2:38][CH2:37]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC3CC3)c2C1
Reaction time: 12 h
Yield: 77.2 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), cyclopropylmethylamine (142 mg, 2 mmol) and N,N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and added with 50 mL of ethyl acetate and washed successively with saturated ammonium chloride (15 mL×3) and saturated sodium chloride solution (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(cyclopropylmethylc arb amoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 24a (300 mg) as a brown-red oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:24](=[O:25])[CH2:23][O:22][CH3:21])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with methoxyacetyl chloride (0.014 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and then concentrated. The resulted residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (23 mg, 61%). LCMS calculated for C18H21ClN3O3 (M+H)+: m/z=362.1; Found: 362.0
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[CH3:13].CCOCC>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH3:13]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCOc1ccccc1C=O
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A solution of 12.2 g of salicylaldehyde in 20 ml of dimethylformamide is instilled into a suspension of 4.36 g of sodium hydride (55% dispersion in mineral oil) in 80 ml of dimethylformamide by stirring and ice cooling within 15 minutes. After 3 hours, a solution of 21.5 g of 4-bromobutyric acid ethyl ester in 16 ml of dimethylformamide is instilled by ice cooling within 15 minutes, and the mixture is stirred for 72 hours at room temperature. The batch is poured on ice/water, shaken with ether, the organic phase is washed briefly with 1 n sodium hydroxide solution, dried with sodium sulfate and concentrated by evaporation. The crude product is distilled at 130°-140° C./0.1 mbar in a bulb tube and 11.2 g of 4-(2-formylphenoxy)-butyric acid ethyl ester is thus obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH:4]([N:6]1[C:19]2[CH:18]=[C:17]([C:20](=[S:22])[NH2:21])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:5].[CH:24]1([CH2:30]N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.S>C(O)C>[CH:24]1([CH2:30][NH:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]3[S:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH:4]([CH3:5])[CH2:3][N:2]([CH3:1])[CH3:23])[C:19]=3[CH:18]=2)=[S:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CC(CN(C)C)N1c2ccccc2Sc2ccc(C(=S)NCC3CCCCC3)cc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
A mixture of 10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide (2 g) and cyclohexylmethylamine 11.4 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 125° C. After cooling, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil is purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.06-0.04 mm) under a slight excess pressure of nitrogen (40 kPa) eluting with a 60:40 by volume mixture (1 litre) of ethyl acetate and cyclohexane and collecting 60-cc fractions. The combined fractions 6 to 13 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange gum (2.5 g) is dissolved in isopropanol (8 cc) under reflux and treated, with stirring, with a solution at 50° C. of fumaric acid (0.6 g) in isopropanol (8 cc). The mixture is allowed to cool and stirring is continued for 1 hour at a temperature in the region of 5° C. The solid formed is drained, washed with isopropanol (2×1 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. N-Cyclohexylmethyl-10-[(2RS)-1-dimethylamino-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (2.53 g) is thereby obtained in the form of a yellow solid, m.p. 167° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=[O:22]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:9]([OH:10])[CH2:20][C:21](=[O:22])[CH3:23])[CH:11]=[CH:12][CH:13]=2)=[CH:2]1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)CC(O)c1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg of 3-(3-thienyl)benzaldehyde was dissolved in 3 ml of acetone, and 441 mg of potassium carbonate was added. The mixture was stirred overnight at s room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by medium-pressure liquid chromatography [hexane/ethyl acetate =3/1]to give 1-[3-(3-thienyl)phenyl]-3-oxo-1-butanol as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.F[C:16]1[C:17]([CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[C:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of 4-(pyridin-2-ylamino)phenol (47 mg, 0.25 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (56 mg, 0.25 mmol), and cesium carbonate (123 mg, 0.376 mmol) in DMSO (0.85 mL) was heated at 80° C. for 20 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 3% MeOH in EtOAc, to provide 1-(4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as off-white solid. MS (ESI, pos. ion) m/z: 389.9 (M+1). IC50 (uM) 0.003589.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([O:11][CH:12]([O:25][CH2:26][CH3:27])[CH2:13][N:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=[O:16])[CH3:10]>O.C(O)C>[CH2:9]([O:11][CH:12]([O:25][CH2:26][CH3:27])[CH2:13][N:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[N:2][OH:3])[C:15]1=[O:16])[CH3:10]
Reactant: NO
Reactant: CCOC(CN1C(=O)C(=O)c2ccccc21)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(CN1C(=O)C(=NO)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
A solution of 5.38 g of hydroxylamine hydrochloride and 5.38 g of sodium acetate in 40 ml of water was added to a suspension of 11.1 g of 1-(2,2-diethoxyethyl)isatin in 100 ml of ethanol. The mixture was stirred at room temperature for 1 hour, followed by concentration. The concentrate was diluted with chloroform and washed with an aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous sodium sulfate and concentrated, and the residue was recrystallized from ethyl acetate to obtain 7.10 g (61%) of 1-(2,2-diethoxyethyl)-3-(hydroxyimino)indolin-2-one as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([N:8]([CH2:12][CH2:13][Cl:14])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:5]=1)([O-])=O.Cl>C(OCC)(=O)C.CO.[Pd]>[ClH:11].[Cl:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][Cl:14])[C:7]1[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N(CCCl)CCCl)cc1
Yield: 160 %

Procedure:
4-Nitro-[N,N-bis(2-chloroethyl)]aniline (5.0 g; 19.0 mmol) was dissolved in a mixed solvent of 50 ml of ethyl acetate and 25 ml of methanol, followed by the addition of 5.0 ml of 4N hydrochloric acid. Using 10% Pd/C, the reactant was subjected to hydrogenation under normal pressure at room temperature. The Pd/C was filtered off and the solvent was distilled out. The residue was crystallized from ethanol-ethyl ether, whereby 4.1 g (15.2 mmol) of the title compound was obtained (yield: 80%). m.p. 230°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10]2[N:14]([CH2:15][CH2:16][OH:17])[C:13]3[C:18]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=[CH:21][C:12]=3[N:11]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:17][CH2:16][CH2:15][N:14]1[C:13]2[C:18]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=[CH:21][C:12]=2[N:11]=[C:10]1[NH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[O:30][CH3:31])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(O)(CCC)c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(CCO)c12
Solvent: c1ccncc1
Product: CCCC(O)(CCC)c1cccc2nc(Nc3c(C)cc(Cl)cc3OC)n(CCOC(C)=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 4-[2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazol-7-yl]heptan-4-ol (100 mg, 0.22 mmol) in pyridine (5 mL) was treated with acetic anhydride (1 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 97 mg (0.20 mmol, 89%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (390 mg), 4-(methanesulfonyl)phenyl boronic acid (350 mg), 2 M aqueous Na2CO3 solution (1.50 mL), and 1,4-dioxane (10 mL) is sparged with Ar for 10 min. Pd(PPh3)4 (100 mg) is added and the resulting mixture is stirred at 170° C. for 1 h in a microwave oven. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40→40:60) to give the title compound. LC (method 2): tR=1.23 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][Cl:14])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:23]=[O:25])=[CH:7][CH:6]=1)[CH2:12][CH2:13][Cl:14]
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.12 h

Procedure:
The known compound phenylisocyanate N-mustard 19 can be prepared by following the literature procedure35,36 with modification (Scheme 3). The commercially available 4-fluoronitrobenzene (15) is reacted with diethanolamine under refluxing to give 4-[N,N-bis(2-hydroxyethyl)amino]nitrobenzene (16), which is then converted to 4-[N,N-bis(2-chloroethyl)amino]nitrobenzene (17) by treating with thionyl chloride. Catalytic hydrogenation (10% Pd/C, H2) of compound 17 in ethyl acetate affords N,N-bis(2-chloroethyl)benzene-1,4-diamine (18), which is immediately treated with HCl in ethyl acetate to yield hydrochloride salt of 18. The hydrochloride salt 18 is suspended in CHCl3 and cooled in an ice-bath. To the suspension is added triethylamine and stirred in Argon atmosphere for 5 to 10 min. and then is added dropwise triphosgene solution in CHCl3 and continuously stirred for 20 min. The reaction mixture is evaporated under reduced pressure and the residue is the triturated with THF, filtered and the filtrate containing phenylisocyanate 19, which is used directly for the next reaction without purification. Compound 18 and 19 can be used for the synthesis of the newly invented compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:13]([NH:17][S:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])=[O:10])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
A solution of (3-chlorophenyl)methanesulfonyl chloride (3.00 g, 13.33 mmol) in dry THF (50 mL) was added dropwise to a solution of butylamine (2.63 mL, 26.65 mmol) in dry THF (50 mL) at 0° C. and under an atmosphere of nitrogen. After the addition was completed the ice-bath was removed and the mixture was stirred at rt for 1.5 h. It was evaporated and the residue was partitioned between DCM and HCl (1M). The combined organic layers were washed with water, dried with MgSO4 and evaporated to dryness to give the title compound (2.89 g, 83%) as a white powder; 1H NMR (500 MHz, CDCl3): δ 7.29-7.42 (m, 4H), 4.22 (s, 2H), 4.16 (bs, 1H), 2.99-3.05 (m, 2H), 1.46-1.53 (m, 2H), 1.29-1.38 (m, 2H), 0.92 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 132.2, 129.0, 128.3, 127.7, 126.6, 126.4, 55.9, 41.2, 30.0, 17.3, 11.21; Mass Spectrum: M−H+ 260.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(OCC)(=O)C>CN(C=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Oc2ccc(Br)cn2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-trifluoromethoxyphenol (4.4 ml) and sodium hydride (60% dispersion in mineral oil, 1.35 g) in dry DMF (3 ml) was added a solution of 2,5-dibromopyridine in dry DMF (3 mL). The mixture was heated at 60° C. for 8 h. Upon cooling, ethyl acetate was added and the mixture was washed with NH4Cl 1N. The organic layer was dried (Na2SO4) and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent:AcOEt/Hexane 1:10) to afford 1.08 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 ml of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 ml of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiber glass pad to clarify, the filtrate was acidified to 6.6 with 6M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3(C)CCCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC1(C(=O)CN2C(=O)N(CC(=O)O)N=C(C3CCCCC3)c3ccccc32)CCCCC1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that {5-cyclohexyl-1-[2-(1-methyl-cyclohexyl)-2-oxo-ethyl]-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl}-acetic acid (Example 133, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.40 (1H, s), 7.48 (3H, m), 7.31 (2H, m), 7.20 (1H, t), 7.10 (1H, d), 7.02 (1H, d), 4.76 (1H, d), 4.58 (1H, d), 4.23 (2H, m), 3.67 (2H, s), 2.79 (1H, m), 1.99-1.25 (20H, m), 1.19 (3H, s). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 58.41; H, 7.21; N, 8.18%; C33H40N4O5S.C7H17NO5.1.4H2O requires: C, 58.17; H, 7.31; N, 8.48%.