Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([OH:31])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure B, from #5 (1.62 g, 2.79 mmol, 1 eq.), dichloromethane (10 mL, 0.3 M) and trifluoroacetic acid (3 mL) was synthesized #@5 (1.42 g, 97%) as a solid which was used without further purification. LC-MS m/z 525.3 [M+H+] 547.3 [M+Na+] retention time=0.95 minute; 1H NMR (400 MHz, DMSO-d6), characteristic signals: δ 7.89 (d, J=7.6 Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (dd, J=7.6, 7.4 Hz, 2H), 7.28-7.34 (m, 2H), 4.14-4.32 (m, 4H), 3.24 (s, 3H), 2.92 (br s, 3H), 2.51-2.57 (m, 1H, assumed; partially obscured by solvent peak), 2.20 (dd, J=15.9, 9.5 Hz, 1H), 1.95-2.06 (m, 1H), 1.70-1.83 (br m, 1H), 1.22-1.36 (br m, 1H), 0.84-0.93 (m, 9H), 0.70 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:21][CH2:22][N:23]([C:6]([C:5]2[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=2[CH3:11])=[O:8])[CH2:24][CH2:25]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1ccc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 83.3 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (607 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (870 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:27][CH2:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C(=C\c1ccc(C)cc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CCl4 (1 mL) under N2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was stirred at reflux under N2 for 1.5 hours. The mixture was cooled to room temperature, diluted with Et2O and filtered to remove the precipitated succinimide. The filtrate was concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1.[H][H]>[Pd]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=1
Reactant: Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(-c2cccs2)cc1N
Yield: 89.5 %

Procedure:
To a solution of 4-thienyl-2-nitroaniline (1 equiv, 400 mg, 1.82 mmol) was added 10% Pd/C (0.05 equiv, 97 mg, 0.09 mmol). The resulting suspension was stirred for overnight over 1 atm of hydrogen. The solids were filtered through celite pad and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography with gradient of MeOH (0-10%) in CH2Cl2 to afford compound 30 (310 mg, 90%) and a white solid. LRMS (ESI): (calc) 190.2 (found) 191.0 (MH)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[Cu](C#N)[C:28]#[N:29]>CN(C)C=O.[Cl-].[NH4+].[OH-].[NH4+]>[C:28]([C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1)#[N:29]
Reactant: N#C[Cu]C#N
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1cc(C#N)ccc1OC2)c1ccc(F)cc1F
Yield: 79.3 %

Procedure:
A solution of 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp (33.7 mg, 0.0772 mmol, 1 equiv) and copper cyanide (22 mg, 0.24 mmol, 3.2 equiv) in N,N-dimethylformamide (1 mL) was heated at 250° C. in the microwave for 30 min. The reaction mixture was diluted with 9:1 saturated aqueous ammonium chloride solution/ammonium hydroxide (10 mL). The resulting mixture was extracted with dichloromethane (3×5 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (11:4/hexanes:ethylacetate) provided 161bp as a white solid (23.4 mg, 79%). 1H NMR (500 MHz, CDCl3) δ 7.40-7.42 (m, 2H), 7.32 (m, 1H), 6.99 (t, J=8.1 Hz, 1H), 6.92 (m, 1H), 6.88 (s, 1H), 5.23 (s, 2H), 3.40 (s, 3H). LCMS (ESI) m/z: 383.1
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[CH3:35][S:36]([O-:38])=[O:37].[Na+]>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][S:36]([CH3:35])(=[O:38])=[O:37])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reactant: CS(=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.11 g) was added to a solution of the product from Example 27 step b) (0.2 g) in DMF (5 ml), and the solution stirred for 10 min. Sodium methanesulfinate (63 mg) was then added and the mixture stirred for a further 3 hours. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (50 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cnc(Cl)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cnc(Cl)nc1
Yield: 35.7 %

Procedure:
A solution of 2-chloro-5-ethylpyrimidine (1.15 g, 8.1 mmol) in 20 mL of carbon tetrachloride was treated with N-bromosuccinimide (1.50 g, 8.4 mmol) and a catalytic amount (about 1 mol percent based on reactants) of benzoyl peroxide and then heated to 75° C. After several hours and additional catalyst, the starting material was completely consumed. The solids were removed and the filtrate was concentrated. The resulting residue was further purified by flash column chromatography on silica gel using a mixture of ethyl acetate (EtOAc) and petroleum ether as the eluant. The solvents were removed under reduced pressure to yield 0.64 g (36%) of 5-(1-bromoethyl)-2-chloropyrimidine (A) as a clear liquid: 1H NMR (CDCl3) δ 8.70 (s, 2H), 5.15 (q, J=8.0 Hz, 1H), 2.10 (d, J=8.0 Hz, 3H); GCMS (FID) m/z 222 (M+). Some of the corresponding dibromo compound 0.44 g (18%) was also isolated, as a white solid: mp 84-85° C.; 1H NMR (CDCl3) d 9.00 (s, 2H), 3.00 (s, 3H); LC-MS (ESIMS) m/z 298 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1>>[O:30]=[C:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]1[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(N3C(=O)CCc4ccccc43)c2)c1C(=O)OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene and 2-oxo-1,2,3,4-tetrahydroquinoline are treated in the same manner as in Example 6-(2) to give 1-[2-(2-oxo-1,2,3,4-tetrahydroquinolin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16]CC)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:19])[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(Cl)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1-c1ccccc1C(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A mixture of ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate (27.10 g), ethanol (60 ml) and 1N aqueous sodium hydroxide solution (120 ml) was stirred at 100° C. for 2 hr. To the reaction mixture was added 8N aqueous sodium hydroxide m solution (10 ml), and the mixture was further stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with 33 v/v % ethanol-water (100 ml). The filtrate was adjusted to pH 2 with formic acid (23 ml) and the mixture was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was air-dried for 1 hr and dried under reduced pressure at 60° C. to give the title compound (22.082 g, 91%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[NH2:17][C:18]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:44])[CH2:19][NH:20][C:21](=[O:43])[CH2:22][N:23]1[C:27](=[O:28])[N:26]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[N:24]1>ClCCl>[C:10]([NH:17][C:18]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:44])[CH2:19][NH:20][C:21](=[O:43])[CH2:22][N:23]1[C:27](=[O:28])[N:26]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[N:24]1)(=[O:12])[CH3:11]
Reactant: CC(N)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC(C)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
At RT, 12 μl (68 μmol) of N,N-diisopropylethylamine and then 6 μl (62 μmol) of acetic anhydride were added to a solution of 38 mg (62 μmol) of the compound of Example 53A in 0.96 ml of dichloromethane, and the mixture was stirred for 1 h. The volatile components were then removed on a rotary evaporator. Since LC/MS analysis of the crude product indicated additional formation of an O-acetylated byproduct, the residue was dissolved in 2 ml of methanol and 800 μl of 2 N aqueous sodium hydroxide solution were added. After 72 h, the mixture was acidified with 1 N hydrochloric acid and separated by preparative HPLC [Method 8]. In this step, the two product diastereomers were obtained in separated form. This gave 6 mg (16% of theory) of the title compound (Diastereomer 1) and 7 mg (19% of theory) of the second diastereomer (see Example 39).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:27])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:8]=1[CH3:26]>C1COCC1.CO>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:27])=[O:4])=[C:8]2[CH3:26])=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Aqueous NaOH (1.18 ml) is added to a stirring suspension of [2-methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.2 g, 0.54 mmol) in 4:1 THF/MeOH (5 ml). The reaction mixture is allowed to stir at room temperature for 4 hours and then the solvent is removed in vacuo. The crude residue is dissolved in 1:1 THF/water and acidified to pH 3-4 using 6M HCl. After stirring for 30 minutes the resulting suspension is filtered and dried in vacuo at 110° C. to yield the titled product as a yellow solid. (MH+ 326)
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)/[CH:25]=[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])\[CH3:27]>O>[CH3:27]/[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[CH:25]\[CH2:24][O:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:6])[CH:16]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
In 80 m of DMF were poured 13.1 g (78.0 mmol) of methyl 2,4-dihydroxybenzoate and 18.9 g (86.9 mmol) of potassium carbonate, and 12.0 g (86.9 mmol) of geranyl bromide was added thereto dropwise at 5° C. After the addition, the mixture was stirred at room temperature for 1 hour, poured into 300 ml of water, and extracted with 250 ml of ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography to obtain 18.1 g (yield: 75%) of methyl 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 31) as a colorless, clear and oily substance. The analytical results are shown below. ##STR52##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:43][C:44]1[C:45](F)=[CH:46][C:47]([F:71])=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][N:55]=2)(=[O:52])=[O:51])[CH:49]=1>CS(C)=O>[Cl:43][C:44]1[CH:49]=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][N:55]=2)(=[O:51])=[O:52])[C:47]([F:71])=[CH:46][C:45]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of tert-butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 114, 200 mg, 0.401 mmol) in dimethyl sulfoxide (5 mL) was added potassium carbonate (111 mg, 0.802 mmol) followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (Preparation 110, 182 mg, 0.401 mmol). The reaction mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 30% heptane in ethyl acetate to give the title compound (320 mg, 85%) as yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=c1[nH]ncc2ccc(O)cc12
Product: O=c1[nH]ncc2ccc(OCC3CO3)cc12

Procedure:
7-Hydroxy-1(2H)-phthalazinone was reacted with epibromohydrin in a similar manner to that described in Example 1(iii) to give 7-(2,3-epoxypropoxy)-1(2H)-phthalazinone, which after recrystallisation from ethyl acetate had m.p. 164°-166°.
Reaction SMILES: C(C1CC1CCC(Cl)=O)C(C)C.C1(C(Cl)=O)CCCCC1.[C:22]([NH:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](=[O:47])[CH2:38][CH2:39][CH:40]2[CH2:42][CH:41]2[CH2:43][CH:44]([CH3:46])[CH3:45])=[C:32]([O:48][C:49](=[O:59])[CH2:50][CH2:51][CH:52]2[CH2:54][CH:53]2[CH2:55][CH:56]([CH3:58])[CH3:57])[CH:31]=1)=[O:29])([CH3:25])([CH3:24])[CH3:23]>>[CH2:55]([CH:53]1[CH2:54][CH:52]1[CH2:51][CH2:50][C:49]([O:48][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][C:37](=[O:47])[CH2:38][CH2:39][CH:40]1[CH2:42][CH:41]1[CH2:43][CH:44]([CH3:46])[CH3:45])[CH:28]([OH:29])[CH2:27][NH:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:59])[CH:56]([CH3:57])[CH3:58]
Reactant: CC(C)CC1CC1CCC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)CCC1CC1CC(C)C
Agent: CC(C)CC1CC1CCC(=O)Cl
Agent: O=C(Cl)C1CCCCC1
Product: CC(C)CC1CC1CCC(=O)Oc1ccc(C(O)CNC(C)(C)C)cc1OC(=O)CCC1CC1CC(C)C

Procedure:
When 2-isobutylcyclopropanepropionyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2-isobutylcyclopropanepropionyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2-isobutylcyclopropanepropionyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=2)=[C:4]([F:26])[CH:3]=1.O.[C:28]1(C)C=CC(S(O)(=O)=O)=C[CH:29]=1>C(O)CC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:28][CH3:29])=[O:11])=[CH:6][C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=2)=[C:4]([F:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 342 %

Procedure:
To a solution of 100 mg of 3-{4-chloro-2-fluoro-5-[(methoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-165) in 1.0 ml of propanol was added 10 mg of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the excess propanol was distilled out under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 76 mg (yield, 71%) of 3-{4-chloro-2-fluoro-5-[(propoxycarbonyl)methoxy]phenyl}-1-methyl-6-trifluoromethyl-2-oxo -1,2-dihydropyrazine (present compound 1-167).
Reaction SMILES: [C:1](/[C:3](=[N:23]\[OH:24])/[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].Cl.[NH2:26]O.C([O-])(O)=O.[Na+].[OH-].[Na+]>CCO.O.[Cl-].[Na+].O>[NH2:2][C:1]1[C:3]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)=[N:23][O:24][N:26]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(/C(C#N)=N/O)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3N)cc2)CC1
Temperature: 25 °C

Procedure:
To tert-butyl 4-{4-[(Z)-cyano(hydroxyimino)methyl]phenyl}piperazine-1-carboxylate (1.39 g, 4.21 mmol) in EtOH (50 mL) was added an aqueous solution of pre-mixed hydroxylamine hydrochloride (440 mg, 6.32 mmol) and NaHCO3 (535 mg, 6.32 mmol) in water (15 mL) and the reaction was refluxed overnight. An additional aliquot of hydroxylamine hydrochloride (440 mg, 6.32 mmol) and NaHCO3 (535 mg, 6.32 mmol) in water (10 mL) was added and the reaction was refluxed for 2 hours. Aqueous NaOH (1.0 M, 42.1 mL) was added and the reaction was refluxed for 1 hour. An additional aliquot of NaOH (1.0 M, 21 mL) was added and the reaction was refluxed for 3 hours. After cooling to rt, the reaction mixture was poured into brine and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6) to afford tert-butyl 4-[4-(4-amino-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(OC2CCN(C[C@H]3CN(c4ccc(OC)cc4)C(=O)O3)CC2)cc1
Solvent: CS(C)=O
Product: COc1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-methoxyphenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 249°-250°; [α]D =-27.8° (DMSO);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:30]=[O:31])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(CNc2ccc(Br)c(Cl)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amine (539, 2.60 g, 7.83 mmol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 4.20 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C. tert-Butyllithium (1.70 M in hexane, 10.2 mL) was added to the reaction over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.80 mL, 0.0232 mol) was added to the reaction. The reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for another 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid (540, 1.0 g, 45.4%). MS (ESI) [M−H+]−=279.0.