Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21]Cl)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13])[CH3:17]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(CCCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CCC(C#N)c1ccc(OC)c(OC)c1)OCC
Reaction time: 1 h

Procedure:
An optionally substituted phenylacetonitrile is then alkylated with an ω-halopropionaldehyde acetal using a strong metallic base, in a polar, aprotic solvent. The desired phenylacetonitrile derivative is first deprotonated by adding about 1 eq of a strong metallic base, e.g., NaH, in a polar aprotic solvent at 15°-21° C. over 25-50 minutes. The resulting mixture is then stirred for 1-3 hours, and about 1 eq of 3-chloropropionaldehyde diethylacetal is added to yield a derivative of formula 5 (step 3). For example, 2-(3,4-dimethoxyphenyl)acetonitrile in dimethyl formamide (DMF) is added to NaH at 18°-20° C. over a 30 minute period, stirred for one hour, and then treated with 3-chloropropionaldehyde diethylacetal in DMF to yield 2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[NH2:13][C:14]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:15]=1[NH:16]C.Br.O>C(O)(=O)C>[CH3:22][C:20]1[CH:21]=[C:14]2[C:15](=[CH:18][CH:19]=1)[N:16]=[C:6]1[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[C:5]1=[N:13]2
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CNc1ccc(C)cc1N
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2nc3[nH]c4ccc(Br)cc4c3nc2c1
Reaction time: 2 h

Procedure:
A solution of 2.26 g 5-bromoisatin (0.01 mole) and 1.36 g 2-amino N-methyl-p-toluidine (0.01 mole) in 15 ml acetic acid is boiled with reflux for 45 minutes. Finally hydrogen bromide is introduced and the mixture is boiled for further 2 hours. After cooling it is poured into water. The dried reaction product is recrystallized from acetic acid.
Reaction SMILES: [OH-].[Na+].[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([O-:6])([O-:5])=[O:4].[Na+].[Na+].[N+]([O-])(O)=O>O>[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([OH:5])([OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O

Procedure:
To 22.5 ml of a 0.67 M aqueous solution of cis-[Pt(NH3)2 -(H2O)](NO3)2, the pH of which had been adjusted to 4 with sodium hydroxide, there was added 4.23 grams disodium D-glucose-6-phosphate dissolved in 30 ml of water. The pH of the reaction mixture was then adjusted to 5.0 using 2 M nitric acid. The solution was stoppered, and stirred for 42 days as in the previous examples. The above-identified, water-soluble blue complex was isolated by the method described in Example 1 in a yield of 2.69 grams.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([C:27](=[O:29])[NH2:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[CH3:32])C=CC=CC=1.CS(C)=O.[CH2:38]([NH2:40])[CH3:39].O1CCCC1>C(OCC)(=O)C.O>[C:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:30][CH3:31])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:40][CH2:38][CH3:39])=[O:7])=[C:11]([CH3:32])[CH:12]=1)(=[O:29])[NH2:28]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C)c3)c2cc1C(N)=O
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)cc1C
Reaction time: 0.08 h

Procedure:
[4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-methyl-phenyl]-carbamic acid phenyl ester (65 mg) was added to dimethylsulfoxide (1.0 ml), and then an ethylamine-containing 2N tetrahydrofuran solution (0.37 ml) was added and the mixture was stirred for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered out to obtain the title compound (38 mg).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccccc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
4-Iodobenzoic acid (3.0 g, 11.58 mmol) was suspended in CH2Cl2 (50 mL). Oxalyl chloride (2.20 mL, 23.71 mmol) was added dropwise, followed by addition of three drops of DMF. The reaction mixture was stirred at room temperature for 3 h. CH2Cl2 and the excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (35 mL) with anisole (1.70 mL, 15.41 mmol). Cooled in an ice bath, AlCl3 (2.40 g, 17.78 mmol) was added in portions. The mixture was stirred at 0° C. for 3 h, poured into 1 N HCl (50 mL) with ice, the mixture was extracted with CH2Cl2 (2×100 mL). The combined CH2Cl2 extract was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown solid. The crude product was triturated with hot hexanes to give 3.91 g (98%) of compound 142 as light beige solid. 1H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H). LCMS (APCI): m/z, 339 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>ClCCl>[C:31]([NH:35][S:19]([CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])[CH2:12][CH2:13]1)(=[O:21])=[O:20])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)CCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
To a stirred solution of [4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexyl]-ethanesulfonyl chloride (60 mg, 0.12 mmol) (Example 105) in dichloromethane (5 mL) was added tert-butylamine (0.065 mL, 0.62 mmol), the mixture stirred at ambient temperature for 45 minutes, then evaporated. The residue was taken up in ethyl acetate (20 mL) and washed with 2N aqueous hydrochloric acid (20 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica eluting with diethyl ether:dichloromethane:iso-hexane 1:1:2 to afford the desired product (35 mg). MS (ES+) 556 ([MNa]+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][OH:32])=[N:24][CH:25]=1>>[OH:32][CH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: Nc1ccc(N2CCC[C@H]2CO)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CCC[C@H]2CO)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and [(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol. LCMS calcd for C21H19F3N4O3 (m/e) 432, obsd 433 (M+H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][C@H:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C@@H:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C[C@@H]1COCCO1
Agent: Cl
Product: O=C(C[C@@H]1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (52 mg, 71%), MS (ISP) m/z=459.5 [(M+H)+], mp 181° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) (R)-2-(1,4-dioxan-2-yl)acetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][CH2:22][CH2:21][C:20]=3[CH:24]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:23]1[C:19]2[CH:18]=[CH:17][C:16]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[CH:24][C:20]=2[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To a solution of 4-(2,3-dihydro-benzofuran-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.5 mmol) in 10 mL of DCM, was added 1 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours, then solvent was removed by reduced pressure to yield the title product (0.3 g, 1.2 mmol, 77% yield). MS (ESI) m/z 232.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.14 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([NH:39][CH:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccc(F)cc5c4)c3n2)CC1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (531.3 mg, 0.93 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (556.6 mg, 2.78 mmol), NaHCO3 (467.2 mg, 5.56 mmol) in NMP (10 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-ylamino)piperidine-1-carboxylate: LCMS tR=3.24 Min (5 min run, UV254nm), Mass calculated for M+737.4, observed m/z 738.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].[OH2:30]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:30])[CH:10]([OH:9])[C:11](=[CH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:2]
Reactant: C=C(CCCCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OCC
Reactant: O
Solvent: C1CCOC1
Product: C=C(CCCCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OCC

Procedure:
8.15 g (20.25 mmol) of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester are heated under reflux in 40 ml of tetrahydrofuran and 20 ml of water for 4 hours with stirring. The reaction mixture is concentrated to dryness by evaporation in vacuo at 45°, and the honey-like residue is concentrated by evaporation twice more after the addition of toluene. The crude product is dissolved in dichloromethane, dried with sodium sulfate, filtered and concentrated by evaporation. Drying under a high vacuum at room temperature yields 9.03 g of 10-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-decanoic acid ethyl ester in the form of a yellowish honey.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[C:12]([C:18]([O-:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:11].C1(OC2C=CC=CC=2)C=CC=CC=1>>[OH:20][C:18]1[C:5]2[C:4](=[C:3]([C:2]([F:1])([F:22])[F:21])[CH:8]=[CH:7][CH:6]=2)[N:9]=[C:10]([CH3:11])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C(=O)[O-])=C(C)Nc1ccccc1C(F)(F)F
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(C)nc2c(C(F)(F)F)cccc2c1O
Temperature: 240 °C
Yield: 61.3 %

Procedure:
A suspension of 5 g of the product of Step A and 10 g of phenyl oxide was heated to 240° C and was then cooled to room temperature. The phenyl oxide was evaporated and the resulting crystals were added to 20 ml of isopropyl ether. The mixture was filtered to obtain 2.9 g of ethyl 4-hydroxy-2-methyl-8-trifluoromethyl-quinoline-3-carboxylate melting at 165° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[OH-].[Na+]>C(O)C>[C:17]1([CH2:16][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([OH:27])=[O:3])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Yield: 97.9 %

Procedure:
To a solution of 2.05 g of 2-(1-naphthylmethyl)-6-phenylhexanoic acid ethyl ester in 30 ml of ethanol was added 10 ml of a 2N-aqueous sodium hydroxide solution. The mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was washed with diethyl ether to remove neutral materials. Then, the aqueous layer was acidified by adding concentrated hydrochloric acid. The solution was extracted with diethyl ether, and the ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.85 g of 2-(1-naphthylmethyl)-6-phenylhexanoic acid as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.[CH3:20][O:21][C:22]([C@@H:24]1[CH2:26][C@H:25]1[CH2:27]OS(C)(=O)=O)=[O:23].C(N(CC)CC)C>C(#N)C>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:26][C@H:25]1[CH2:27][N:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:17][C:7]=3[S:8][CH:9]=2)[CH2:16][CH2:15]1)=[O:23]
Reactant: FC(F)(F)c1ccc2c(N3CCNCC3)csc2c1
Reactant: COC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1

Procedure:
Heat at reflux for 16 h, a mixture of 1-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazine, free base of Example 2b, (23.0 g, 71.3 mmol), trans-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester (Example 5a) (15.3 g, 73.5 mmol), and triethylamine (40 mL, 288 mmol) in acetonitrile (600 mL). Concentrate the reaction mixture under reduced pressure and dilute the resultant oil with EtOAc (30 mL). Filter the resulting precipitate (unreacted starting piperazine) away and purify the filtrate by column chromatography over silica gel (EtOAc/heptane/MeOH/triethylamine, 20:20:1). Concentration of the appropriate fractions gives 18.0 g of colorless oil, m/z=413 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.[F:20][C:21]1[CH:49]=[CH:48][C:24]([CH2:25][NH:26][C:27](=[O:47])[C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39](I)=[CH:38]3)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.CN(C=O)C>O.CCOC(C)=O>[F:20][C:21]1[CH:49]=[CH:48][C:24]([CH2:25][NH:26][C:27](=[O:47])[C:28]2[CH:29]=[CH:30][C:31]([S:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:39]([C:6]4[CH:11]=[N:10][CH:9]=[CH:8][N:7]=4)=[CH:38]3)(=[O:36])=[O:35])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3cnccn3)c3ccccc32)cc1
Reaction time: 16 h

Procedure:
Degas DMF with N2 for 30 minutes. Add 2-tributylstannyl pyrazine (0.214 g, 0.58 mmol), N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide 0.300 g, 0.56 mmol) and tetrakis(triphenylphosphine)Pd(0) (0.100 g, 0.086 mmol) to DMF (5.0 ml). Heat and stir at 100° under N2 for 16 h. Pour the reaction mixture into H2O-EtOAc. Separate the EtOAc layer and extract several times with H2O, wash with brine, dry (MgSO4) and filter through celite. Remove the solvent on the rotary evaporator to give an oil. Chromatograph on the chromatron using a 1 mm plate and elute with 1% CH3OH—CH2Cl2 to give the title compound. Mass spectrum (m/e) (M+H) 487.1240; found: 487.1220.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27]([CH3:29])([CH3:28])[C:26](=[O:30])[N:25](CC5C=CC(OC)=CC=5)[C:24]4=[O:40])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27]([CH3:28])([CH3:29])[C:26](=[O:30])[NH:25][C:24]4=[O:40])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1ccc(CN2C(=O)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C(C)(C)C2=O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4(C)C)cc3)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
To a mixture of (4-bromophenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165, 3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (119 mg) described in Preparation Example 53, cesium carbonate (260 mg) and copper(I) iodide (38 mg) were added toluene (8 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was stirred with heating under reflux for 29 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione. The obtained 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione was dissolved in 1,2-dichloroethane (4 mL), trifluoromethanesulfonic acid (92 μL) was added and the mixture was stirred at 80° C. for 13 hr. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform/methanol (10:1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (34 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10]Br.O>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1cccc(O)c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), was added bromine (45 mL, 845 mmol) in chloroform (200 mL) drop wise over a period of 2 h at room temperature. The reaction mixture was stirred at room temperature overnight and filtered to collect crude 2-bromo-5-hydroxy benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 mL, filtered through a pad of Celite and silica gel (40 g) and washed with ether (1000 mL). The filtrate was concentrated in vacuo to give a second crop of the crude desired aldehyde (60 g) as a dark brown solid. The above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135° C.