Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[N:21][O:22][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[NH:33][C:32]4=[O:37])=[CH:38][CH:39]=3)[CH3:18])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 51 %

Procedure:
Following a procedure similar to that described in Example 40(f), 170 mg of 4'-(phenylsulfonylamino)-acetophenone were reacted with 197 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:98 by volume mixture of methanol and methylene chloride as the eluent, to give 170 mg of the title compound, melting at 213-215° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:20]([OH:22])=O)=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH3:26][C:25]1[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:28][CH3:27])=[CH:18][C:17]=1[NH:16][CH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:10][CH:11]=1
Reactant: Cc1ccc(C(=O)O)cc1NCc1cnc(NC(=O)OC(C)(C)C)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(NCc2cnc(NC(=O)OC(C)(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoic acid (30 mg, 0.08 mmol) in DMF (1 mL) were added HATU (95 mg, 0.25 mmol), DIEA (74 □L, 0.42 mmol) and methylamine hydrochloride (9 mg, 0.13 mmol). The reaction mixture was stirred for overnight at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product (29 mg, 93% yield) was used without further purification. MS m/z: 372 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].[CH:18]([NH2:21])([CH3:20])[CH3:19]>O1CCCC1.C(Cl)Cl>[CH:18]([NH:21][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])([CH3:20])[CH3:19]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CC(C)N
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)NCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml) was treated with sodium iodide (484 mg, 3.2 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of isopropylamine (3.01 ml, 35.3 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 18 hours at ambient temperature, after which time an additional 10 equivalents of isopropylamine was added to drive the reaction. The reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: C([N:3]([CH2:22][CH3:23])[CH:4]=[C:5]([C:11](=[O:21])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=1[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:24]1(N)CC1>C1(C)C=CC=CC=1>[CH:22]1([NH:3][CH:4]=[C:5]([C:11](=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:23][CH2:24]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(CC)CC)C(=O)c1cc(F)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 77.1 %

Procedure:
17.5 g of ethyl 3-diethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are heated to boiling under reflux with 2.9 g of cyclopropylamine and 50 ml of toluene for 30 minutes. The toluene is removed by distillation in vacuo, and the residue, which solidifies to crystals, is recrystallized from cyclohexane/light petroleum. 12.9 g of ethyl 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 89°-90° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20](O)=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([N:30]3[CH2:31][CH2:32][CH2:33][CH:29]3[C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:34])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 18 h
Yield: 77.9 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.25 g, 0.80 mmol) was dissolved in N,N-dimethylformamide (3 ml), and proline tert-butyl ester (0.15 g, 0.88 mmol), WSC (0.31 g, 1.6 mmol) and HOBt (0.22 g, 1.6 mmol) were successively added thereto. The reaction mixture was stirred for 18 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from isopropyl ether to give the titled compound (0.29 g, 78%) as white crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1>C(#N)C>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[CH:12]=[N:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCc1cncn1Cc1ccc(C#N)cc1

Procedure:
A solution of 4-(tert-butyldimethylsilyloxymethyl)-1-triphenylmethylimidazole (4.66 g, 10.26 mmol) and 1-bromomethyl-4-cyanobenzene (2.01 g, 10.26 mmol) in acetonitrile (50 mL) was refluxed 4 h. The reaction was cooled, acetonitrile removed in vacuo, and the residue dissolved in methanol (30 mL). This solution was refluxed for 2 h, cooled and methanol evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The crude product was chromatographed on silica with 3% methanol in chloroform. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].N1C=CC=CC=1>CCCCCC>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Oc2ccccc2)CC1
Yield: 37.6 %

Procedure:
A reaction similar to Production example 2-1 using t-Butyl 4-aminopiperidin-1-ylcarboxylate (328 mg, 1.64 mmol), phenyl chloroformate (0.226 ml, 1.80 mmol) and pyridine (0.146 ml, 1.80 mmol); and the obtained crystals were suspended in hexane:ethyl acetate=4:1, filtered off, and the filtrate was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane:ethyl acetate=4:1 to 1:1). The purified crystals were then suspended in hexane:ethyl acetate=4:1 and filtered off. The title compound (215 mg, 0.617 mmol, 40.9%) was obtained as colorless crystals, together with the previously obtained crystals.
Reaction SMILES: C([N:8]1[C:12]2=[C:13]([NH:28][S:29]([CH:32]3[CH2:34][CH2:33]3)(=[O:31])=[O:30])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OC(=O)C)C>C(Cl)Cl>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:14]2[C:13]([NH:28][S:29]([CH:32]3[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[C:12]3[NH:8][CH2:9][CH2:10][N:11]3[C:16](=[O:17])[C:15]=2[CH3:18])=[C:21]([F:27])[CH:22]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
Borontribromide (20 mg, 0.0001 mol) was added to a stirred solution of cyclopropanesulfonic acid [1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyridin-8-yl]-amide (1A: 30 mg, 0.0001 mol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with methanol and concentrated. The concentrate was partitioned between ethyl acetate and water. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (4% methanol in DCM) afforded 7 mg of the product (28% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][S:5][CH2:6][CH3:7].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>CCCCCC.C1COCC1>[CH2:10]([Br:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][CH2:3][CH2:4][S:5][CH2:6][CH3:7]
Reactant: CCSCCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSCCOCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
NaH (1.85 g, 0.046 mol) was washed with hexane and then suspended in dry THF (60 mL). 3-Thiapentane-1-ol (4.67 g, 0.04 mol) in THF (20 mL) was added and stirred for 1 h at room temperature. 1,6-Dibromohexane (9.76 g, 0.04 mol) in THF (20 mL) was added and the mixture was refluxed for 20 h. After evaporation of the solvent, the residue was dissolved in ethyl acetetate (200 mL). The organic phase was washed with water (2×50 mL), and dried (Na2SO4). The crude product was purified by Kugelrohr distillation to give 7-oxa-10-thiadodecyl bromide (3.34 g, 31%); bp 48° C. -56° C./0.04 torr; NMR: 1.25 (3H, t, J=7 Hz), 1.2-1.9 (8H, m), 2.59 (2H, q, J=7 Hz), 2.68 (2H, t, J=7 Hz), and 3.2-3.7 ppm (6H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[O:11][C:10](=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:20].CN1CCOCC1>CN(C)C=O>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][NH:17][C:12]([CH2:13][N:8]([CH2:9][C:10]([OH:11])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)OC(=O)C1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)NCC(=O)c1ccc(Br)cc1
Yield: 80.2 %

Procedure:
2,6-Dioxo-morpholine-4-carboxylic acid tert-butyl ester (2.5 g, 11.6 mmol) was added to a solution of 2-amino-1-(4-bromo-phenyl)-ethanone hydrochloride (3.05 g, 12.2 mmol) and 4-methylmorpholine (1.92 mL, 17.4 mmol) in dimethylformamide (15 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2×50 mL), and saturated sodium bicarbonate (2×50 mL). The basic extracts were neutralized and extracted with ethyl acetate (2×75 mL). The combined organic phases from the second extraction were dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to provide ({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetic acid (4 g, 9.3 mmol, 80%). C17H21BrN2O6 calculated 428.0 observed [M+1]+431.1; rt=2.36 min.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:7][C:6]2[CH:16]=[CH:17][S:18][C:5]1=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]2[CH:16]=[CH:17][S:18][C:5]1=2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2ccsc2n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccsc21
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of ethyl 6,7-dihydro-7-isopropyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (1.12 g, 4.2 mmol), sodium hydroxide (6.3 mL, 2 N solution in water, 12.6 mmol) and methanol (20 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated to remove methanol. The concentrate was diluted with water, cooled to 0° C. and acidified with concentrated hydrochloric acid. The resulting precipitates were collected by vacuum filtration and dried to provide the title compound as an off-white solid (0.81 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 8.86 (s, 1H), 7.25 (d, 1H), 7.16 (d, 1H), 4.87 (br, 1H), 1.73 (d, 6H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+].[CH2:14]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>O.C(O)(C)C>[ClH:1].[OH:30][CH:28]([CH2:27][O:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:29][NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCOCC(O)CNCCCC[C@H](N)C(=O)O
Yield: 23.8 %

Procedure:
L-lysine hydrochloride (18.3 g, 0.1 mols) and 2.0 g (0.2 mols) of sodium hydroxide were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 10.1 g of Nε-(2-hydroxy-3-dodecyloxypropyl)-L-lysine hydrochloride (yield 23.7%).
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=O)[CH:7](C(OCC)=O)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]1[N:22]([CH2:23][CH2:24][C:25]#[C:26][CH3:27])[N:21]=[CH:20][C:19]=1[C:28]#[N:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[NH2:29][C:28]1[C:7]2[C:6](=[O:16])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][C:8]=2[N:17]=[C:18]2[N:22]([CH2:23][CH2:24][C:25]#[C:26][CH3:27])[N:21]=[CH:20][C:19]=12
Reactant: CCCCN1CC(=O)C(C(=O)OCC)C1=O
Reactant: CC#CCCn1ncc(C#N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC#CCCn1ncc2c(N)c3c(nc21)CN(CCCC)C3=O

Procedure:
A solution of 1-(n-butyl)-3-ethoxycarbonyl-pyrrolidin-2,4-dione (1.02 g.) in wet acetonitrile (23 ml.) was heated under reflux for 1.5 hours. The acetonitrile was evaporated under reduced pressure, leaving a clear oil which was immediately dissolved in toluene (28 ml.). To this solution was added 5-amino-1-(pent-3-ynyl)-4-cyanopyrazole (0.6 g.) and a catalytic amount of toluene-p-sulphonic acid (0.05 g.). The mixture was heated under reflux overnight, collecting water in a Dean-Stark trap. The reaction mixture was cooled to 0° and diluted with ether. The resulting precipitate was collected by filtration, giving 0.89 g. of 5-[N-(n-butyl)-2-oxo-3-pyrrolin-4-yl]amino-1-(pent-3-ynyl)-4-cyanopyrazole, which was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33]>>[CH2:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CNCC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, 1H), 3.3-3.8 (m, 14H), 2.96 (s, 3H), 2.2 (m, 1H), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Cl:16])=[O:25]
Reactant: NC1CCN2CCc3ccccc3C2C1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)NC1CCN2CCc3ccccc3C2C1

Procedure:
By a procedure analogous to that of Example 1, 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine is reacted with o-chlorophenyl isocyanate to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([Li])CCC.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, to a mixture of (4-chlorophenyl)acetic acid (13.6 g) in THF (140 mL) was added n-butyllithium (1.6 M hexane solution, 100 mL) at −60° C. to −70° C., and the mixture was allowed to warm to 0° C. A mixture of methyl iodide (4.96 mL) in THF (40 mL) was added to the reaction mixture at 0° C.-10° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was extracted with 1N aqueous sodium hydroxide solution (2×100 mL), and the extract was acidified with 3N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.3 g).
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]=1.[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][O:28][CH2:29][C:30]([NH:32][NH2:33])=O)=[CH:25][CH:24]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][CH2:29][C:30]2[N:4]3[C:5]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=4[C:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:8][CH2:9][C:3]3=[N:33][N:32]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(COCC(=O)NN)cc1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(COCc2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2)=NC3)cc1

Procedure:
A solution of 15,0 g 2-(methylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine [cf. G. A. Archer et al., J. Org. Chem. 29, 231 (1964)] and 11,5 g 2-(p-methoxybenzyloxy)-acetic acid-hydrazide in 100 ml hexamethyl-phosphoric acid triamide is heated for 10 hours at 140°. The reaction mixture is worked up analogously to Example 1. The crude product is crystallised from ethyl acetate-petrol ether, whereby 1-[(p-methoxybenzyloxy)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine M.P. 157°-159° is obtained.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.96-8.01 (m, 1H), 7.88-7.92 (m, 1H), 7.09-7.21 (m, 3H), 3.80-3.83 (m, 4H), 3.73 (s, 2H), 3.08-3.10 (m, 4H); MS (APCI+) M/Z 401 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[CH:35](O)=[O:36].C(N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([CH:35]=[O:36])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=CO
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCN(C=O)CC3)CC2)CC1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) and formic acid (5.37 μL, 140 μmol) in methylenehloride (0.7 mL) was added carbonyldiimidazole (23.4 mg, 140 μmol). The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechloride/methanol (v:v 19:1) as solvent to yield the title compound as a white solid (25 mg, 67%). MS ISP (m/e): 534.2/536.3 (100/29) [(M+H)]+.