Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:4]1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([CH2:17][N:3]2[CH:7]=[CH:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)=[N:4]2)[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccn(CC3CC3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
Add sodium hydride (64 mg, 2.65 mmol) to a solution of 4-(1H-pyrazol-3-yl)-benzonitrile (300 mg, 1.77 mmol) in DMF (5 mL) under nitrogen atmosphere. Stir the mixture for 15 min at 0° C. and add (bromomethyl)cyclopropane (206 □l, 2.12 mmol). Stir the mixture for 5 min at 0° C. and then at room temperature overnight. Quenck the reaction mixture with water and extract twice with EtOAc. Dry the combined organics extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (75:25) to obtain the desired intermediate (256 mg, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2NN=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C2CC(c3ccccc3)=NN2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(C2CC2c2ccccc2)c1
Temperature: 250 °C
Yield: 58.2 %

Procedure:
To a 250 ml round bottom flask equipped with nitrogen inlet, thermometer, and reflux condenser was charged 3.5 g (0.0147 moles) of 5-(3-hydroxyphenyl)-3-phenyl-2-pyrazoline, and 2.2 g (0.1 moles) of powdered sodium hydroxide. The two solids were mixed thoroughly, then heated slowly to 250° C., under a rapid stream of nitrogen. The reaction mixture was heated continuously at 250° C. for a total of 2 hours, then cooled to ambient temperature. The resulting residue was the dissolved in 200 mls of water, then acidified to pH 2 with 1 N aqueous hydrochloric acid. The acidic solution was extracted with 3×100 mls of ethyl ether, and the ether extract was washed with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was the dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. The resulting crude product was chromatographed on silica gel with a 15% ethyl acetate, 85% hexane mobile phase. The pure fractions were combined and concentrated under reduced pressure on a rotary evaporator to afford 1.8 g of the title compound 1-(3-hydroxyphenyl)-2-phenyl-cyclopropane as a pale yellow liquid in a 58% yield. 1H NMR (CDCl3, tms=0 ppm) 1.4(t,2H); 2.2(m,2H); 5.5(s,1H); 6.5-6.8(m,3H); 3.1-3.4(m,6H)
Reaction SMILES: [CH2:1]([N:3]1[CH2:22][CH2:21][C:5]2([CH2:9][N:8]([C:10]3[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH2:19])=[C:12]([CH3:20])[CH:11]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].C(O)(=O)C.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([I:36])[CH:31]=[CH:30][N:29]=1>CO.[Pd]>[Cl:27][C:28]1[C:33]([C:34]2[NH:16][C:14]3[CH:15]=[C:10]([N:8]4[CH2:7][CH2:6][C:5]5([CH2:21][CH2:22][N:3]([CH2:1][CH3:2])[CH2:4]5)[CH2:9]4)[CH:11]=[C:12]([CH3:20])[C:13]=3[N:19]=2)=[C:32]([I:36])[CH:31]=[CH:30][N:29]=1
Reactant: CCN1CCC2(CCN(c3cc(C)c(N)c([N+](=O)[O-])c3)C2)C1
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(I)ccnc5Cl)[nH]c4c3)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a solution of 4-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-2-methyl-6-nitro-phenylamine (304 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and then filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (5:1, CH2Cl2/MeOH) to afford the title compound (450 mg, 86%). 1H NMR (MeOH-d4) δ 1.38 (t, J=8 Hz, 3H), 2.10-2.21 (4H), 2.56 (s, 3H), 3.28-3.57 (10H), 6.55 (s, 1H), 6.57 (s, 1H), 8.03 (d, J=6 Hz, 1H), 8.13 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:6](COCC[Si](C)(C)C)[CH:5]=[N:4][C:3]=1[C:15]([OH:17])=O.[NH2:18][CH2:19][C:20]1[C:21]([F:37])=[C:22]([O:27][C:28]2[CH:29]=[C:30]([CH:33]=[C:34]([Cl:36])[CH:35]=2)[C:31]#[N:32])[C:23]([Cl:26])=[CH:24][CH:25]=1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:15]([C:3]2[NH:4][CH:5]=[N:6][C:2]=2[CH3:1])=[O:17])=[C:21]([F:37])[C:22]=1[O:27][C:28]1[CH:29]=[C:30]([C:31]#[N:32])[CH:33]=[C:34]([Cl:36])[CH:35]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1c(C(=O)O)ncn1COCC[Si](C)(C)C
Product: Cc1nc[nH]c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Yield: 254.4 %

Procedure:
The procedure and process are similar to that described herein except that 5-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-4-carboxylic acid (0.077 g, 0.30 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.093 g, 0.30 mmol) were employed to provide the title compound (0.32 g, 25% overall) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% NH4OH. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H), 8.43 (t, J=5.84 Hz, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.44-7.54 (m, 3H), 7.32 (t, J=7.83 Hz, 1H), 4.45 (d, J=6.04 Hz, 2H), 2.43 (s, 3H). ES-LCMS: m/z 419.0, 421.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:3]=1.[CH2:17]([O:20][C:21]1([CH3:50])[CH2:26][CH2:25][N:24]([C:27]2[N:32]3[N:33]=[C:34]([CH2:36]I)[CH:35]=[C:31]3[N:30]=[C:29]([CH3:38])[C:28]=2[C@H:39]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]1)[CH:18]=[CH2:19].[H-].[Na+]>CN(C=O)C>[CH2:17]([O:20][C:21]1([CH3:50])[CH2:22][CH2:23][N:24]([C:27]2[N:32]3[N:33]=[C:34]([CH2:36][O:10][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=4[O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH3:9])[CH:35]=[C:31]3[N:30]=[C:29]([CH3:38])[C:28]=2[C@H:39]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:25][CH2:26]1)[CH:18]=[CH2:19]
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C(C)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COC(C)c4ccc(C)cc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
A mixture of 1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethanol (41.5 mg, 0.188 mmol) and (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.171 mmol) in DMF (5 mL) was added sodium hydride (7.53 mg, 0.188 mmol) at 0° C. It was then stirred at 0° C. for 4 h and then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was then purified by biotage, eluting with 25% EtOAc/hexane to isolate (2S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-((1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (20 mg, 0.030 mmol, 17.27% yield) as an oil. LCMS (M+1)=677.5.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.[CH:27]([CH:30]1[NH:35][CH2:34][CH2:33][NH:32][C:31]1=[O:36])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH2:20]([N:8]1[CH2:9][CH2:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C@@H:7]1[CH2:6][N:35]1[CH2:34][CH2:33][NH:32][C:31](=[O:36])[CH:30]1[CH:27]([CH3:29])[CH3:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)C1NCCNC1=O
Reactant: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
((2R)-1,4-dibenzyl-2-piperazinyl)methyl methanesulfonate (0.450 g, 1.202 mmol) was combined with 3-isopropylpiperazin-2-one (0.179 g, 1.262 mmol, ChemBridge, San Diego, Calif.) and potassium carbonate (0.498 g, 3.60 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (5.46 mL) and heated at 130° C. After 1 h, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration, the crude residue was purified by silica gel chromatography (2.5-8.5% MeOH in CH2Cl2) to give 4-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone (212 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]([CH3:21])=[C:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(Cc2ccccc2)c2cc(O)ccc21
Product: CCCn1c(C)c(Cc2ccccc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-benzyl-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:15][CH2:9][C:8]([C:5]1[C:4]([C:11]([F:14])([F:12])[F:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: [Br-]
Reactant: CC(=O)c1ncc(Br)cc1C(F)(F)F
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(Br)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
Dissolve 1-(5-bromo-3-(trifluoromethyl)pyridin-2-yl)ethanone (0.7 g, 0.0026 mol) in anhydrous THF at room temperature under N2 atmosphere. Add phenyltrimethyl-ammonium tribromide (1.47 g, 0.0039 moles, 1.5 eq.) to the reaction mixture and reflux overnight. Cool the reaction mixture to room temperature, filter the insoluble solid and concentrate the filtrate under vacuum. Purify by column chromatography to afford the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20].[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O>C(OCC)(=O)C>[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20])#[N:23]
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(-c2[nH]c3ccc(Br)cc3c2C)cc(C)c1O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2[nH]c3ccc(C#N)cc3c2C)cc(C)c1O

Procedure:
1.32 g of 5-bromo-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole and 0.54 g of copper cyanide were added to 10 ml of N-methylpyrrolidone, and the mixture was refluxed for 4 hours. To the reaction mixture was added ethyl acetate, and the mixture was washed with 20% aqueous ammonia solution and water, and dried. The solvent was evaporated, and the residue was purified by silica gel column chromatography. Recrystallization of the crude product from ether-petroleum ether gave 5-cyano-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=2)[C:5]=1[C:6]#[N:7])([O-])=O.CC(C)=O.[Cl-].[NH4+]>[Zn].O>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:6]#[N:7]
Reactant: COc1cccc(COc2cccc([N+](=O)[O-])c2C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c(N)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a mixture of 2-nitro-6-(3-methoxybenzyloxy)benzonitrile (Example 193c) (480 mg, 1.69 mmol) in 5:1 acetone:water (9 mL) was added zinc (552 mg, 8.44 mmol) and ammonium chloride (911 mg, 16.9 mmol). The reaction was stirred at room temperature for 30 minutes, then filtered and concentrated. The residue was purified by flash chromatography (55:45 EtOAc:Hexane) to provide 2-amino-6-(benzyloxy)benzonitrile (337 mg, 78%). 1H NMR (400 MHz, d-DMSO) δ 3.73 (s, 3H), 5.04 (s, 1H), 6.27 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 3H), 7.27 (t, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:7]([Si:10]([CH3:12])([CH3:11])[O:5][CH2:4][C@H:2]1[CH2:1][O:3]1)([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CO1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (S)-glycidol (2.5 g, 33.7 mmol) in 100 mL of 1:1 DCM/DMF was cooled to 0° C. and treated with TBDMS-Cl (6.10 g, 40.5 mmol) and imidazole (3.45 g, 50.6 mmol). The mixture was stirred overnight at 0° C. Solution was diluted with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to provide A-1 as a colorless oil. Data for A-1: LRMS m/z (M+H)=189.21 found; 189.34 required
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH:11]=[C:12]([CH2:21]Br)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[CH:23]([O:26][P:27]([O:32]C(C)C)[O:28][CH:29]([CH3:31])[CH3:30])([CH3:25])[CH3:24]>>[CH:1]([NH:3][CH:4](/[CH:11]=[C:12](/[CH2:21][P:27]([O:28][CH:29]([CH3:31])[CH3:30])([O:26][CH:23]([CH3:25])[CH3:24])=[O:32])\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)CCCC(=CC(CC(=O)OCC)NC=O)CBr
Product: CCOC(=O)CCC/C(=C\C(CC(=O)OCC)NC=O)CP(=O)(OC(C)C)OC(C)C
Reaction time: 19 h

Procedure:
8.7 g (25 mmol) of diethyl 2-formylamino-4-bromomethyl-hept-3-ene-1,7-dicarboxylate and 21 ml (75 mmol) of triisopropylphosphite (90%) are heated to 80°-90° C. and the mixture is stirred for 19 hours under a pressure of ca. 100 mbar. Excess triisopropylphosphite is removed by distillation and the residue obtained after evaporation is chromatographed over 150 g of silica gel first with ethyl acetate and then with ethyl acetate/ethanol (9:1) as eluant, giving diethyl E-2-formylamino-4-diisopropylphosphonomethyl-hept-3-ene-1,7-dicarboxylate as a yellowish oil.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:45][C:46]([F:53])([C:49]([F:52])([F:51])[F:50])[CH2:47][NH2:48]>>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:48][CH2:47][C:46]([F:53])([F:45])[C:49]([F:52])([F:51])[F:50])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester (65 mg, 0.11 mmol) and 2,2,3,3,3-penta-fluoropropylamine (663 mg, 4.3 mmol) were stirred for 24 h at ambient temperature. After evaporation of all volatile components and chromatography on silica (gradient of heptane/ethyl acetate 0 to 80%), the title compound was obtained as white solid (>98%). MS: m/e=606(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(CC)CC.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([S:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:38])=[O:37])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(S(=O)(=O)c2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.129 g, 0.43 mmol) in dichloromethane (8 mL) and Et3N (0.13 mL, 0.86 mmol) was added benzenesulfonyl chloride (62 μL, 0.47 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue obtained was partitioned between EtOAc and aqueous NaOH. The organic layer was then separated, washed with brine (2×10 mL), concentrated under reduced pressure. The crude product was purified using either flash column chromatography (SiO2, 33% EtOAc in hexane) to give 3-(4-methoxybenzyl)-7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (0.147 g, 77%) or used in the next step without any further purification. M.p.=136-138° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.39 (s, 1H), 8.12 (s, 1H), 7.88-7.83 (m, 2H), 7.72-7.59 (m, 3H), 7.18-7.13 (m, 2H), 6.86-6.8 (m, 2H), 5.55 (s, 2H), 4.36 (s, 2H), 3.68 (s, 3H), 3.43, t, J=6.4 Hz, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54-2.48 (m, 2H); LCMS [M+H]: 435.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:34]([NH:33][C:25]2[C:24]([CH:21]([CH3:22])[CH3:23])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:30]([CH3:32])[CH3:31])=[O:35])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(NCc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(=O)OCCc1ccc(N(Cc2ccccc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 15.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using 2-(4-benzylaminophenyl)ethyl acetate (5.0 g) and 2,6-diisopropylphenyl isocyanate (5.7 g) as starting materials, 2-{4-[1-benzyl-3-(2,6-diisopropylphenyl)ureido]phenyl}ethyl acetate (1.39 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=2)[CH:8]=1)=[O:6]
Reactant: N#Cc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 51 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 9 mg (0.22 mmol) of 60% sodium hydride, 44 mg (0.22 mmol) of 6-bromomethyl-pyridine-2-carbonitrile and 0.7 mL of N,N-dimethylformamide. Yield: 27 mg of a white solid: LC-MSD, m/z for C25H19N3O2 [M+H]+=394.1; HPLC retention time: 2.1 min.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:32]([CH:33]([F:44])[C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)=[C:31]([CH:45]4[CH2:50][CH2:49][C:48]([F:52])([F:51])[CH2:47][CH2:46]4)[C:30]4[CH:29]([OH:53])[CH2:28][C:27]([CH3:55])([CH3:54])[CH2:26][C:25]=4[N:24]=3)[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:32]([CH:33]([F:44])[C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:39]=4)=[C:31]([CH:45]4[CH2:46][CH2:47][C:48]([F:52])([F:51])[CH2:49][CH2:50]4)[C:30]4[CH:29]([OH:53])[CH2:28][C:27]([CH3:55])([CH3:54])[CH2:26][C:25]=4[N:24]=3)[CH2:19][CH2:18]2)=[N:13][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCCCC(=O)O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To the crude (−)-2-{1-[5-(4-Ethoxycarbonylbutoxyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol obtained in Example (23-1), 2 ml of tetrahydrofuran, 2 ml of ethanol and 1 ml (1.00 mmol) of 1 N sodium hydroxide aqueous solution were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, 1 N hydrochloric acid was poured into the reaction solution under ice cooling and the reaction solution was extracted with methylene chloride. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by high performance liquid chromatography [YMC-pack ODS-A; acetonitrile/aqueous solution of 0.1% acetic acid and 0.1% triethylamine=85/15 (V/V)] to provide 63 mg of the title compound as a white solid (yield in two steps: 64%).