Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:18]([CH3:20])[CH3:19])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:17])[C:14]([OH:16])=O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:47][C@@H:48]1[CH2:53][NH:52][CH2:51][CH2:50][N:49]1[C:54]1[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][N:55]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:17])[C:14]([N:52]1[CH2:51][CH2:50][N:49]([C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][N:55]=2)[C@H:48]([CH3:47])[CH2:53]1)=[O:16])=[O:8])[CH:18]([CH3:20])[CH3:19]
Reactant: C[C@@H]1CNCCN1c1ccc([N+](=O)[O-])cn1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C)C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)[C@H](C)C1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylic acid (770 mg, 2.7 mmol) was dissolved in DMA (17 mL) and HATU (1.0 g, 2.7 mmol) was added. The reaction mixture was stirred for 20 min and then (R)-2-methyl-1-(5-nitro-pyridin-2-yl)-piperazine di-HCl (700 mg, 2 mmol; Preparation 47) was added followed by N,N-diisopropylethylamine (2.0 mL, 11 mmol) and the reaction mixture was stirred at 55° C. overnight, cooled to RT, concentrated by rotary evaporation and extracted with EtOAc/water. The organic layer was washed with water, and then brine, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography (0-100% ethyl acetate:hexanes) to yield the title intermediate (970 mg) as a yellow oil. (m/z): [M+H]+ calcd for C23H34N6O6 491.25 found 491.7.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]3[N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[N:18]=[C:17]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH2:16]3)[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N:6]3[CH2:7][CH2:8][CH:3]([NH:2][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:4][CH2:5]3)[CH:10]=2)[CH2:16][C:17]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:18]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
5-[3-(4-Amino-piperidin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (50.0 mg, 0.11 mmol) prepared in Example 99, triethylamine (55.0 mg, 0.54 mmol) and methanesulfonyl chloride (18.5 mg, 0.16 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:17]([O:19]CC)=O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:22][C:23]1[C:24](=O)[O:25][C:26](C)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=1O>C1COCC1>[C:1]1([C:9]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:16][C:23](=[O:22])[C:24]([O:25][CH2:26][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:17]2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(c2ccccc2)OC(=O)C(O)=C1O
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C(O)=C1OCc1ccccc1

Procedure:
A total of 3.5 mL (10.5 mmol) of 3.0M phenylmagnesium bromide was added to a solution of 1.6 mL (10 mmol) of ethyl benzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give 5,5-diphenyl-4-hydroxy-3-phenylmethoxy-2(5H)-furanone as an oil, which was purified over SiO2 using acetone/hexanes (3/7).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])cnc1F
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(F)c(CBr)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.9 %

Procedure:
2-Fluoro-3-methyl-5-nitro-pyridine (445 mg, 2.85 mmol) was dissolved in 20 mL DCM. NBS (1.01 g, 5.7 mmol, 2 eq.) was added. The reaction was stirred at room temperature for 2 days. HPLC showed 20% conversion. The reaction was concentrated down and purified (silica gel, 0-80% EtOAc/hexane) to give light yellow oil (100 mg, 15%). 1H NMR (300 MHz, CD3OD): δ 8.39 (m, 2H), 7.61 (m, 1H), 4.86 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.CS(O)(=O)=O>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[CH:13]1([NH:12][C:4]2[CH:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)=[CH:31][CH:30]=3)[N:7]=[CH:6][C:5]=2[CH2:8][C:9]([NH2:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)Cc1cnc(Cl)cc1NC1CCCCC1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CS(=O)(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NC1CCCCC1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To 60 mg of 6-chloro-4-(cyclohexylamino)pyridine-3-carboxyamide (the compound of Example 339) suspended in 0.5 mL of diphenyl ether, 84 mg of 4-morpholinoaniline and 23 mg of methanesulfonic acid were added, and stirred at 180° C. for 30 minutes. After cooling, the reaction mixture was dissolved in chloroform, washed with saturated sodium bicarbonate in water, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1 to 20:1) to obtain 77 mg (82%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1.[C:23]([O:26][CH2:27]Br)(=[O:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([O:26][CH2:27][N:1]1[CH:5]=[C:4]([C:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)([OH:10])[CH:7]([CH3:9])[CH3:8])[N:3]=[CH:2]1)(=[O:25])[CH3:24]
Reactant: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Reactant: CC(=O)OCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3cn(COC(C)=O)cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
1-(1H-Imidazol-4-yl)-1-(6-methoxynaphthalen-2-yl)-2-methyl-1-propanol (100 mg) was dissolved in THF (6 ml), and to the solution were added bromomethyl acetate (160 mg) and triethylamine (40 mg). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluent, dichloromethane-methanol=20:1) to give the titled compound (30 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[CH:11]3[C:28]3[C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:31]=[C:30]([F:38])[C:29]=3[F:39])[C:5]2=[CH:4][CH:3]=1.[CH3:41]OC([Si](C)(C)C)C.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>FC(F)(F)C(O)=O>[CH3:25][CH2:24][N:12]([CH:11]([CH3:10])[CH3:28])[CH:13]([CH3:14])[CH3:41].[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26][N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH:11]3[C:28]3[C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:31]=[C:30]([F:38])[C:29]=3[F:39])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(F)c(F)c1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(C)[Si](C)(C)C
Reactant: C1COCCN1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(F)c(F)c1C1N(CCCN2CCOCC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Product: CCN(C(C)C)C(C)C
Yield: 55.6 %

Procedure:
In a manner similar to the method described in example 60b, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-1′-(3-chloro-propyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in example 73b (0.3 g, 0.41 mmol) was reacted with morpholine (10 mL), trifluoroacetic acid (10 mL) and then N,N′-diisopropylethylamine (1 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (0.15 g, 55.6%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]([CH3:30])[C:25](OCC)=[O:26])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].C(=O)=O>CO>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:25](=[O:26])[CH:24]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)=[CH:9]1)[CH3:30]
Reactant: CN(C)CCN
Reactant: CCOC(=O)C(C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Agent: O=C=O
Solvent: CO
Product: CC(C(=O)NCCN(C)C)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propionate (425 mg), N,N-dimethylethylenediamine (2 ml) and methanol (20 ml) was boiled under reflux for 18 hours with the exclusion of carbon dioxide. The mixture was cooled and filtered, the filtrate was diluted with water (50 ml) and stirred with ether. The mixture was left standing for 18 hours and the solid which precipitated was collected by filtration, washed with water and then ether and dried to give N-(2-dimethylaminoethyl)-2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propionamide, m.p. 163-164° C.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](O)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:26]([C:22]2[N:23]=[CH:24][O:25][C:21]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:27])=[N:8]1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: CC(F)(F)CCCCn1ccc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I.O>CS(C)=O>[CH:30]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][N:7]([CH3:35])[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[CH:11]1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:9])([CH3:32])[CH3:31]
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCN(C(C)C)C(C)C)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)N(C)CCN(C(C)C)C(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.4 Parts of N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide is dissolved in 110 parts of dimethylsulfoxide. Then 0.24 part of sodium hydride, as a 56% suspension in mineral oil, is added. The mixture is stirred for 30 minutes at room temperature. 1.42 Parts of methyl iodide is added portionwise at room temperature and the resultant mixture is stirred overnight in a nitrogen atmosphere. The mixture is then poured into water and extracted with methylene chloride. The methylene chloride extract is dried over anhydrous calcium sulfate and stripped under reduced pressure to give N-(2-diisopropylaminoethyl)-6,7-dimethoxy-N-methyl-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)on1
Product: Cc1cc(-c2cc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)ccn2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[2-(3-methyl-isoxazol-5-yl)-pyridin-4-yl]-3-oxo-propionic acid tert.-butyl ester (Example K6) (170 mg, 0.56 mmol) according to the general procedure M. Obtained as a brown solid (206 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)c(C)c1

Procedure:
Using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 187 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (275 mg) was obtained.
Reaction SMILES: [Li].[CH3:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.O.N#N>N.C(O)C.C1COCC1>[CH3:16][O:15][C:12]1[CH2:13][CH:14]=[C:9]([CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH3:2])[CH2:10][CH:11]=1
Reactant: CCCNCCCc1ccc(OC)cc1
Agent: N
Agent: N#N
Agent: [Li]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNCCCC1=CCC(OC)=CC1
Reaction time: 0.75 h
Yield: 93.5 %

Procedure:
A solution was prepared by dissolving 9.9 g of lithium in 2 l of anhydrous liquid ammonia. 98.7 g of 4-(3-n-propylamino)propylanisole were dissolved in a mixture of 27.8 ml of anhydrous ethanol and 300 ml of THF. This solution was added slowly in dropwise fashion with stirring to the lithium in liquid ammonia solution. After the addition had been completed. The reaction mixture was stirred for about 45 minutes. Water was then added slowly until the blue color of dissolved Li had been discharged. A stream of N2 was passed over the reaction mixture overnight to evaporate the ammonia. Additional water was then added to dissolve the salts which had formed. The alkaline aqueous solution was extracted three times with equal volumes of diethyl ether. The ethereal extracts were combined and dried. Evaporation of the ether yielded 93.2 g of 1-methoxy-4-(3-n-propylamino)propyl-1,4-cyclohexadiene; yield=93.5%.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29]>ClCCl.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[CH2:1][CH:2]=[CH2:3])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C=CCNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A portion of the crude 4-(allylamino)-1-(t-butoxycarbonyl)piperidine (400 mg, 1.66 mmol) was dissolved in 10 mL of dichloromethane and treated with N,N-diisopropylethylamine (0.700 mL, 519 mg, 4.0 mmol) and 4-nitrobenzyl chloroformate (392 mg, 1.82 mmol). After stirring 3 h at rt, the mixture was diluted with 30 mL of ethyl acetate and washed with 15 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane, to give 572 mg of the title compound as a colorless syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.[C:25]([C:29]([CH2:31][N:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])[CH2:35][CH:34]([NH2:50])[C:33]1=[O:51])=[O:30])([CH3:28])([CH3:27])[CH3:26].[Cl-]>O1CCCC1.C(N(CC)CC)C>[C:25]([C:29]([CH2:31][N:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])[CH2:35][CH:34]([NH:50][C:14]([NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=2)=[O:16])[C:33]1=[O:51])=[O:30])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(C)(C)C(=O)CN1C(=O)C(N)CN(c2ccccc2F)c2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(c3ccccc3F)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reaction time: 0.17 h
Yield: 223.5 %

Procedure:
Ethyl 3-aminobenzoate (69 mg) was dissolved in tetrahydrofuran (10 ml), the solution was cooled on ice-water. Triphosgene (45 mg) was added at internal temperature 5° C., triethylamine (162 mg) was added thereto over 10 minutes period, the mixture was allowed to come to room temperature and stirred for 10 minutes. A solution of 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (150 mg) in tetrahydrofuran (5 ml), the mixture was additionally chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1), to thereby obtain 190 mg of the title compound as colorless crystals (Yield: 83%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C:27]([CH:34]=O)=[N:26]1>CO.N1CCCCC1>[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0442 g, 0.133 mmol) synthesized in Example B45, Step 3 in methanol (3 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0206 g, 0.140 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0292 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([C:21]([OH:23])=[O:22])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:24](Cl)(=O)C(Cl)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)O)=CC[C@@H]12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Methoxyestra-1,3,5(10),16-tetraene-17-carboxylic acid (Compound J) (2.00 g) obtained according to the method described in Tetrahedron Letters, 26: 1109 (1985) was dissolved in dichloromethane (75 mL), and oxalyl chloride (2.3 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, the residue was dissolved in dichloromethane (60 mL), and methanol (30 mL) and triethylamine (3.58 mL) were added thereto, followed by stirring at room temperature for 11.5 hours. After completion of the reaction, the reaction solution was concentrated, methanol (20 mL) and 2 mol/L hydrochloric acid (40 mL) were added to the residue, and the resulting precipitate was collected by filtration, and washed with 1 mol/L hydrochloric acid and then water, followed by drying under reduced pressure to give methyl 3-methoxyestra-1,3,5(10), 16-tetraene-17-carboxylate (2.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH3:28])=[O:26])[C:9](=[O:20])[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:26])[O:27][CH3:28])[C:9](=[O:20])[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCCN(C(=O)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC(=O)N(CCCNC(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
tert-butyl 2-((3-chlorophenyl)(3-(methoxycarbonylamino)propyl)amino)-2-oxoethyl(methyl)carbamate (130 mg, 0.31 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 1 h, a solution of saturated sodium bicarbonate was added drop wise to adjust the pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×10 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 3-(N-(3-chlorophenyl)-2-(methylamino)acetamido)propylcarbamate (95 mg, 95%).