Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16][NH2:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:21])=[C:13]([F:12])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: O=CC=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1ccc(CNCC=Cc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The cis-diaryl compounds were prepared as shown above. To a solution of 4-chlorocinnamaldehyde (1.45 g, 8.70 mmol) in 100 mL of dichloroethane was added 3,4-difluorobenzylamine followed by sodium triacetoxyborohydride (3.7 g, 17.5 mmol, 2 eq.). The mixture was stirred overnight at room temperature, washed with aq. NaHCO3, brine, dried over MgSO4, filtered, concentrated and chromatographed with 40% ethyl acetate-hexanes to provide 0.84 g of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine. The [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine was coupled with 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride to provide 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide. When 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide was subjected to the Diels-Alder reaction conditions shown above, it gave 60 as the major product. Epimerization of the trans-lactam gave 61 and reduction of the double bond of 61 gave 62.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(O)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:25]=1)=[O:6]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
3.2 g 2-Chloro-4,6-dimethoxy-1,3,5-traizine (CDMT) was charged to a mixture of 2.8 g 2-chloro-4-(methylsulfonyl)benzoic acid (Formula F) in 80 mL methylene dichloride (MDC) under nitrogen atmosphere at 25-30° C. and stirred for about 20 mins 4.9 g N-methyl morpholine (NMM) was added to the reaction mixture over period of about 15 mins maintaining temperature of 20-30° C. Reaction mixture was maintained under stirring at this temperature for about 3 hrs. 2 g 4-chloro-3-(pyridin-2-yl)benzenamine (Formula E) was then added to the reaction mixture and stirring was done for additional 3 hrs at same temperature. Then the temperature of reaction mixture was raised to 35-40° C. and stirring was done, intermittently checking reaction progress by TLC. On completion of the reaction, reaction mixture was cooled to 20-30° C. and quenched with 40 mL water. Organic layer was separated and the aqueous layer was washed with 20 mL MDC. MDC organic layer was collected and washed twice with 40 mL saturated sodium bicarbonate solution followed by a water washing (40 mL). Organic layer was dried over sodium sulphate and solvent was distilled off under vacuum at 35-45° C. to obtain a residue. To this residue, 30 mL Iso-propyl alcohol (IPA) was added and reaction temperature was raised to 60-70° C., wherein stirring was performed for about 30 mins followed by slow cooling to 20-30° C. Reaction was maintained for about 1 hr at same temperature under stirring. The precipitated product was filtered on Buchner funnel, washed with 10 mL IPA and dried at 40-45° C. under vacuum to get 2.5 g 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (I) having HPLC area purity of 99.3%.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:17](=[O:20])[CH:18]=[CH2:19])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:28][CH:29]([C:34]1[CH:35]=[CH:36][C:37]([CH:40]=[O:41])=[N:38][CH:39]=1)[C:30]([OH:33])([CH3:32])[CH3:31].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:16]([CH2:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:17](=[O:20])[CH2:18][CH2:19][C:40]([C:37]2[CH:36]=[CH:35][C:34]([CH:29]([OH:28])[C:30]([OH:33])([CH3:31])[CH3:32])=[CH:39][N:38]=2)=[O:41])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)n1ncc2c(S(=O)(=O)C3CC3)cccc21
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(O)C(O)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)n2ncc3c(S(=O)(=O)C4CC4)cccc32)nc1
Yield: 70.3 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)-1H-indazol-1-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.80 g), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (0.99 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (0.12 g), triethylamine (0.26 ml), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography to give the title compound (1.90 g, yield 71%) as a yellow amorphous solid from the fraction eluted with ethyl acetate. MS: 584 (MH+).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)=[O:17])[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20]([OH:23])([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C#C[Si](C)(C)C
Reactant: C=CCOC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOC(=O)N1CCC(O)(C#C[Si](C)(C)C)C1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsilylacetylene (16.3 ml) in tetrahydrofuran (100 ml) were added successively a solution of n-butyllithium in n-hexane (1.50M, 70 ml) and a solution of 1-allyloxycarbonyl-3-oxopyrrolidine (15 g) in tetrahydrofuran (15 ml) at -50° C. After stirring at -50° C. for 1 hour, to the mixture was added a mixture of aqueous ammonium chloride and ethyl acetate at 0° C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The organic layers were combined washed with 1N hydrochloric acid, water and brine successively and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 1-allyloxycarbonyl-3-hydroxy-3-trimethylsilylethynylpyrrolidine (19.5 g).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.[CH2:11]([C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[C:20]([N:23]3[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]3=[O:30])[CH:21]=[CH:22][C:15]=2[N:14]=1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O.C1COCC1>[F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][O:9][C:26]2[CH:27]=[CH:28][N:23]([C:20]3[CH:21]=[CH:22][C:15]4[N:14]=[C:13]([CH2:11][CH3:12])[N:17]([CH3:18])[C:16]=4[CH:19]=3)[C:24](=[O:30])[CH:25]=2)[S:6][CH:7]=1
Reactant: OCc1nc(C(F)F)cs1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4nc(C(F)F)cs4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
A mixture of (4-(difluoromethyl)-1,3-thiazol-2-yl)methanol (61.3 mg), 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), triphenylphosphine (146 mg), bis(2-methoxyethyl) azodicarboxylate (130 mg) and THF (3 ml) was stirred at room temperature for 3 h. The mixture was diluted with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (10.1 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH:17]([N:21]1[C:29]2[C:24](=[CH:25][C:26](O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:18][CH2:19][CH3:20])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH:17]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:11][CH2:10][CH2:9][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([NH:2][CH3:1])[N:8]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:18][CH2:19][CH3:20])[CH3:13]
Reactant: CNc1cccc(CCO)n1
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(O)ccc21
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3cccc(NC)n3)ccc21
Yield: 25 %

Procedure:
The title compound was synthesized from 2-(6-methylamino-pyridin-2-yl)-ethanol and 3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester using the procedure described in Example 14, step (c), in 25% yield. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([P:12]([O:17][CH2:18][CH3:19])(=[O:16])[O:13][CH2:14][CH3:15])[N:9]=[C:8](P(OCC)(=O)OCC)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:1]([NH:5][C:6]1[N:7]=[C:8]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[N:9]=[C:10]([P:12]([O:13][CH2:14][CH3:15])(=[O:16])[O:17][CH2:18][CH3:19])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(P(=O)(OCC)OCC)nc(P(=O)(OCC)OCC)n1
Reactant: CCNCC
Product: CCCCNc1nc(N(CC)CC)nc(P(=O)(OCC)OCC)n1

Procedure:
Tetraethyl 2-n-butylamino-1,3,5-triazine-4,6-diphosphonate prepared as described in Example 17 was dissolved in excess diethylamine and heated at reflux (59°-60° C.) for 6 hours to produce diethyl 2-n-butylamino-4-diethylamino-1,3,5-triazine-6-phosphonate.
Reaction SMILES: C(=O)([O-])[O-].[Zn+2:5].[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]>O>[Zn:5].[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: [Zn+2]
Agent: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: [Zn]

Procedure:
20 g of zinc carbonate (zinc content: 32%) was dispersed in 500 ml of water and dissolved therein by stirring, and 60 g of glutamic acid was added thereto to perform a reaction, then the solution was continually stirred until the zinc carbonate and glutamic acid were entirely dissolved. Bubbles were generated in the initial stage of the reaction but they disappeared after a certain time. The resulting reaction solution was centrifuged to remove insoluble materials, and the clear supernatant was separated. The supernatant was freeze-dried to obtain about 70 g of zinc-glutamic acid chelate (zinc content: 6.5%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:5])[CH:6]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A round-bottomed flask was charged with 2-fluoro-5-bromobenzaldehyde (1.01 g) and tetrahydrofuran (50 mL), placed under a nitrogen atmosphere then cooled to −78° C. To this solution was added a 1M solution of phenylmagnesium bromide (5 mL). The reaction was stirred for 15 min then removed from the cold bath and allowed to warm to 0° C. Quenching was achieved by the addition of water and diethyl ether. The organic layer was collected, dried over magnesium sulfate then concentrated to an oil. The residue was dissolved in methylene chloride (100 mL) and treated with Dess-Martin periodinane (2.12 g) at room temperature. The reaction mixture was stirred for 30 min then loaded directly onto a silica gel pad. The pad was eluted with methylene chloride, and the desired fractions were combined and concentrated to dryness to provide (5-bromo-2-fluorophenyl)(phenyl)methanone as a yellow oil (0.80 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 7.8 (m, 1 H) 7.7 (m, 3 H) 7.6 (m, 1 H) 7.5 (m, 2 H) 7.3 (m, 1 H)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[N:7]2.[I-].[F:21][C:22]([F:27])([F:26])[CH2:23][CH2:24][Zn+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C1C=CC=C(N(C)C)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)C>[CH3:19][C:14]1[CH:13]=[C:12]([C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH2:24][CH2:23][C:22]([F:27])([F:26])[F:21])[N:7]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)cccc3n2)c1
Reactant: FC(F)(F)CC[Zn+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1cccc(N(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2ccc3c(CCC(F)(F)F)cccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
5-bromo-2-(3,5-dimethylphenyl)quinoline (1.15 g, 3.68 mmol), Palladium(II) acetate (0.017 g, 0.074 mmol), and CPhos (0.064 g, 0.147 mmol) were charged into a flask and diluted with 100 mL of tetrahydrofuran. This mixture was degassed with nitrogen followed by the addition of (3,3,3-trifluoropropyl)zinc(II) iodide (1.07 g, 3.68 mmol) via syringe. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride then was extracted 2×200 mL of ethyl acetate, and dried over sodium sulfate. The crude material was coated on Celite and purified by column chromatography using a 20% DCM in Heptanes solvent system. The product was recrystallized in heptanes to afford 0.90 g of the target compound (81% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[CH3:14].[H][H]>[Ni].O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)C=Cc1ccc(CO)cc1C
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(CO)cc1C

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-acrylic acid methyl ester (4.7 g, 22.8 mmol), Raney nickel (0.668 g) and tetrahydrofuran (618 mL) is shaken under 60 psig. Hydrogen 24 hr. The catalyst is filtered off, and the mixture is concentrated to afford the product as a pale yellow oil, 4.3 g, 91%. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[CH:26]N2CCCC2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[K+].[NH2:35][C:36]([NH2:38])=[S:37]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][C:15](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:16][CH2:17]3)=[CH:26][N:38]=[C:36]([SH:37])[N:35]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: O=C(C(=CN1CCCC1)CCN1CCC(=Cc2ccccc2F)CC1)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2nc(S)ncc2CCN2CCC(=Cc3ccccc3F)CC2)cc1
Reaction time: 5 h
Yield: 35.4 %

Procedure:
To 3.70 g of the crude 1-[4-(4-fluorophenyl)-4-oxo-3-pyrrolidinomethylenebutyl]-4-(2-fluorobenzylidene)piperidine obtained in Example 5 were added a solution of 0.45 g of potassium hydroxide in 40 ml of ethanol and 1.23 g of thiourea, followed by reflux with heating with stirring for 5 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added a saturated aqueous ammonium chloride solution and a little amount of ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from ethyl acetate to give 1.27 g of 4-(4-fluorophenyl)-5-[2-[4-(2-fluorobenzylidene)piperidin-1-yl]ethyl]-2-mercaptopyrimidine.
Reaction SMILES: [O:1]=[C:2]([N:26]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:33][C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:3]([S:6][C:7]1[N:8]=[N:9][C:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:19][C:20]([O:22]CC)=[O:21])[C:11]=2[N:25]=1)[CH2:4][CH3:5].[OH-].[Na+]>O1CCOCC1>[O:1]=[C:2]([N:26]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=2[S:33][C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:3]([S:6][C:7]1[N:8]=[N:9][C:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:19][C:20]([OH:22])=[O:21])[C:11]=2[N:25]=1)[CH2:4][CH3:5]
Reactant: CCOC(=O)Cn1c2ccccc2c2nnc(SC(CC)C(=O)N3c4ccccc4Sc4ccccc43)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(Sc1nnc2c3ccccc3n(CC(=O)O)c2n1)C(=O)N1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Compound 28 (161 mg, 0.2901 mmol) was dissolved in 15 ml 1,4-dioxane and 0.58 ml 1 M NaOH was added to the solution. The reaction mixture was stirred at room temperature. After 14 h, TLC indicated that there was no starting material remained and the reaction was stopped. The pH of the reaction was adjusted to 4-5 using concentrated HAc. The mixture was extracted by ethyl acetate for three times and the organic phase was combined. The organic phase was dried by anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column (DCM/MeOH-60:1) and the viscous oil 29 was obtained. 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J=8.0, 1H), 7.94 (br, 1H), 7.62-7.68 (m, 2H), 7.35-7.49 (m, 4H), 7.24-7.30 (m, 3H), 7.07 (br, 1H), 5.40 (t, J=7.0, 1H), 5.01 (s, 2H), 2.03 (br, 1H), 1.84 (br, 1H), 0.92 (br, 3H). HRMS calcd for C27H21N5O3S2527.1086. found 527.1093.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C(OCC)=O)[CH:7]2[C:12]([OH:14])=[O:13].[CH3:20]CO.[OH-].[Na+].S(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]([O:14][CH3:20])=[O:13]
Reactant: CCO
Reactant: CCOC(=O)N1CCc2c(Br)cccc2C1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)C1NCCc2c(Br)cccc21
Reaction time: 18 h
Yield: 80 %

Procedure:
5-Bromo-2-(ethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1 g, 3.05 mmol) (Ortwine, et al., J. Med. Chem, 1992, 35, 1345), in two batches, was heated in a microwave to 150° C. in 1,4-dioxane (4 mL)/EtOH (2 mL)/2N NaOH (5 mL) for a total of 3 h. The combined reaction mixtures were concentrated, dissolved in MeOH (30 mL) and thionyl chloride (0.222 mL, 3.05 mmol) was slowly added. After 18 h, the solvent was removed and the residue was partitioned with EtOAc (50 mL)/saturated NaHCO3(30 mL), the phases separated and aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL) and dried (MgSO4) to afford 0.56 g (80%) of Intermediate 4A as a yellow oil. MS (ESI) m/z: 270-272 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:16]([C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([O-:18])=[O:17]
Reactant: Oc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(COc2ccccc2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Yield: 84.3 %

Procedure:
The product from Example 221b (0.16 g, 0.52 mmol) was reacted with 90% 4-mercapto-phenol (0.073 g, 0.52 mmol) in DMF at 80° C. under nitrogen in the presence of potassium carbonate (0.126 g, 0.91 mmol). The reaction was quenched after 18 h by pouring into dilute HCl and extraction with ether. The combined extracts were dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title compound (0.155 g, 84%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3[CH:10]=[C:11]([Br:14])[CH:12]=[CH:13][C:8]=3[N:7]=[CH:6]2)[CH2:2]1.C=O.[BH3-][C:18]#N.[Na+]>CO.CC(O)=O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][N:5]([CH:3]3[CH2:4][N:1]([CH3:18])[CH2:2]3)[C:9]=2[CH:10]=1
Reactant: Brc1ccc2ncn(C3CNC3)c2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC(n2cnc3ccc(Br)cc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(azetidin-3-yl)-6-bromo-1H-benzo[d]imidazole (100 mg, 0.396 mmol) in MeOH (10 mL) was added HCHO (300 mg, 3.96 mmol) and AcOH (two drops). The reaction mixture was stirred at room temperature for 30 min. NaCNBH3 (29.7 mg, 0.476 mmol) was then added and the reaction mixture stirred at room temperature for 2 h. The solvents were then removed by concentration and the residue was used for next step without purification. ESI-MS (m/z): 266.1 [M+1]
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.COCCOC.Br[C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[C:36]([CH:37]([F:48])[C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)=[C:35]([CH:49]4[CH2:54][CH2:53][C:52]([F:56])([F:55])[CH2:51][CH2:50]4)[C:34]4[CH:33]([O:57]CC5C=CC(OC)=CC=5)[CH2:32][C:31]([CH3:68])([CH3:67])[CH2:30][C:29]=4[N:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1>C1(C)C=CC=CC=1>[F:56][C:52]1([F:55])[CH2:51][CH2:50][CH:49]([C:35]2[C:34]3[CH:33]([OH:57])[CH2:32][C:31]([CH3:67])([CH3:68])[CH2:30][C:29]=3[N:28]=[C:27]([CH:24]3[CH2:23][CH2:22][N:21]([C:18]4[N:19]=[CH:20][C:15]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)=[CH:16][N:17]=4)[CH2:26][CH2:25]3)[C:36]=2[CH:37]([F:48])[C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:45])([F:47])[F:46])=[CH:42][CH:43]=2)[CH2:54][CH2:53]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: OC1CCNCC1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(N5CCC(O)CC5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 13 and Example 7 were performed except for using 4-hydroxy piperidine and 1,2-dimethoxyethane instead of isonipecotic acid ethyl ester and toluene, and from 150 mg (0.180 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 55 mg of the title compound was obtained as a light yellow solid (yield: 42%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)C>[Br:15][CH2:16][C:17]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:18]
Reactant: O=C(Cl)CBr
Reactant: CCCNCCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCN(CCC)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a mixture of dipropylamine (10.1 g), triethylamine (10.1 g) and anhydrous diethyl ether (80 ml) is added dropwise a solution of bromoacetyl chloride (15.8 g) in anhydrous diethyl ether (40 ml) while the temperature of the mixture is kept at -40° C. After addition, the temperature is gradually raised, and the mixture is stirred at room temperature for one hour. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure, and purified by distillation under reduced pressure to give the desired compound (14 g), b.p. 100-103° C./1 mmHg.