Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31]([C:41]2[CH:42]=[CH:43][C:44]3[NH:45][C:46]4[C:51]([C:52]=3[CH:53]=2)=[CH:50][C:49]([C:54]2[C:59]3[O:60][C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=5[C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:48][CH:47]=4)=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.CCCCCC>[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31]([C:41]2[CH:42]=[CH:43][C:44]3[N:45]([C:2]4[CH:3]=[CH:4][C:5]([C:8]5[C:21]6[C:16]([C:15]([C:22]7[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=7)=[C:14]7[C:9]=5[CH:10]=[CH:11][CH:12]=[CH:13]7)=[CH:17][CH:18]=[CH:19][CH:20]=6)=[CH:6][CH:7]=4)[C:46]4[C:51]([C:52]=3[CH:53]=2)=[CH:50][C:49]([C:54]2[C:59]3[O:60][C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=5[C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:48][CH:47]=4)=[CH:30][CH:29]=1
Reactant: c1ccc2c(c1)oc1c(-c3ccc4[nH]c5ccc(-c6cccc7c6oc6ccccc67)cc5c4c3)cccc12
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccc(-c6cccc7c6oc6ccccc67)cc5c5cc(-c6cccc7c6oc6ccccc67)ccc54)cc3)c3ccccc23)cc1
Yield: 59 %

Procedure:
To a 100-mL three-neck flask were added 0.99 g (2.4 mmol) of 9-(4-bromophenyl)-10-phenylanthracene, 1.2 g (2.4 mmol) of 3,6-bis(dibenzofuran-4-yl)-9H-carbazole, and 0.62 g (6.4 mmol) of sodium tert-butoxide. After the air in the flask was replaced with nitrogen, to this mixture were added 20 mL of toluene and 0.2 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution). This mixture was degassed by being stirred while the pressure was reduced. After the degassing, 62 mg (0.11 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. This mixture was stirred at 110° C. for 20 hours under a nitrogen stream. After the stirring, 100 mL of toluene was added to the obtained mixture, and the mixture was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The oily substance obtained by concentration of the filtrate was recrystallized from toluene/hexane, so that 1.2 g of a yellow solid was obtained in 59% yield. The synthesis scheme of Step 2 is illustrated in (b-8).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>B(Br)(Br)Br.C(Cl)Cl>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cc3ccccc3)nn2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(Cc3ccccc3)nn2)cc1F

Procedure:
A solution of 3-benzyl-6-(3-fluoro-4-methoxy-phenyl)-pyridazine (Step 2, 1.5 g, 5.1 mmol) in 25 mL of 1 M BBr3/CH2Cl2 was stirred at RT for 16 h. The solution was then concentrated in vacuo and the residue was re-dissolved in 100 mL of EtOAc. The organic phase was washed with 40 mL of water followed by 40 mL of brine, dried over Na2SO4 and concentrated in vacuo to give the title compound. The solid has poor solubility in EtOAc and CH2Cl2 and was washed with 50% EtOAc/hexane and then used in the next step (yellow solid). MS (ESI pos. ion) m/z: 281.3 (M+H). Calc'd Exact Mass for C17H13FN2O: 280.30.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH:45][C:46](=[O:58])[C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]=1[C:59]1[CH:67]=[C:66]2[C:62]([CH2:63][N:64]([C@@H:69]([CH:74]([CH3:76])[CH3:75])[C:70]([O:72]C)=[O:71])[C:65]2=[O:68])=[CH:61][CH:60]=1>>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH:45][C:46](=[O:58])[C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([F:55])([F:57])[F:56])=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]=1[C:59]1[CH:67]=[C:66]2[C:62]([CH2:63][N:64]([C@@H:69]([CH:74]([CH3:76])[CH3:75])[C:70]([OH:72])=[O:71])[C:65]2=[O:68])=[CH:61][CH:60]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(OC(F)(F)F)cc4)cc3OC)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: COc1cc(NC(=O)c2ccc(OC(F)(F)F)cc2)ccc1-c1ccc2c(c1)C(=O)N([C@H](C(=O)O)C(C)C)C2
Yield: 82.2 %

Procedure:
The compound of example 464 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 463.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1>[CH2:1]([N:9]1[C:13]([CH:22]=[O:23])=[CH:12][CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CCn2cccn2)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnn1CCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 42.2 %

Procedure:
To a stirred, pre-cooled solution of 1-phenethyl-1H-pyrazole (1.10 g, 6.39 mmol) in THF (30 mL) at −78° C., was added dropwise n-BuLi (4.8 mL, 7.66 mmol; 1.6 M in hexane) at such a rate that the internal temperature stayed below −70° C. The mixture was stirred at −78° C. for 1.5 h, during which time the anion precipitated out as a yellow solid. Then DMF (1.25 mL, 15.97 mmol) was added neat and dropwise, and the reaction stirred at −78° C. for 90 min when TLC indicated the reaction was not progressing any further. It was quenched with NH4Cl solution (10 mL), allowed to warm to rt and extracted with EtOAc (4×50 mL). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-10% EtOAc/heptane provided 2-phenethyl-2H-pyrazole-3-carbaldehyde (540 mg, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 3.09-3.15 (m, 2H), 4.74-4.80 (m, 2H), 6.88 (d, J=2.10 Hz, 1H), 7.16-7.20 (m, 2H), 7.20-7.32 (m, 3H), 7.58 (d, J=2.01 Hz, 1H), 9.77 (s, 1H); LCMS-MS (ESI+) 200.88 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:29])[NH:12][C:13]1[C:14]([CH3:28])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26]O)=[CH:20][CH:19]=1)[CH3:9].[F:30][C:31]([F:43])([F:42])[C:32]1[NH:36][N:35]=[CH:34][C:33]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:40]([O:39][C:37]([C:33]1[CH:34]=[N:35][N:36]([CH2:26][C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:28])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:29])=[CH:19][CH:20]=2)[C:32]=1[C:31]([F:30])([F:42])[F:43])=[O:38])[CH3:41]
Reactant: Cc1noc(-c2ccc(C#CCO)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(CC#Cc2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {5-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-3-methyl-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.49 mmol), ethyl 5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.101 g, 0.49 mmol), and triphenylphosphine (0.127 g, 0.49 mmol) in THF (4 mL) was added diisopropyl azodicarboxylate (0.10 mL, 0.49 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]#[N:17]>C1COCC1.C(N(CC)CC)C>[C:16]([CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-Boc piperazine (1 g) in dry THF (20 ml), triethylamine (3 ml), followed by chloroacetonitrile (5.02 ml) were added dropwise. The reaction mixture was allowed to stir at room temperature for overnight. The solvent was removed under vacuum and residue was diluted ethyl acetate (20 ml). The organic layer was concentrated to dryness under reduced pressure to afford tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate, which was used for the next reaction without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)S(=O)(=O)NCCc1ccc(-c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NCCc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 0.5 g (1.5 mmol) of material from Example 119 in 20 mL of ethyl alcohol was added 0.056 g (1.5 mmol) of sodium borohydride. The mixture was stirred at ambient temperature for 2 hr and then 10 mL of ethyl acetate and 10 mL of water was added. The organic layer was separated and the aqueous layer was extracted two times with 5 mL each of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford 0.5 g (100%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH2:13][NH2:14]>CO>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:13][NH2:14])=[O:8]
Reactant: NN
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Solvent: CO
Product: NNC(=O)c1cnc(Cl)c(Br)c1
Temperature: 70 °C
Yield: 20 %

Procedure:
Methyl 5-bromo-6-chloronicotinate (100 mg, 0.399 mmol) was added to hydrazine (19.19 mg, 0.599 mmol) in methanol (8 mL) and heated overnight at 70° C. The reaction was monitored by TLC. Upon completion of the reaction, the solvent was removed by vacuum, and the compound was purified by column chromatography affording the title compound (20 mg). 1H NMR (400 MHz, CD3OD): δ 8.33 (d, 1H, J=2.4 Hz), 8.01 (d, 1H, J=2.4 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.O1CCOCC1.CCOCC.[ClH:40]>>[C:25]([CH:22]1[CH2:23][CH2:24][CH:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)[CH2:20][CH2:21]1)([CH3:28])([CH3:26])[CH3:27].[ClH:40]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OC3CCC(C(C)(C)C)CC3)ccc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCNC3)CC1

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.89 g, 2.3 mmol) in 4 M of HCl in 1,4-dioxane (10 mL, 40 mmol) and ether (40 mL) was stirred at room temperature for 3 hrs to form white precipitate. The solid was collected by filtration to give desired product as HCl salt (0.73 g, yield: 98%). (400 MHz, DMSO) δ 7.09 (d, 1H), 6.81 (d, 1H), 6.80 (s, 1H), 4.20 (m, 1H), 4.14 (m, 2H), 3.31 (m, 2H), 2.95 (t, 2H), 2.09 (d, 2H), 1.77 (d, 2H), 1.27 (m, 2H), 1.20-0.98 (m, 3H), 0.85 (s, 9H).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N+]=[N-].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[C:17]([N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:11]([OH:13])=[O:12])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: O=C(O)CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
N-Benzylglycine hydrochloride (7.38 g, 36.6 mmol), tert-butyl azidoformate (10.7 mL, 73.2 mmol) and sodium bicarbonate (12.3 g) were reacted in 150 mL dioxane/H2O-1:1 (v/v) at 45° (24 hr) and then at room temperature (24 h). The reaction suspension was evaporated to dryness and the resulting white residue was dissolved in 200 mL glacial acetic acid/H2O--1:1(v/v) with cooling to 4°. Water (800 ml) was slowly added with rapid stirring and cooling. The resulting turbid solution was seeded with Boc-N-benzyl-glycine obtained from Method A and allowed to stand in an ice bath for 30 min. The resulting material was gathered by filtration, washed with water followed by petroleum ether (bp 30°-75°) and dried to give 8.34 g (86%) of crude product as a white solid. Recrystallization from dichloromethane petroleum ether (bp 30°-75°) gave 7.34 g (76%) of white, crystalline product identical to Boc-N-benzylglycine (Method A) by NMR and melting point (106°).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=2)[C:19](OC)=[O:20])=[CH:8][C:7]=1[CH3:29].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=2)[CH:24]=[CH:23][C:18]=1[CH2:19][OH:20]
Reactant: COC(=O)c1ccc(CCCc2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CCCc2ccc(CO)c(CO)c2)ccc1OCC(O)C(C)(C)C

Procedure:
In a manner similar to Example 1h, by reacting 900 mg (2.1 mmol) of dimethyl 4-{3-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]propyl}phthalate with 375 mg (10 mmol) of lithium aluminum hydride. A thick colorless oil is obtained (m=780 mg, y=96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:17]([O:5][C:4]1[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7](=[O:8])[CH:6]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)OC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Dimedone (5,5-dimethylcyclohexane-1,3-dione, 99%, 14.2 g), pyridine (9 ml) and methylene chloride (100 ml) were mixed in a flask and butyryl chloride (11.4 g) was added dropwise. The mixture was stirred for 26 hours at room temperature and filtered. The filtrate was washed with HCl (6 N, 100 ml), water (100 ml), saturated Na2CO3 (50 ml), water (50 ml), dried (MgSO4). The solvent was removed under reduced pressure to yield 3-butyroxy-5,5-dimethylcyclohex-2-en-1-one as a yellow liquid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]12([CH2:20][OH:21])[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:21][CH2:20][C:12]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC12CCC(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC23CCC(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
Solid para-toluenesulfonyl chloride (0.449 g) was added to a solution of bicyclo-[2,2,2]oct-1-ylmethanol (300 mg) and triethylamine (0.45 ml) in anhydrous acetonitrile (6 ml) under nitrogen. The mixture was stirred at room temperature for 16 hours then heated at reflux for 18 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ether:hexane (1:9) and further purified by preparative normal-phase HPLC on a Dynamax™ Silica column with hexane:ethyl acetate gradient elution to give the sub-title compound as an oil (0.180 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:26]([CH:27]4[CH2:29][CH2:28]4)[N:25]=[N:24][N:23]=3)[CH:17]=1)[CH2:10][C:9]2([CH3:31])[CH3:30])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH:27]1([N:26]2[C:22]([C:18]3[CH:17]=[C:16]([CH:11]4[CH2:10][C:9]([CH3:30])([CH3:31])[C:8]5[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=5)[NH:12]4)[CH:21]=[CH:20][CH:19]=3)=[N:23][N:24]=[N:25]2)[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3nnnn3C3CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (908.0 mg, 2.2 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (100 mL×2), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (770.2 mg, 90%) as a off-yellow solid: MS (ESI) M+1=390.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH3:21].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([C:17](=[O:19])[CH3:18])[CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1oc2cccc(NC(C)=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2cccc(N(C)C(C)=O)c2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To 4-acetylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (300 mg, 1.15 mmol, 1 eq, prepared according to Example 48, Step 1) under nitrogen was added 5 mL of DMF, iodomethane (79 uL, 1.26 mmol, 1.1 eq), and sodium hydride (60%, 51 mg, 1.26 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 4 h. After work up and flash column chromatography (5-40% ethyl acetate/hexanes), 4-(acetyl-methyl-amino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 35% yield (112 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.2 Hz, 3 H) 1.7 (s, 3 H) 2.5 (s, 3 H) 3.2 (s, 3 H) 4.4 (m, 2 H) 7.3 (dd, J=7.6, 0.8 Hz, 1 H) 7.6 (dd, J=8.5, 7.7 Hz, 1 H) 7.8 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 45.4 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.57 g) described in Preparation Example 167 and pyrrolidin-2-one (327 mg) and by the reaction and treatment in the same manner as in Preparation Example 48, the title compound (720 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:16][Si](Cl)(C)C>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C(O)CCc1c[nH]c2ccc(Br)cc12
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)CCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The 5-bromoindole-3-propionic acid 87 (4.0 g, 14.91 mmol) was dissolved in methanol (MeOH, 100 mL) and Trimethylsilyl chloride (TMSCl, 33.0 mL, 32.8 mmol, 1.0 M in CH2Cl2) was added dropwise The mixture was stirred for 24 hours, followed by refluxing for 1 hour. The reaction was allowed to cool to room temperature and the solvent was evaporated to ester as a white solid, (M+1=284).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH3:5].COC[C@H](OC1C=C(C=CC=1)N)C>>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13])[CH3:5]
Reactant: COC[C@H](C)Oc1cccc([N+](=O)[O-])c1
Agent: COC[C@@H](C)Oc1cccc(N)c1
Product: COC[C@H](C)Oc1cccc(N)c1

Procedure:
Reduction of 1-{[(1S)-2-Methoxy-1-methylethyl]oxy}-3-nitrobenzene following the procedure described for Intermediate 81 part (ii) gave the title compound (Intermediate 82) as oil; 1H NMR δ 1.17 (d, 3H), 3.26 (s, 3H), 3.35-3.42 (m, 1H), 3.42-3.51 (m, 1H), 4.37-4.49 (m, 1H), 4.90 (s, 2H), 6.03-6.11 (m, 1H), 6.10-6.19 (m, 2H), 6.81-6.94 (m, 1H); MS m/e MH+ 182.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][CH:41]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@H:27]([C:36]3[CH:41]=[N:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[OH:28])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(F)(F)F)nc3)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-bromo-2-(trifluoromethyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].Br[CH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCBr
Reactant: Oc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1Br

Procedure:
A solution of 2-bromophenol (17.3 g, 100 mmol) in 50 mL of H2O was added NaOH (8 g, 200 mmol), 3-bromopropanoic acid (15.3 g, 100 mmol), and the mixture was stirred at reflux overnight. The reaction solution was diluted with H2O, extracted with EtOAc. The aqueous layer was acidified to pH=1˜2 and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford 3-(2-bromophenoxy)propanoic acid.