Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][N:11]2[N:39]=[C:15]3[CH2:16][C:17](=O)[C:18]4[CH2:19][S:20][N:21]=[C:22]([N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([C:14]=43)=[N:12]2)[C:4]=1[CH3:40].C1(P(=[CH:60][C:61]([O:63][CH3:64])=[O:62])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:34]([O:33][C:31]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:22]1[C:13]2[C:14]3[C:15](=[N:39][N:11]([CH2:10][C:5]4[C:4]([CH3:40])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[N:12]=2)[CH:16]=[C:17]([CH2:60][C:61]([O:63][CH3:64])=[O:62])[C:18]=3[CH2:19][S:20][N:21]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 10 h
Yield: 33.3 %

Procedure:
A mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (752 mg), methyl triphenylphosphanylideneacetate (617 mg) and toluene (14 ml) was heated with stirring at 60° C. for 10 hours. Ethyl acetate was added to the reaction mixture, followed by washing with water. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain the title compound (275 mg, 33%) as an oil.
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[CH:4]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2].[H-].[Na+].[N+:26]([C:29]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:30]=1[CH:31]=O)([O-:28])=[O:27].C(OCC)(=O)C>C1COCC1>[C:1]([C:3](=[CH:31][C:30]1[CH:33]=[C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:36][C:29]=1[N+:26]([O-:28])=[O:27])[CH:4]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:2]
Reactant: CCOP(=O)(OCC)C(C#N)C(CCC(=O)O)C1CCOCC1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(CCC(=O)O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-cyano-5-(diethoxy-phosphoryl)-4-(tetrahydro-pyran-4-yl)-pentanoic acid (2.68 g, 7.7 mmol) in THF (300 mL), sodium hydride (60%, 1.24 g) was added portionwise at room temperature. 2-Nitro-5-phenoxy-benzaldehyde (1.9 g, 7.7 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the resulting solution was washed with saturated aqueous NH4Cl solution. The organic phase was separated, dried with MgSO4, and filtered. The filtrate was evaporated in vacuo to yield an oil which was triturated with heptane to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[O:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:11]([C:4]2[C:5]([C:8]([N:32]3[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:29][CH2:30][CH2:31]3)=[O:10])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][O:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ccc2c(c1)NCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N1CCOc2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 56.2 %

Procedure:
To a mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (112 mg, 0.244 mmol), 100 mg (0.70 mmol) of 3,4-dihydro-2H-benzo[1,4]oxazine, and 0.174 mL (1.0 mmol) of DIEA in CH2Cl2 (2.5 mL) was added 0.19 mL 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After 3 h the reaction mixture was directly purified via flash column (50% EtOAc in hexane) to afford 79 mg of 4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as a white powder. MS m/z: 576.38 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH:17]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:20]([CH:17]3[CH2:19][CH2:18]3)(=[O:22])=[O:21])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)C3CC3)c2)cc1Cl
Yield: 29.3 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added cyclopropanesulfonyl chloride (9.8 μl, 96 mmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give cyclopropanesulfonic acid [5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-amide (8.5 mg, >95% purity, yield: 29.2%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 334 [M+H]+, retention time=1.90 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-0.99 (m, 4H) 2.80-2.85 (m, 1H) 7.84 (dd, J=8.08, 1.64 Hz, 1H) 7.89 (t, J=2.21 Hz, 1H) 8.08 (d, J=8.08 Hz, 1H) 8.10 (s, 1H) 8.48 (d, J=2.40 Hz, 1H) 8.70 (d, J=1.89 Hz, 1H) 10.15 (br. s., 1H).
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\Cl.C(N)CCC.[O:10]([CH2:17][C:18]#[CH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:1]/[CH:2]=[CH:3]\[C:19]#[C:18][CH2:17][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl/C=C\Cl
Reactant: C#CCOc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: Cl/C=C\C#CCOc1ccccc1
Reaction time: 5.5 h
Yield: 67.6 %

Procedure:
To a 1 L flask under Argon was added CuI (7.86 g, 41.2 mmol) and Pd(PPh3)4 (5 g, 4.3 mmol). The catalyst was covered with 600 mL of degassed THF, cis-1,2-dichloroethylene (50 g, 516 mmol), and butylamine (68 mL, 688 mmol). Phenoxy-2-propyne (45 g, 340 mmol) was added neat over 10 min and the reaction mixture stirred for 5.5 h. Air was bubbled through the reaction mixture for 15 min and the reaction filtered through a pad of celite and washed with pentane. The filtrate was washed with water and brine and the aqueous fractions extracted with ether. The organic fractions were combined, dried (MgSO4), filtered through celite and concentrated. The residue was chromatographed over silica gel (hexane) to give 44.3 g of a yellow oil (67%).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2)#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([O:30][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:24]=[CH:23]2)#[N:19]
Reactant: N#Cc1ccc2cc(O)ccc2c1
Reactant: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc2cc(C#N)ccc2c1
Temperature: 25 °C

Procedure:
The compound (t-butyl 2-fluoro-5-nitrobenzoate) (1.74 g) obtained in a previous production example, 6-cyano-2-naphthol (1.86 g) and potassium carbonate (8.2 g) were heated to 50° C. in N,N-dimethylformamide and reacted for 2 hours. After cooling to room temperature, water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (300 g, hexane:ethyl acetate=5:1) to obtain 3.23 g of t-butyl 2-(6-cyano-2-naphthyloxy)-5-nitrobenzoate.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8](CC)(P(O)(O)=O)[C:9]([OH:11])=[O:10])C.[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:27]=1C=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][C:27]=1/[CH:6]=[CH:8]/[C:9]([OH:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCC(CC)(C(=O)O)P(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 2.5 M n-butyl lithium (3.64 mL) in dry tetrahydrofuran (THF) (20 mL) that is cooled to −70° C. under nitrogen is added a solution of diethyl phosphonoacetic acid (0.89 g) in THF (5 mL). After 30 minutes a solution of 2,4-dibenzyloxybenzaldehyde (1.46 g) in THF (5 mL) is slowly added to the cooled solution so as to maintain the temperature. The resulting mixture is stirred at −70° C. for 3 hours and then at 25° C. for 18 hours. The resulting suspension is treated with water, the THF is removed in vacuo,the residue is extracted with ethyl acetate, the extract is dried and evaporated. The residual solid is recrystallized from isopropanol to yield (E)-3-(2,4-dibenzyloxyphenyl)prop-2-enoic acid as colourless crystals (0.6 g), m.p. 153-155° C. H NMR (DMSO) 5.15 (2H,s), 5.21(2H,s), 6.4(1H,d,J=16 Hz), 6.7(1H,d), 6.85(1H,s), 7.3-7.5(10H,m), 7.6(1H,d), 7.8(1H,d,J=16 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][NH:19][CH:20]3[C:28]4[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:19]([CH:20]1[C:28]2[C:23](=[C:24]([O:29][CH3:30])[CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)[CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1CCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(C)=O
Reaction time: 1.5 h

Procedure:
To a solution of 1-(4,5-diphenyloxazol-2-yl)methylamino-2,3-dihydro-4-methoxy-1H-indene (0.22 g) and pyridine (0.2 ml) in dichloromethane (5 ml) was added acetyl chloride (0.15 ml) at 0° C. The mixture was stirred for 1.5 hours at the same temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-[N-acetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.08 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([NH:14][CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][CH:15]([NH:14][C:11](=[O:13])[CH3:12])[CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Yield: 100.3 %

Procedure:
After dissolving 56.4 g of 1-fluoro-4-nitrobenzene (0.4 mol) and 51.2 g of 3-acetamido-pyrrolidine (0.4 mol) in 400 ml of NMP, 66.4 g of potassium carbonate (0.48 mol) are added under a nitrogen atmosphere and the mixture is heated at 100° C. for 18 hours. The reaction medium is allowed to cool and is then poured into 2 l of water. The yellow precipitate formed is filtered off, washed with water and then dried in a vacuum oven over P2O5. 100 g (100%) of N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (1) are thus obtained in the form of a yellow solid.
Reaction SMILES: [CH:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]C1.[OH2:11].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH:6]1([C:1]([S:7]([NH2:10])(=[O:8])=[O:9])=[O:11])[CH2:3][CH2:4][CH2:5]1
Reactant: O
Reactant: NS(=O)(=O)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)C(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of intermediate 5 from Example 344 (700 mg, 2.7 mmol) in THF (90 mL), methanol (50 mL) and water (12 mL) mixture, lithium hydroxide monohydrate (1700 mg, 2.0 mmol) was added. The reaction mixture was stirred at rt. for overnight. Then it was acidified with 1N HCl solution to pH=3 to 5. Extracted with ethyl acetate (2×20 mL) and the organic layers were combined and dried (MgSO4). Evaporation of solvent gave thick colorless oil as product (intermediate 7) (0.58, 88% yield).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:63])([F:62])[C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>ClCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([NH:59][CH2:58][C:57]2[CH:56]=[CH:55][C:54]([C:53]([F:52])([F:62])[F:63])=[CH:61][CH:60]=2)=[O:23])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.15 g, 0.41 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.62 mmol). The mixture was stirred for 15 min followed by addition of 4-trifluoromethylbenzylamine) (0.14 g, 0.82 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.08 g, 38%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.1 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.45-7.41 (m, 3H), 7.39-7.26 (m, 3H), 7.11-7.07 (m, 2H), 7.01-6.97 (m, 2H), 6.92-6.89 (m, 3H), 6.54 (d, J=8.4 Hz, 2H), 6.21 (s, 1H), 5.93 (s, 1H), 4.54-4.46 (m, 2H), 4.29 (s, 2H), 2.46-2.42 (m, 1H), 1.61-1.49 (m, 2H), 1.22-1.18 (m, 1H). ES-MS m/z 517 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NCCc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCc1ccc(O)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
3-Nitrophthalic anhydride (1.93 g, 0.01 mol, 1 eq) and 2-(4-hydroxyphenyl)-ethylamine (2.06 g, 0.015 mol, 1.5 eq) were refluxed under heating in toluene (20 ml) for 3 hours. The reaction mi i t ure was cooled to room temperature, and ethyl acetate (100 ml) was added to this reaction mixture. The organic layer was washed twice with dil. aqueous hydrochloric acid solution (30 ml), further washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give N-[2-(4-hydroxyphenyl)ethyl]-3-nitrophthalimide (2.92 g, 92.8%) as a colorless solid. This was further purified by recrystallization from methanol to give colorless crystals (1.9 g, 60.8%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Product: CC(C)CCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and then reacted with isoamylamine (10.5 g, 0.12 mole) to provide the crude product as a yellow solid. This solid was recrystallized from hexane to provide the desired product as a solid, m.p. 99°-100° C. Analysis: Calculated: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 64.8; % H, 6.6; % N, 16.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:26])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[H-].[Na+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[CH2:35]([O:34][C:32](=[O:33])[O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:12]3[C:11]([CH3:27])=[CH:10][N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:28])[C:13]=3[N:14]=[C:15]([CH3:26])[N:16]=2)[CH2:19][CH2:20]1)[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: Cc1nc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)OCC1CCN(c2nc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 0 °C
Yield: 27.5 %

Procedure:
{1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (1.15 g) synthesized in the similar manner as example 1 in tetrahydrofuran (25 mL) was stirred, then NaH (60% in paraffin, 0.10 g) was added and the mixture was healed at reflux for 3 hours. After cooling to 0° C., ethyl chloroformate (0.28 g) in a small amount of tetrahydrofuran was added and the reaction mixture was allowed to reach room temperature and evaporated. The residue was purified over a silica gel on a glass filter (eluent: CH2Cl2/CH3CN=95:5 then 90:10) to give the title product (366 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.I[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:22])[C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NCC(=O)N2
Reactant: CI
Product: COc1ccc2c(c1)C(c1ccccc1)=NCC(=O)N2C
Yield: 55 %

Procedure:
By replacing 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (XXIIaa) in the example by 7-methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIao), and ethylene-carbonate by iodomethane, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 10–112° C. 1H-NMR (CDCl3, 300 MHz): d 3.38 (s, 3H, NCH3), 3.75 (s, 3H, OCH3), 4.30 (AB system, ? d=1.00, JAB=10.6, 2H, —CH2), 6.77–6.78 (m, 1H Ar), 7.09–7.14 (m, 1H Ar), 7.31 (s, 1H Ar), 7.38–7.46 (m, 3H Ar), 7.44–7.67 (m, 2H Ar).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][C:20]=1[CH3:21])[C:17]1[N:13]([CH:14]=[C:15]([C:22]3[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2)=O.Cl.[NH:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[NH2:33]>C(O)(=O)C>[CH:27]([N:26]1[C:22]([C:15]2[N:16]=[C:17]3[C:18]4[CH:19]=[C:20]([CH3:21])[C:7]([C:5]5[N:32]([CH:34]6[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]6)[N:33]=[CH:3][CH:4]=5)=[CH:8][C:9]=4[O:10][CH2:11][CH2:12][N:13]3[CH:14]=2)=[N:23][CH:24]=[N:25]1)([CH3:28])[CH3:29]
Reactant: Cc1cc2c(cc1C(=O)/C=C/N(C)C)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: CN1CCC(NN)CC1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc2c(cc1-c1ccnn1C1CCN(C)CC1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A mixture of (2E)-3-(dimethylamino)-1-{13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (110 mg, 0.30 mmol) and 4-hydrazinyl-1-methylpiperidine hydrochloride (42 mg, 0.24 mmol) in acetic acid (2.0 mL) was stirred at 100° C. for 1 hour under nitrogen atmosphere. After concentration, the residue was purified by preparative HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 264 (30 mg, 21% yield). LCMS (ESI): RT=5.04 min, m/z: 473.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 6.92 (s, 1H), 6.27-6.26 (m, 1H), 5.85 (t, J=13 Hz, 1H), 4.55 (t, J=20 Hz, 4H), 3.76 (s, 1H), 2.86 (s, 2H), 2.19-2.11 (m, 8H), 1.78 (s, 2H), 1.74 (d, J=14.5 Hz, 2H), 4.51 (d, J=7 Hz, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][C:16]3[CH:24]=[CH:25][C:13]([Cl:12])=[CH:14][CH:15]=3)[CH2:23][CH2:22]2)=[O:9])=[CH:10][CH:11]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C=NCc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)N1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 54.4 %

Procedure:
To a solution of 4-chlorobenzylisocyanate (0.59 g, 3.5 mmol) in anhydrous THF (15 mL) at 0° C. was added 1-(4-chlorobenzyl)piperazine (0.74 g, 3.5 mmol). The resultant mixture was stirred at ambient temperature. After 20 hours the mixture was concentrated of volatiles. The resulting solid was washed with ethyl acetate and dried in vacuo to afford 0.72 g of 1-(((4-chlorobenzyl)amino)carbonyl)-4-(4-chlorobenzyl)piperazine as a white solid; NMR (CDCl3) 7.4 (m, 4), 7.3 (m, 2), 7.2 (m, 2), 4.44.1 (m, 6), 3.6 (m, 4), 3.0 (m, 2) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[O:17]=[C:16]1[C:15](=[O:20])[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[C:13]1[O:12][CH2:10][CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O

Procedure:
4-Aminobenzonitrile (17.58 g, 149 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (25.31 g, 149 mmol) in absolute ethanol (450 mL). The mixture was heated at reflux overnight and the resulting suspension filtered hot to remove a small amount of a dirty yellow solid (discarded). The filtrate was gradually concentrated to afford several crops of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile, as a bright yellow solid, which were collected by filtration and combined. Yield: 29.11 g (81%): 1H NMR (DMSO-d6): δ11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 4.79 (q, 2H), 1.46 (t, 3H).