Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](O)=[O:21].CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20]([N:3]1[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)=[O:21]
Reactant: COC(=O)C1Cc2ccccc2CN1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2ccccc2CN1C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate hydrochloride (2.0 g, 9 mmol) and 3,5-dimethylbenzoic acid (1.6 g, 10 mmol) in DMF (15 ml) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.9 ml, 10 mmol). The reaction mixture is slowly warmed to r.t. and stirring continued for 2 hours. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 1:3 to give methyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate as a colorless oil. This material is hydrolized with 1M sodium hydroxide in THF to give N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[O:28][CH2:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20](O)[C:19]=3[CH:30]=1)[CH:6]=[CH:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.Cl[CH2:54][C:55]#[N:56].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[O:28][CH2:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]([S:40][CH2:54][C:55]#[N:56])[C:19]=3[CH:30]=1)[CH:6]=[CH:5]2
Reactant: OC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2OCc2ncccc21
Reactant: N#CCCl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CCSC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2OCc2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.3 g (0.74 mmol) of the product from Example 1, step 6 and 0.3 g (0.74 mmol) of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) in 30 ml of toluene is refluxed for 15′. The solution is washed with water, dried and concentrated. The residue is dissolved in 25 ml of dichloromethane and 0.07 g (0.93 mmol) of chloroacetonitrile and 0.14 ml (0.10 g; 1.0 mmol) of N,N,N-triethylamine are added. The whole is stirred overnight at room temperature. The solution is washed with water, dried, concentrated and chromatographied trough SiO2 eluting with dichloromethane/methanol 98:2. The yield of title product is 0.12 g (35%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:24]([CH3:26])[CH3:25])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CCN(C(C)C)C(C)C.[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]>C(Cl)Cl>[Br:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:2][NH:1][C:45]([N:42]3[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]3)=[O:46])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(=O)N1CCN(C(=O)Cl)CC1
Reactant: CC(C)N(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Br)ccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)NCCN(C(C)C)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Br)ccc32)CC1
Reaction time: 8 h

Procedure:
To a solution of rac-3-[(2-Amino-ethyl)-isopropyl-amino]-6-bromo-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (270 mg, 0.48 mmol) and DIPEA (167 uL, 0.96 mmol) in 5 mL of DCM was added 4-acetyl-piperazine-1-carbonyl chloride (137 mg, 0.72 mmol) at room temperature, and stirred at same temperature overnight. The reaction mixture was rinsed with 20 mL water. The organic layer was dried over Na2SO4, and concentrated in vacuo, then purified by flash column chromatopgraphy to 180 mg white solid. MS: [M+H]+=590.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of benzyl 3-(benzyloxy)-4-methylbenzoate (4.30 g) in methanol (40 mL) and THF (40 mL) was added a solution of sodium hydroxide (2.60 g) in water (40 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was adjusted with 1N hydrochloric acid to pH<4. The precipitated crystals were collected by filtration, and dried to give the title compound (2.80 g) as white crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10](N3CCC(N4CCCC4)CC3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.Cl.[OH:68][CH2:69][C@H:70]1[N:74]([CH:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)[CH2:73][C@H:72]([NH:81][C:82](=[O:84])[CH3:83])[CH2:71]1>CN(C=O)C>[CH:1]1([C:4]2[C:9]([C:10]([N:78]3[CH2:77][CH2:76][CH:75]([N:74]4[C@H:70]([CH2:69][OH:68])[CH2:71][C@@H:72]([NH:81][C:82](=[O:84])[CH3:83])[CH2:73]4)[CH2:80][CH2:79]3)=[O:11])=[C:8]([CH3:23])[N:7]=[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)nc(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCN(C(=O)c3c(C)nc(-c4cccc(OC(F)(F)F)c4)nc3C3CC3)CC2)C1

Procedure:
In analogy to the procedure described for intermediate 2,4-cyclopropyl-6-methyl-2-(3-trifluoromethoxy-phenyl)-pyrimidine-5-carboxylic acid (example 36) was reacted with HATU, triethylamine and N-((3R,5S)-5-hydroxymethyl-1-piperidin-4-yl-pyrrolidin-3-yl)-acetamide dihydrochloride (intermediate 8) in DMF. Subsequent purification by preparative HPLC afforded the title compound as a gum. MS: 562.3 (MH+).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>ClCCl>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCC1CCN(CC2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of dichloromethane and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of dichloromethane cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of dichloromethane is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. After a process control, 100 ml of 1M NaOH is added to the mixture, the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate compound (12) is crystallised from ethyl acetate, to obtain 14.29 g of white solid. Yield 83%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:7](=[O:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])C.[O-][Si]([O-])=O.[Mg+2]>C(O)C.C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:7](=[O:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: CNC
Reactant: CCOC(=O)CNc1ccncc1[N+](=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)CNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Condensed dimethylamine (20 ml) was added in portions to a solution of crude N-(3-nitro-4-pyridinyl)glycine ethyl ester (4.0 g, 0.018 mole) in absolute ethanol (10 ml). The reaction was allowed to stir at ambient temperature over the weekend. The mixture was diluted with petroleum ether and the solid was collected by filtration. The solid 3-g was dissolved in tetrahydrofuran, filtered and diluted with isopropyl ether to produce a dark amorphous solid which was filtered off. The filtrate was further diluted with petroleum ether and placed in the freezer to produce a dark orange crystalline solid. The solid (2.5 g) was dissolved in methylene chloride, treated with Florisil®, and the filtrate was evaporated to a yellow solid, which was dried under high vacuum at 70° C. to give 1.8 g (45%), mp 142°-143° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[N:18]=1>CN(C)C=O>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[N:18]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
L-Alanine methyl ester hydrochloride (8.4 g, 0.06 mol) was dissolved in 100 ml of anhydrous N,N-dimethylformamide, and 16.6 ml (0.12 mol) of triethylamine were added. Subsequently, while stirring vigorously, 10.7 g (0.05 mol) of 2,6-dichloro-3-nitropyridine in 20 ml of anhydrous N,N-dimethylformamide were slowly added dropwise, during which the reaction temperature rose above 40° C. After a further 3 h at room temperature, the reaction mixture was poured into about 400 ml of ice-water, extracted three times with ethyl acetate, dried (sodium sulfate) and concentrated. After chromatography on silica gel (ethyl acetate/heptane=1:5 then 1:2), 9.0 g (69%) of compound A were isolated as a yellow oil,
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COc1ccc(CO)cc1)OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Caesium carbonate (39.4 g) was added to a solution of 4-hydroxymethyl-phenol (10 g) and 2-bromo-1,1-diethoxyethane (12.73 mL) in DMF (200 mL) and the resulting mixture stirred at 90° C. for 16 h. The reaction was poured into water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic solutions were washed with water (250 mL) and brine (250 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with an isohexane to diethyl ether gradient to give the subtitled compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C@@H:11]([O:13]C1CCCCO1)[CH3:12])=[CH2:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:10])[C@@H:11]([OH:13])[CH3:12]
Reactant: C=C(c1ccc(F)cc1F)[C@H](C)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=C(c1ccc(F)cc1F)[C@H](C)O
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of compound 5a, (3S)-2-(2,4-Difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-butene, (81 g, 0.302 mole) and pyridinium-p-toluenesulfonate (32.7 g, 0.130 mole) in 1200 ml of ethanol was heated at 60° C. for 9 hours. The reaction mixture was concentrated in vacuo and co-evaporated with toluene. Toluene was then added to the residue and the resulting solid was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was chromatographed on silica gel. Elution with 10% ethyl acetate in hexane gave the title compound 6a as light yellow oil (44.96 g, 81%)
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:23])[CH:11]2[NH:15]C(OC(C)(C)C)=O)[C:8]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([O:4][CH:5]=[CH:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:23])[CH:11]2[NH2:15])[C:8]=1[C:24]([O:26][CH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2SC1
Temperature: 20 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A mixture of 3-(2-acetoxy-vinyl)-2-benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (1.65 g) (obtained as described above in Example 5), p-toluenesulphonic acid monohydrate (1.14 g) and acetonitrile (50 cc) is stirred for 16 hours at 20° C. It is then taken up in a 5% strength sodium bicarbonate solution (50 cc) and extracted with ethyl acetate (50 cc), and the organic phase is washed with a saturated sodium chloride solution (2×20 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (20 mm Hg) at 20° C. 3-(2-Acetoxy-vinyl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (E-form) (1.26 g) is obtained in the form of a crude red oil.
Reaction SMILES: C(O[CH:4]=[C:5]([C:15]#[N:16])[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])C.[C:17]1([NH:23][N:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC>[CH:25](=[N:24][N:23]([CH:4]=[C:5]([C:15]#[N:16])[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC=C(C#N)C(=O)OCC[Si](C)(C)C
Reactant: C(=NNc1ccccc1)c1ccccc1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOC(=O)C(C#N)=CN(N=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
2-(Trimethylsilyl)ethyl 2-ethoxymethylenecyanoacetate (10.0 g, 41.4 mmol) and benzaldehyde-phenylhydrazone (8.13 g, 41.4 mmol) were combined in 50 mL xylenes under N2 and heated at reflux for 5 h, cooled to room temperature, then treated with hexane (50 mL) and allowed to stir overnight. The precipitate was filtered off, washed with hexane and dried to afford 5.46 g of crude product. Purification by chromatography afforded 2.69 g (16%) of 2-(trimethylsilyl)ethyl 3-(N′-benzylidene-N-phenylhydrazino)-2-cyanoacrylate, as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][C:12]1=[O:13]
Reactant: O=C1CCCO1
Reactant: NCCCCCCN
Product: NCCCCCCN1CCCC1=O
Temperature: 25 °C

Procedure:
Hexamethylenediamine (100 g, 0.86 mole) was heated with γ-butyrolactone (23.36 ml, 0.31 mole) at 210° C. under nitrogen for 24 hours in a three-neck reaction flask equipped with air reflux condenser. After the reaction, most of the unreacted diamine was crystallized upon cooling to room temperature; therefore, most of the excess diamine was filtered off. The remaining unreacted diamine in solution was vacuum distilled, then N-(6-aminohexyl)-2-pyrrolidone was obtained at 140° C. (0.9 torr) as a colorless liquid. Yield: 35 g (62%). Mass Spectra: m/e (relative intensity) 185(M+1+, 16.97).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.Cl[C:22](OC1C=CC=CC=1)=[O:23].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:48]3[C:47](=[O:49])[N:46]([CH2:50][CH3:51])[CH2:45][C:44]([CH3:53])([CH3:52])[O:43][C:42]=3[N:41]=[C:40]([N:54]3[CH2:60][CH:59]4[O:61][CH:56]([CH2:57][CH2:58]4)[CH2:55]3)[N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:22]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[C:48]4[C:47](=[O:49])[N:46]([CH2:50][CH3:51])[CH2:45][C:44]([CH3:53])([CH3:52])[O:43][C:42]=4[N:41]=[C:40]([N:54]4[CH2:55][CH:56]5[O:61][CH:59]([CH2:58][CH2:57]5)[CH2:60]4)[N:39]=3)=[CH:36][CH:37]=2)=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)c2C1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4cccc(OC(F)F)c4)cc3)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.4 %

Procedure:
96.84 mg of 3-difluoromethoxyphenylamine (590.31 μmol), 206.20 μl of DIEA (1.18 mmol) and 30.81 μl of phenyl choroformate (237.83 μmol) are added to 4 ml of THF in a microwave tube. The mixture is stirred at room temperature for 20 minutes. 250 mg of 4-(4-aminophenyl)-6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one (590.31 μmol) are added and the resulting mixture is heated for 1 hour at 120° C. in a Biotage microwave machine. The reaction medium is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (98/2 v/v) to give 180 mg of 1-(3-difluoromethoxyphenyl)-3-{4-[6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}urea.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>C(Cl)Cl>[CH3:25][CH2:24][CH2:23][CH2:22][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:32])=[CH:34][CH:35]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 92 mg of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 100 mg of triethylamine followed by 130 mg of 4-(n-butyloxy)benzoyl chloride. The reaction mixture is stirred at room temperature for 24 hours and then treated with 4 ml of 1N sodium hydroxide. The mixture is extracted with 10 ml of ethyl acetate and the extract washed with 1N sodium hydroxide and 5 ml of brine. The organic layer is dried over anhydrous sodium sulfate and filtered through hydrous magnesium silicate. The filtrate is concentrate in vacuo to a residue which is stirred with ether-hexanes to give 160 mg of the desired product as a white solid:mass spectrum (CI), 361 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=O)[CH:16]=[CH:17][CH:18]=1.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(C(=O)C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A solution of 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-l-yl)benzonitrile (0.008 mol) in ethyl acetate (150 ml) is shaken under 50 psi of hydrogen gas in the presence of 10% palladium an carbon catalyst (1.0 g). The reaction is filtered through a celite pad and evaporated to give 4-(3-(3(2-quinolinylmethyloxy)phenyl)propyl)benzonitrile.
Reaction SMILES: C(OC(C)C)(C)C.C([Li])CCC.CCCCCC.Br[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1.[NH:25]1[C:33](=[O:34])[C:31](=[O:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>O1CCCC1>[OH:32][C:31]1([C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[C:29](=[O:30])[NH:28][C:26](=[O:27])[NH:25][C:33]1=[O:34]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1ccsc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: O=C1NC(=O)C(O)(c2ccsc2)C(=O)N1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Isopropyl ether (40 ml.) was cooled to -70° C. Butyl lithium in hexane (2.4 M, 10 ml., 24 mmoles) was added over 10 minutes, keeping the temperature -70° to -60° C. 3-Bromothiophene (1.9 ml., 20 mmoles) was added over 20 minutes, keeping the temperature -72° to -68° C. The mixture was stirred for an additional 30 minutes at -72° to 70° C. Sublimed alloxan (3 g., 21 mmoles) in 25 ml. of tetrahydrofuran was added over 40 minutes, keeping the temperature -70° to -65° C. Stirring at this temperature was continued for 15 minutes. The cooling bath was removed and the reaction mixture stirred for one hour at room temperature, then cooled to 5° C. Hydrochloric acid (1 N, 40 ml.) was added slowly, and the organic phase separated. The aqueous phase was extracted with 35 ml. of ethyl acetate. The combined organic phase/extract was washed with 10 ml. of water, dried over anhydrous sodium sulfate and concentrated to yield solid 5-hydroxy-5-(3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione (1.41 g., 31%; m/e 226).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:36])[NH:15][C:16]2[CH:17]=[C:18]3[C:34](=[O:35])[NH:33][N:32]=[CH:31][C:20]4=[C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:22][C:23]([CH:24]=2)=[C:19]34)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[O:35]=[C:34]1[C:18]2[C:19]3[C:20](=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:22][C:23]=3[CH:24]=[C:16]([NH:15][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:36])[CH:17]=2)[CH:31]=[N:32][NH:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)C4CCNCC4)cc1c23
Yield: 97 %

Procedure:
Preparation of example 31 from the title compound of Example 29 (20 mg, 0.041 mmol) and 45% TFA in CH2Cl2 (1 mL) was carried out analogously to Example 20. Isolation, also in an analogous manner, afforded the title compound (20 mg, 0.040 mmol) as a yellow powder in 97% yield.