Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26](=[O:32])[C:27](OCC)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(=O)C([NH:71][CH2:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[O:80][CH3:81])=O)C=CC=1OC1C=CN=C2C=C(C3C=CC(OCCN4CCOCC4)=C(OC)C=3)SC=12>>[CH2:23]([N:21]1[CH:22]=[C:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:25][C:26](=[O:32])[C:27]([NH:71][CH2:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=4[O:80][CH3:81])=[O:28])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:19]=[CH:20]1)[CH3:24]
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CC)cn4)sc23)c(F)c1
Reactant: COc1ccccc1CCNC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)C(=O)NCCc5ccccc5OC)cc4F)c3s2)c1
Yield: 90 %

Procedure:
Starting from the amino ester 142 and following the same procedure as described for the synthesis of compound 136 (example 52, scheme 40), title compound 141 was obtained as white solid in 90% yield. 1H NMR (DMSO-d6) δ (ppm): 11.04 (s, 1H), 9.06 (t, J=6.4 Hz, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.02 (dd, J=2.4 and 12.8 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.84-7.78 (m, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.67 (s, 1H), 7.52 (t, J=5.2 Hz, 1H), 7.20 (td, J=1.6 and 8.0 Hz, 1H), 7.14 (dd, J=1.6 and 7.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.79 (s, 3H), 3.42 (q, J=7.2 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 1.40 (7.2 Hz, 3H). MS (m/z): 560.2 (M+H).
Reaction SMILES: [Li].[N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:22][C:23]1([CH3:34])[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:22][C:23]1([CH3:34])[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]=[CH:3][N:4]=[CH:5]4)=[CH:30][CH:31]=2)[NH:26][CH2:25][CH2:24]1
Reactant: CC1(C)CCNc2cc(N)ccc21
Reactant: O=C(O)c1ccccc1Nc1ccc2ncncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCNc2cc(NC(=O)c3ccccc3Nc3ccc4ncncc4c3)ccc21

Procedure:
A mixture of the lithium salt of 2-(quinazolin-6-ylamino)-benzoic acid (Step B, 533 mg, 0.72 mmol), 4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine (127 mg, 0.72 mmol), TBTU (462 mg, 1.44 mmol) and DIEA (0.25 mL, 1.44 mmol) in 3 mL of DMF was submitted to microwave irradiation (80° C., 30 min). Water (5 mL) was added to the mixture, and the resultant precipitate was filtered and dried. The crude material was purified with flash chromatography (SiO2, 50% EtOAc/hexane) to afford a white solid. MS (ES+): 424.0 (M+H)+. Calc'd for C26H25N5O: 423.51.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([OH:20])[C:18]=1[OH:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([S:14][CH3:15])=[S:13])[CH2:8][CH2:7]1.[C:21](Cl)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:20][C:17]1[CH:16]=[C:4]([CH:3]=[C:2]([O:1][C:17](=[O:20])[CH3:16])[C:18]=1[O:19][C:2](=[O:1])[CH3:18])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([S:14][CH3:15])=[S:13])[CH2:10][CH2:11]1)(=[O:23])[CH3:22]
Reactant: CSC(=S)N1CCN(Cc2cc(O)c(O)c(O)c2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CSC(=S)N1CCN(Cc2cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c2)CC1
Yield: 113 %

Procedure:
To 395 mg (1.0 mmol.) of methyl 4-(3,4,5-trihydroxybenzyl)-1-piperazinecarbodithioate was added 2 ml of dry pyridine. To the resulting suspension was added 0.22 ml (3.1 mmol.) of acetyl chloride under chilling with ice. The mixture was then stirred, and further stirred overnight at room temperature. The mixture was then extracted with ethyl acetate after addition of water. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and processed to distill off the solvent. The residue was purified by silica gel column chromatography and crystallized from ether to give 249 mg of the desired compound as a white crystalline product, m.p. 141°-143° C., yield 63.4%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: COCCNCCOC
Product: COCCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 5, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and bis(2-methoxyethyl)amine were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-bis-(2-methoxy-ethyl)-amine as light yellow oil, MS: 493 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ncccn1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=C(c1ncccn1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.43 (s,1H), 7.45 (m, 1H), 7.50 (m,1H), 7.55 (m,1H), 7.64 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97 (s, 1H), 8.86 (d, 2H), 10.63 (s, 1H). MS: m/z441.9 (M++1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[CH:30][CH:31]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Under ice-cooling, to a solution of methyl 4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzoate (535 mg, 1.25 mmol) in tetrahydrofuran (20 mL) was added 1.5M diisobutyl aluminum hydride toluene solution (2.4 mL, 3.64 mmol). The mixture was stirred at room temperature for 2 hr and sodium sulfate 10 hydrate (1.29 g, 4 mmol) was added. The mixture was stirred at room temperature for 1 hr. The resulting insoluble materials were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:3) to give the title compound (409 mg, yield 81%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH-].[K+].[SH2:13]>CO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[SH:13])([O-:10])=[O:9]
Reactant: S
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cnccc1S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-chloro-3-nitropyridine (18 g, 0.114M) was added to a cooled solution of 10 g of potassium hydroxide and 70 mL of methanol saturated with hydrogen sulfide. The reaction stirred for 2 hours at 25° C. and the solvents were removed by vacuum. The residue was acidified and filtered. (mp. 132° C.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1Cl

Procedure:
The sub-title compound was prepared by the method of example 9 step (i) using 4-bromo-2-chlorobenzenesulfonyl chloride and benzene.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([Cl:5])=[CH2:4].Br[C:7]1[C:8]([O:10][C:11](=[O:13])[CH:12]=1)=[O:9]>>[Cl:5][C:3]1[CH2:4][C:12]2[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=2[CH2:1][CH:2]=1
Reactant: C=CC(=C)Cl
Reactant: O=C1C=C(Br)C(=O)O1
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 50 °C

Procedure:
Chloroprene (13.6 g) and bromomaleic anhydride 14.6 g) were added together and the solution was heated to 50° C. for 11.5 hours. The reaction mixture was taken up in hot petroleum ether (bp 60° to 80° C.) and filtered. After cooling to room temperature, a solid was collected (6.2 g)- An additional 5 g of material remained in the mother liquors. The material consisted of a mixture of 4-chloro-3,6-dihydrophthalic anhydride, 4-chloro-l-bromo-1,2,3,6-tetrahydrophthalic anhydride and 4-chloro-2-bromo-1,2,3,6-tetrahydrophthalic anhydride.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To LAH (9.11 g, 240 mmol) in THF (100 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (25 g, 160 mmol) in THF (100 mL) dropwise at 0° C. The reaction mixture was left to stir for 30 min at 0° C., and allowed to warm to room temperature. The reaction was monitored by TLC until the ketone was fully converted to the alcohol. The reaction mixture was treated with sodium sulfate decahydrate in small portions, filtered through a pad of Celite, and concentrated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13])([O-])=O>[C].[Pd].CO>[CH2:17]1[N:10]2[C:5]3[C:4]([NH:1][C:12](=[O:13])[C@@H:11]2[CH2:15][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=C(O)[C@@H]1CCCN1c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2N2CCC[C@@H]12
Yield: 83.7 %

Procedure:
The 1-(2-nitrophenyl)-L-proline (1.56 g) obtained in Reference Example 1 was catalytically reduced at ordinary temperature, in the presence of 0.6 g of a 10% palladium-carbon catalyst, in 150 ml of methanol. After completion of the reaction, the catalyst was removed and then the reaction solution was concentrated to dryness to give 1.04 g (yield 83.3%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C(=O)CCl)=[CH:21][CH:20]=1)[CH3:18].Cl.[CH2:32]([OH:34])[CH3:33]>>[ClH:11].[CH2:32]([O:34][C:15](=[O:17])[CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[C:8]=1[Cl:12])[C:2](=[O:1])[C:3]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[CH:23][CH:24]=1)([CH3:18])[CH2:4]2)[CH3:33]
Reactant: CCO
Reactant: CC1(c2ccc(CNC(=O)CCl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(CN)cc1)C2
Temperature: 5 °C

Procedure:
{1-Oxo-2-[4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy}acetic acid (2.0 g., 0.004 mole), absolute ethanol (20 ml.) and 12N hydrochloric acid (7 ml.) are combined and heated at reflux for 3 hours. On cooling to 5° C. 1.14 g. of ethyl[1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride precipitates and melts at 211°-213° C. after crystallization from ethanol.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:51])[CH2:6][N:7]([C:13](=[O:50])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:17]=[C:16]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:15]=1)[CH2:8][C:9]([O:11]C)=[O:10]>>[C:9]([CH2:8][N:7]([C:13](=[O:50])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:17]=[C:16]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:15]=1)[CH2:6][C:5]([OH:51])=[O:4])([OH:11])=[O:10]
Reactant: CCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-[3,5-bis(tetradecyloxy)benzoyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester as in Example 11 gave N-(carboxymethyl)-N-[3,5-bis(tetradecyloxy)benzoyl]glycine, mp 88°-90°.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (27) (J. Org. Chem., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) in DMF (41 mL) was added NaH (60% in mineral oil, 330 mg, 8.3 mmol) in one portion at 0C and the mixture was stirred for 1 h followed by addition of methyl iodide (0.28 mL, 4.5 mmol). The reaction mixture was allowed to warm up to the room temperature, stirred for an additional hour and quenched with AcOH (1 mL) to form a suspension which was stirred for 10 min and concentrated under reduced pressure to give a solid. This material was dissolved in AcOEt, the solution was washed with cold saturated NaHCO3 solution and water, dried over Na2SO4, and concentrated to produce the title compound 28 as a pale yellow solid (640 mg, 93% yield). 1H NMR (400 MHz, CD3OD) δ(ppm): 8.51 (s, 1H), 7.75 (d, J=3.3 Hz, 1H), 6.62 (d, J=3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+1) 168.1 (100%), 170.1 (34%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:28][CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: c1cc(N2CCNCC2)ccc1OC1CCCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(N2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Yield: 91.2 %

Procedure:
A mixture of 1-[4-(tetrahydropyran-2-yloxy)phenyl]piperazine (2.1 g, 8.05 mmol) prepared in Reference Example 184, 4-trifluoromethoxy-1-bromobenzene (1.9 g, 8.05 mmol), palladium acetate (72 mg, 0.32 mmol), BINAP (300 mg, 0.48 mmol) and sodium tert-butoxide (1.0 g, 10.5 mmol) in toluene (30 ml) was refluxed under a nitrogen atmosphere for 5 hours. Ethyl acetate and water were added to the reaction mixture, which was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenyl)piperazine (3.1 g, yield 90%) as a white powder.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([Cl:32])=[CH:34][CH:35]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(CBr)cc1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc(Cl)cc2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 4-chlorobenzylbromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.27-7.34 (m, 2H) 7.19-7.26 (m, 2H) 6.95-7.03 (m, 1H) 6.68-6.80 (m, 1H) 5.69-5.89 (m, 2H) 5.16-5.48 (m, 1H) 4.15-4.27 (m, 2H) 3.64-3.71 (m, 3H) 2.63-2.77 (m, 2H) 2.05-2.16 (m, 2H) 1.93-2.04 (m, 3H) 1.01-1.19 (m, 9H); LCMS (m/z) ES+=549 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]3[CH2:23][CH2:24][CH2:25][N:15]3[CH2:14]2)=[CH:9][CH:8]=1.[I:26]I.CO>CCCCCC.C1COCC1.C(Cl)Cl.CCN(CC)CC>[I:26][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]3[CH2:23][CH2:24][CH2:25][N:15]3[CH2:14]2)=[CH:9][CH:8]=1
Reactant: II
Reactant: Brc1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CO
Product: Ic1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
To a stirred solution of 1.6 M of butyllithium (0.63 mL, 1.0 mmol) in hexane was added slowly a solution of trans-1,2,3,5,6,10b-hexahydro-6-(4'-bromophenyl)pyrrolo[2,1-a]isoquinoline (100 mg, 0.3 mmol) in 5 mL of anhydrous THF at -78° C. under an argon atmosphere. After stirred at -78° C. for 5 min., a solution of iodine (252 mg, 1.0 mmol) in 5 mL of anhydrous. THF was added in one portion. The reaction mixture was stirred at -78° C. for 30 min and then at room temperature for further 15 min, quenched with ice-water (20 mL), extracted with methylene chloride (3×20 mL). The combined methylene chloride extract was washed with 10% sodium bisulfite solution, water, brine, dried over anhydrous MgSO4, filtered and concentrated to afford a yellow oil. Flash chromatography with 2.5% MeOH, 0.05% Et3N in methylene chloride gave 55 mg of thick colorless oil (50% yield). 1H NMR (CDCl3) δ 1.73-2.05 (m, 3H, C2H2 & C1H), 2.30-2.2.44 (m, 1H, C1H), 2.579 (dt, 1H, J=9.0, 8.7 Hz, C3H), 2.869 (dd, 1H, J=5.1, 11.1 Hz, C5H), 2.90-3.03 (m, 2H, C3H & C5H), 3.480 (dd, 1H, J=7.2, 9.0 Hz, C10bH), 4.125 (t, 1H, J=4.8 Hz, C6H), 6.865 (d, 1H, J=7.5 Hz, aryl), 6.995 (d, 2H, J=8.1 Hz, C6 phenyl aryl), 7.04-7.20 (m, 3H, aryl), 7.575 (d, 2H, J=8.1 Hz, C6 phenyl aryl); 13C NMR (CDCl3) δ 22.17 (C2), 30.31 (C1), 45.48 (C3), 54.13 (C10b), 55.95 (C6), 63.67 (C5), 91.60 (4'C), 125.73 (aromatic), 126.30, 129.30, 130.97, 137.23. HRMS calculated 375.0484 (for C18H18NI), measured 375.0490 (relative error 1.6 ppm).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.CN(C)[CH:27]=[O:28].[K+].[Br-]>C(OC)(C)(C)C>[CH3:24][O:23][C:21]1[CH:22]=[C:2]2[C:3]([CH2:4][N:5]([CH:6]3[CH2:11][CH2:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8][CH2:7]3)[C:27](=[O:28])[NH:1]2)=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CNC2CCN(Cc3ccccc3)CC2)c(N)c1
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: COc1ccc2c(c1)NC(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2.5 g (7.682 mmol) of 2-amino-4-methoxy-N-(1-phenylmethyl-4-piperidinyl)-benzylamine, 1.62 g (10 mmol) of N,N′-carbonyldiimidazole, and 25 mL of dimethylformamide was heated to 90° C. with stirring for 2.5 hours. After cooling, the mixture was stirred into 100 mL of ice water, the suspension formed was overlaid with 10 mL of tert-butylmethylether, the precipitate formed was suction filtered, washed with water, and then with tert-butylmethylether. After drying in vacuo, 1.9 g (70% of theoretical) of colorless crystals were obtained. IR (KBr): 1664 (C═O) cm−1; MS: M+=351.
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8]([O:10]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[C:1]1([C:7](=[O:12])[C:8]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: COC(=O)C(=O)c1ccccc1
Solvent: CO
Product: O=C(C(=O)N1CCCCC1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Methyl phenylglyoxylate (12.50 Kg, 76.1 mol, 1 eq) was added dropwise to a stirred mixture of piperidine (19.45 Kg, 228 mol, 3 eq) and methanol (5.0 L) for 3.5 hours to maintain the temperature at 45–55° C. The mixture was stirred at the same temperature for 0.5 hour and kept overnight at +4° C. The precipitated solid was filtered off, washed on the filter with cold methanol (5 L) and dried under reduced pressure to a constant weight to give 15.90 kg (96%) of 1-(phenylglyoxylyl)piperidine with 99.9% purity by GC.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([NH:17][C:18]([CH3:20])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].[Cl-].[Na+]>CS(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([NH:17][C:18]([CH3:20])=[O:19])[C:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC1C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1(NC(C)=O)C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution of 0.84 g of (RS)-1-benzyl-3-(methylcarbonylamino)indolin-2-one in 15 ml of dry dimethyl sulfoxide was added 3 ml of a 1M solution of potassium t-butoxide in dry dimethyl sulfoxide at room temperature under a nitrogen atmosphere, followed by stirring for 10 minutes. To the solution was added dropwise 1.11 ml of ethyl bromoacetate, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=3/1) to give 0.83 g (76%) of the title compound as a colorless oil.