Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[NH2:23])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26](N(CC)CC)C.S(OC)(OC)(=O)=O>CCOCC>[CH2:1]([NH:9][C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[NH:23][CH3:26])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CNc1cc(OC)c(OC)cc1C=C(C)C(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 35.9 %

Procedure:
To a nonaqueous ether solution of 3.00 g (8.81 mmol) (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid phenethyl amide and 1.34 ml (9.69 mmol) of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.), 0.92 ml (9.69 mmol) of dimethyl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was slowly added dropwise. Thereafter, reflux was carried out for 2 hours at 34° C. to 35° C. After the completion of the reaction, the solvent was evaporated, and the resulting residue was dissolved in ethyl acetate. Thus obtained ethyl acetate layer was washed with water and was dried with sodium sulfate. The dried solution was concentrated under a reduced pressure, and the resulting crude product was refined by an aminopropyl-modified type silica gel column chromatography (n-hexane/ethyl acetate=1/1), whereby 1.12 g of the aimed compound was obtained as a yellowish crystal (yield: 35.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.CO>C1COCC1.CCOCC>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)C(=O)N1
Yield: 83.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.60 g, 2.2 mmol) and cyclopropanecarbonyl chloride (0.4 mL, 4.4 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL). The solvent was removed in vacuo to give a solid. The solid was slurried in ether (30 mL0 for 1 h. The suspension was filtered and washed with ether (30 mL) to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-amide as a solid (630 mg, 84% yield): mp, 237–239° C.; 1H NMR (DMSO-d6) δ 0.87–0.90 (m, 4H, 2CH2), 1.93–2.09 (m, 2H, CH, CHH), 2.49–2.65 (m, 2H, CH2), 2.64–2.96 (m, 1H, CHH), 5.15 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.61 (d, J=7.2 Hz, 1H, Ar), 7.82 (t, J=7.7 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 9.99 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 8.10, 14.93, 22.00, 30.93, 48.92, 117.07, 118.30, 126.69, 131.49, 135.97, 136.43, 166.67, 167.57, 169.77, 172.55, 172.74; Anal Calcd for C17H15N3O5: C, 59.82; H, 4.43; N, 12.31. Found: C, 59.50; H, 4.39; N, 12.04.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)s3)C[C@H]2OC)nc1Cl
Yield: 72.6 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (30 mg, 0.07 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (16 mg, 0.08 mmol), WSC hydrochloride (44 mg, 0.23 mmol), HOBT (16 mg, 0.12 mmol), diisopropylethylamine (0.015 mL, 0.08 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 31 mg of the title compound as a white solid (87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]3[N:13]=[N:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(NC2CCNCC2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccc(NC2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a mixture of 6-(piperidin-4-ylamino)-pyridazine-3-carbonitrile (D3) (0.15 g, 0.7 mmol) and α,α,α-trifluoro-p-tolualdehyde (0.15 ml, 1.1 mmol) in dichloromethane (2 ml), was added sodium triacetoxyborohydride (0.232 g, 1.1 mmol) and acetic acid (0.041 ml). The reaction mixture was then stirred at room temperature for 18 h. A saturated solution of sodium hydrogen carbonate was then added and the organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by HPLC. The desired fractions were collected and the solvent was evaporated in vacuo to yield E7 (0.101 g, 38%) as a solid. C18H18F3N5 requires 361. Found 362 (MH+); mp: 243.1° C.
Reaction SMILES: [NH2:1][C@@:2]1([C:22]#[N:23])[C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:6][C@@H:5]2[C@H:3]1[C@@:4]2([F:21])[C:18](N)=[O:19].C(O)(=[O:26])C.Cl>O>[NH2:1][C@@:2]1([C:22]#[N:23])[C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:6][C@@H:5]2[C@H:3]1[C@@:4]2([F:21])[C:18]([OH:26])=[O:19]
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 75 °C

Procedure:
A mixture containing 22.5 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 0.1 mL of acetic acid, 0.1 mL of water, and 0.2 mL of concentrated hydrochloric acid was stirred for 6 hrs approximately under heating at 75° C. (external temperature). The reaction mixture was concentrated under reduced pressure to obtain 24.6 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxylic acid (6f) as a light brown solid.
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[ClH:17]>C(O)C.[Pd]>[Cl-:17].[OH:1][C:2]1([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][NH3+:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#CC(c1ccccc1)C1(O)CCOCC1
Reactant: Cl
Agent: [Pd]
Solvent: CCO
Product: [Cl-]
Product: [NH3+]CC(c1ccccc1)C1(O)CCOCC1

Procedure:
To (4-hydroxytetrahydro-2H-pyran-4-yl)(phenyl)acetonitrile (50 mg, 0.230 mmol) in ethanol (2 ml) was added HCl (0.190 ml, 2.301 mmol) then 10% Pd/C (49.0 mg, 0.046 mmol) as a slurry in ethanol. The reaction mixture was put under H2 balloon pressure for 15 hours. The reaction was filtered through a 0.45 um syringe-tip filter, then concentrated in vacuo. The product was used without further purification. 49.6 mg, 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][C@H:28]([C:30]([O:32]C)=[O:31])[CH3:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](C)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN[C@@H](C)C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-L-alaninate (D76) (223 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (60 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then HCl aquous solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL) and water (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-L-alanine (E50) (82 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.34 (3H, d), 1.38 (6H, d), 3.33 (1H, m), 4.28 (2H, q), 4.88-4.94 (1H, m), 7.31 (1H, t), 7.47 (1H, d), 7.64 (1H, d), 8.00 (1H, d), 8.05 (1H, d), 8.22 (1H, dd), 8.40 (1H, d), 11.26 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 366.1 (M—NHC2H3COOH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][OH:43]>>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][O:43][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22]
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: CN(C)CCO
Product: CN(C)CCOC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48c using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and 2-dimethylamino ethanol. LCMS (Method F): 610 (M+H)+, Retention time 3.4 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (4.00 g, 11.7 mmol), N-isopropyl-methyl-amine (3.67 ml, 35.2 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at 50° C. according to the general procedure C. Obtained as a yellow solid (3.27 g, 74%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(Cl)Cl>[N+:17]([C:4]1[CH:3]=[C:2]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])([O-:19])=[O:18]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(N2CCNCC2)ccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 4-fluoro-2-nitro-1-(phenylsulfonyl) benzene (1.0 g, 3.6 mmol), piperazine (0.37 g, 4.3 mmol), and potassium carbonate (0.79 g, 5.7 mmol) is stirred in 35 mL of acetonitrile overnight at reflux. The mixture is cooled to rt and 35 mL of water and CH2Cl2 are added. The layers are separated and the aqueous layer extracted with CH2Cl2 (3×35 mL). The combined organics are dried over MgSO4, filtered, and concentrated. Purification via flash column chromatography (15% MeOH/CH2Cl2) gives 1.1 g (92%) of title compound as a solid, mp 180-182° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([O:29]C)=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(Cl)(Cl)Cl.CO>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([OH:29])=[O:28])[CH:21]=[CH:20]3)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cc(-c3ccc(CCN(C[C@H](O)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A mixture of methyl 6-[4-[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenyl]-2-naphthoate (105 mg) and 1N sodium hydroxide (0.375 ml) in 1,4-dioxane (1 ml) was stirred at room temperature for 12 hours. To the resulting mixture were added 1N hydrochloric acid (0.375 ml) and chloroform-methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chlorofom/methanol=10/1) to give 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-naphthoic acid (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[N:17]=1.[OH-].[K+].C1COCC1>O>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[N:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1
Yield: 110.2 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g), KOH (0.400 g), THF (5.0 mL), and water (5 mL) to afford 0.350 g of the desired product.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.[ClH:34]>C(#N)C.CC(C)=O>[ClH:25].[ClH:34].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1ccc(CN2CCN(c3cccc(-c4ccccc4)c3)CC2)cc1
Reaction time: 16 h

Procedure:
To a solution of 3-[1-piperazinyl]biphenyl (11.9 g) in aceonitrile (200 cc), there is added potassium carbonate (6.9 g) and then, in the course of 20 minutes, a solution of α-chloro-p-xylene (8 g) in acetonitrile (50 cc), at a temperature in the region of 20° C., and stirring is continued for 16 hours. The insoluble material which has formed is separated by filtration. The solution obtained is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (30 cc) and the solution poured onto silica (1 kg) contained in a column 8 cm in diameter. Elution is performed with a mixture (3 liters) of methylene chloride and methanol (97.5:2.5 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetone (600 cc). The solution is cooled to a temperature in the region of 5° C., 2.5N ethereal hydrogen chloride (40 cc) is added and stirring is maintained for approximately 1 hour. The precipitate formed is separated by filtration and washed with acetone (2×40 cc). 3-[4-(4-Methylbenzyl)-1-piperzinyl]biphenyl dihydrochloride (17.3 g), m.p. 241° C., is thereby obtained.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:42]=[CH:41][C:31]([NH:32][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:43])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:44]1C=C[CH:47]=[CH:46][CH:45]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.C(N(C(C)C)[P:66]([N:72]([CH:76]([CH3:78])[CH3:77])[CH:73]([CH3:75])[CH3:74])[O:67]CCC#N)(C)C>C(Cl)Cl>[C:45]([CH2:46][CH2:47][PH:66]([O:43][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:26][C@@H:25]([N:27]2[CH:42]=[CH:41][C:31]([NH:32][C:33](=[O:40])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:30][C:28]2=[O:29])[CH2:24]1)([N:72]([CH:73]([CH3:74])[CH3:75])[CH:76]([CH3:77])[CH3:78])[OH:67])#[N:44]
Reactant: c1ccncc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)n1)c1ccccc1
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: CC(C)N(C(C)C)[PH](O)(CCC#N)O[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
402 mg (0.7 mmol) of 5'-O-trityl-N-benzoyl-2'-deoxycytidine [prepared as described in step (a) above] were dried by azeotropic distillation with pyridine and then dissolved in 3.5 ml of methylene chloride. 60 mg (0.35 mmol) of diisopropylammonium tetrazolide were added to the solution. 245 μl (0.77 mmol) of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite were then added dropwise, under an atmosphere of argon. The resulting mixture was stirred at room temperature for 3.5 hours under same atmosphere. At the end of this time, the methylene chloride was removed by distillation under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed with a 10% w/v aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through 23 g of silica gel (70-230 mesh), using ethyl acetate as the eluent, to give 337 mg (yield 62%) of the title compound as a foam substance.
Reaction SMILES: [CH2:1]=O.[ClH:3].[CH3:4][NH:5][CH3:6].[CH3:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[CH3:18])[C:14](=[O:19])[CH2:13][CH2:12][CH2:11]2>C(OC(=O)C)(=O)C>[ClH:3].[CH3:4][N:5]([CH2:1][CH:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:17]([CH3:18])=[C:8]([CH3:7])[CH:9]=2)[C:14]1=[O:19])[CH3:6]
Reactant: C=O
Reactant: CNC
Reactant: Cc1cc2c(cc1C)C(=O)CCC2
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1cc2c(cc1C)C(=O)C(CN(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
A mixture of 37% formalin (18 g) and dimethylamine hydrochloride (18 g) was stirred at 25° C. for 30 minutes, and stirred at 70° C. for 30 minutes. The reaction temperature was raised to 80° C., and to the mixture was added dropwise acetic anhydride (80 ml). The reaction mixture was stirred at 80° C. for one hour, and thereto was added 3,4-dihydro-6,7-dimethyl-1(2H)-naphthalenone (26 g). The reaction temperature was raised to 90° C., and the mixture was stirred for 6 hours. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue was added acetone. The precipitated crystals were collected by filtration, and washed with acetone to give 2-dimethylaminomethyl-3,4-dihydro-6,7-dimethyl-1(2H)-naphthalenone hydrochloride (39 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl[C:26]([O:29]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[Cl:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]([O:44][C:45]2[CH:46]=[C:47]3[C:51](=[CH:52][CH:53]=2)[NH:50][CH:49]=[CH:48]3)[CH:39]=1.N>C(Cl)Cl>[Cl:37][C:38]1[N:43]=[CH:42][N:41]=[C:40]([O:44][C:45]2[CH:46]=[C:47]3[C:51](=[CH:52][CH:53]=2)[N:50]([C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)=[O:29])[CH2:49][CH2:48]3)[CH:39]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: Clc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Reaction time: 0.5 h

Procedure:
A solution containing 5-amino-2-(4-morpholinyl)benzotrifluoride (3.16 g, 12.8 mmol) and triethylamine (2.48 mL, 17.8 mmol) in CH2Cl2 (87 mL) is added dropwise to a stirred solution of bis(trichloromethyl)carbonate (1.26 g, 4.25 mmol) in CH2Cl2 (43 mL) at 0° C. After 30 min, a solution containing 5-[(6-chloro-4-pyrimidinyl)oxy]-1H-indole (Intermediate IVa; 3.48 g, 14 mmol) and triethylamine (1.96 mL, 14 mmol) in CH2Cl2 (52 mL) is added dropwise. After stirring for a further 15 min an aqueous solution of ammonia (100 mL of 2.5%) is added and the mixture is extracted with CH2Cl2. The combined extracts are washed with saturated aqueous NaCl, dried (K2CO3) and the solvent is evaporated off under reduced pressure to afford a crude product which is recrystallised from EtOH to give the title compound as a colourless crystalline solid: NMR (400 MHz; DMSO-d6) δ 2.11 (m, 4H), 3.20 (t, J=8.3 Hz, 2H), 3.68 (m, 4H), 4.16 (t, J=8.5 Hz, 2H), 6.96 (dd, J=8.6 Hz, J=2.5 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.28 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.84 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 8.62 (s, 1H) and 8.77 (s, 1H).