Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([CH3:12])[C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1c(C)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1c(CO)c(C)n(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 93.4 %

Procedure:
Using ethyl 2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.01 g) and a 1.5 mol/L solution (6.0 mL) of diisobutylaluminum hydride in toluene, a procedure as in Reference Example 5 was performed to give the title compound as a brown oil (yield 0.84 g, 94%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 900 mg (S)-4-benzyloxy-2-tert-butoxycarbonylamino-butyric acid in 10 ml DMF were added 1.5 ml N-ethylmorpholine, 0.43 ml 1-ethoxycarbonylpiperazine and 955 mg TOTU. The solution was stirred for 12 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.23 g.
Reaction SMILES: I[C:2]1[CH:32]=[CH:31][C:5]2[N:6]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH2:33]([OH:37])[CH2:34][C:35]#[CH:36]>N1CCCCC1.[OH-].[NH4+].[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][O:29][C:13]1[CH:12]=[C:11]([CH:9]([N:6]2[C:5]3[CH:31]=[CH:32][C:2]([C:36]#[C:35][CH2:34][CH2:33][OH:37])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH3:10])[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=1
Reactant: C#CCCO
Reactant: COc1cc(C(C)n2cnc3cc(I)ccc32)ccc1OCc1ccc(C(F)(F)F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [NH4+]
Solvent: C1CCNCC1
Product: COc1cc(C(C)n2cnc3cc(C#CCCO)ccc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 205 %

Procedure:
To a stirred mixture of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.210 g, 0.38 mmol), 3-butyn-1-ol (0.041 g, 0.57 mmol), copper(I) iodide (0.019 g, 0.10 mmol) in piperidine (4 mL) was added bis(triphenylphosphine)palladium(II) chloride (0.037 g, 0.053 mmol). The mixture heated to 100° C. in a microwave reactor. After 30 min, the reaction mixture was allowed to cool to room temperature and was diluted with 5N ammonium hydroxide solution (30 mL). The mixture was extracted with dichloromethane (3×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.386 g of a brown solid. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 0.157 g (84%) of the product as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=2.1 Hz, 1H), 8.04 (s, 1H), 8.00-7.93 (m, 1H), 7.90-7.84 (m, 1H), 7.72-7.68 (m, 1H), 7.28-7.23 (m, 1H), 7.13-7.08 (m, 1H), 6.87-6.82 (m, 1H), 6.76-6.64 (m, 2H), 5.55 (q, J=7.0 Hz, 1H), 5.19 (s, 2H), 3.83 (t, J=6.2 Hz, 2H), 3.77 (s, 3H), 2.71 (t, J=6.2 Hz, 2H), 2.00-1.92 (m, 4H) ppm; (M+1)=496.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=1[NH2:15]>>[CH3:12][C:13]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccc(C)c(N)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(C)c(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,5-dimethylaniline to yield 2-[(2,5-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:12][CH3:13].[BH4-].[Na+]>CO.CCOCC.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([NH2:9])[CH:5]=[CH:4][C:3]=1[S:12][CH3:13]
Reactant: CSc1ccc([N+](=O)[O-])c(C)c1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOCC
Product: CSc1ccc(N)c(C)c1Br
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-4-nitro-methylthioanisole (450 mg, 1.81 mmol) in 45 mL of MeOH was added a suspension of copper(11) acetate (85 mg, 0.47 mmol) in 9 mL of MeOH. Sodium borohydride (300 mg, 7.9 mmol) was added as a solid over 0.5 h. The reaction was diluted with Et2O, washed with NaHCO3, dried with Na2SO4, filtered, and conc. to give 387 mg of the title compound. MS:m/e=218 (M+1) 1H NMR (400 Mhz, CDCl3): δ 2.35 (s, 3H), 6.62 (dd, 1H), 6.94 (d, 1H), 7.08 (d, 1H)
Reaction SMILES: [O-]CC.[Na+].[CH:5]([C:7]1[S:11][C:10]([CH3:12])=[C:9]([N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:8]=1)=O.[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N+]=[N-].[Cl-].[NH4+]>C(O)C>[CH3:12][C:10]1[S:11][C:7]2[CH:5]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH:23][C:8]=2[C:9]=1[N:13]([CH3:22])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1sc(C=O)cc1N(C)S(=O)(=O)c1cccs1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution (250 mL) of sodium ethoxide (17.2 g) in ethanol was added dropwise a mixture of N-(5-formyl-2-methyl-3-thienyl)-N-methylthiophene-2-sulfonamide (19 g) and ethyl azidoacetate (32.5 g) at −25° C. After the completion of the dropwise addition, the mixture was gradually warmed to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated. The obtained residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) was concentrated. The obtained yellow oil was dissolved in toluene (50 mL), and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give ethyl 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylate (6.54 g, yield 27%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 161° C.
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(#N)C.[BrH:15].N([O-])=O.[Na+]>O>[Br:15][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Nc1c(F)cccc1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
In a 1 L, three necked, round-bottomed flask fitted with a dropping funnel and a thermometer, were charged 20 g (0.13 mol) of 2-amino-3-fluoro-benzoic acid and 160 mL of acetonitrile. After cooling to 0° C., 160 mL of hydrobromic acid (47%) was added dropwise over 10 min. To the resulting solution, 10 g of NaNO2 (0.145 mol) in water (20 mL) was added dropwise over 1 hour. After addition, the reaction mixture was stirred at 0° C. for 5 min, and 21.8 g of Cu(I) Br (0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in an oil bath for 1 hour. After cooling to 0° C., 700 mL of H2O was added and the precipitate was filtered, washed with cold water and dried under vacuum to give an orange solid corresponding to 2-bromo-3-fluoro-benzoic acid (22 g, 78%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([CH3:9])[CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(O)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(O)cc1C
Yield: 43.8 %

Procedure:
To a microwave vial containing 4-bromo-3-methylphenol (600 mg, 3.21 mmol) in anhydrous DMF (3.0 mL) was added ethyl acrylate (996 mg, 9.94 mmol), palladium (II) acetate (72.0 mg, 0.321 mmol), tri(o-tolyl)phosphine (146 mg, 0.481 mmol) and triethylamine (1.57 mL, 11.23 mmol). The resulting mixture was sealed and subjected to microwave irridation at 120° C. for 2 h after which time the reaction was diluted with EtOAc and filtered through Celite™. The filtrate was then washed with water, brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product as a brown oil which was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-ethyl 3-(4-hydroxy-2-methylphenyl)acrylate (289.8 mg, 1.405 mmol, 44% yield). LC/MS (m/z, MH+): 207.2.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([CH2:31][CH2:32][OH:33])=[C:26]([CH3:34])[CH:25]=1>C(Cl)Cl>[Br:23][C:24]1[CH:25]=[C:26]([CH3:34])[C:27]([CH2:31][CH:32]=[O:33])=[C:28]([CH3:30])[CH:29]=1
Reactant: Cc1cc(Br)cc(C)c1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1CC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Dess-Martin Periodinane (5.2 g, 12.5 mmol) was added portionwise to a solution of 32B (2.6 g, 11.4 mmol) in CH2Cl2 (60 mL) at 0° C. and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was filtered and stirred with NaOH (1.0 M, 40 mL) for 10 min. The organic layer washed with brine, dried over Na2SO4 and concentrated to yield 53A (2.6 g, 99%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 6 H) 3.71 (d, J=1.77 Hz, 2 H) 7.20-7.20 (m, 2 H) 9.66 (t, J=1.89 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH2:32][CH3:33])[CH:24]=2)=[CH:18][C:17]=1[CH3:35].C(O)(=O)C>CC(N(C)C)=O>[CH3:30][O:29][C:26]1[N:27]=[N:28][C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:35])[CH:18]=2)=[CH:24][C:25]=1[C:31]1[NH:4][C:3]2[C:2]([C:32]=1[CH3:33])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Nc1ccccc1Cl
Reactant: CCC(=O)c1cc(-c2cc(C)c(O)c(C)c2)nnc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1C
Temperature: 140 °C

Procedure:
73.4 μl of 2-chloroaniline and 21 mg of anhydrous magnesium sulfate are suspended in 3 ml dimethylacetamide. 100 mg of 1-[6-(4-Hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-propan-1-one and 31.4 mg acetic acid are added and the reaction is degassed with argon. 96 mg of tripotassium phosphate and 35.7 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 16 h. The solution is filtered. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 35 mg.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](C)(C)[NH:5]2.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[NH:8][C:7](=[O:12])[CH2:6]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Reaction time: 0.5 h

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.593 g) and triethylamine (0.725 ml) in THF (5 ml) is cooled at 0°. To this is added benzoyl chloride (0.56 ml). After the addition is complete, the ice bath is removed and additional THF (5 ml) is added. The reaction is stirred for 30 min and then partitioned between ethyl acetate, aq. sodium bicarbonate, and saline. The organic phases are separated and the organic phase is dried over magnesium sulfate and concentrated. The crude product is recrystallized from methanol/dichloromethane/hexane to give the title compound, mp 208.0°-208.5°; MS (m/z) at 252; IR (mineral oil) 1684, 1666, 1502, 757 and 1362 cm-1 ; NMR (CDCl3) 4.58, 6.7, 6.79, 6.98, 7.10, 7.34 and 7.40 δ.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:30]([Cl:29])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1c(Cl)cccc1Cl
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4c(Cl)cccc4Cl)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,6-dichlorobenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 537.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42]C)=O)[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl.O[C:48](C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)([C:52]1[N:53]=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.C(N)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O.CO>[CH2:52]([NH:53][C:40]([C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][NH:9][CH:10]=3)[CH:3]([CH3:4])[CH3:5])[CH:31]=2)[CH:36]=1)=[O:42])[CH3:48]
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (14.0 g) in THF (140 mL) was added methanol (30 mL) and 4N-NaOH (30 mL) at 60° C. The mixture was stirred for 2 h, neutralized with conc.HCl. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The extract was concentrated to give crude mixture of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid. To a solution of the crude mixture was added ethylamine hydrochloride (2.41 g), 1-hydroxybenzotriazole (4.53 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.67 g) under ice cooling. The mixture was stirred at room temperature for 20 h, diluted with water and extracted with ethyl acetate. The extract was concentrated and purified by column chromatography (eluent; hexane:THF=1:2) followed by crystallization from hexane-ethyl acetate to give the titled compound (12.0 g) as a colorless powder.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([OH:44])=O)=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH3:54][N:55]1[CH:59]=[C:58]([S:60]([NH2:63])(=[O:62])=[O:61])[N:57]=[CH:56]1>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:63][S:60]([C:58]4[N:57]=[CH:56][N:55]([CH3:54])[CH:59]=4)(=[O:62])=[O:61])=[O:44])=[C:40]([F:48])[CH:39]=3)[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: Cn1cnc(S(N)(=O)=O)c1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: Cn1cnc(S(=O)(=O)NC(=O)c2cc(Cl)c(OCC34CC5CC(CC(C5)C3)C4)cc2F)c1

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with 1-methyl-1H-imidazole-4-sulfonamide, the title compound was obtained as a colorless solid (0.16 g, 33%): 1H NMR (300 MHz, DMSO-d6) δ 8.03-8.01 (m, 1H), 7.85-7.80 (m, 1H), 7.66-7.60 (m, 1H), 7.21-7.14 (m, 1H), 3.73 (s, 3H), 3.70 (s, 2H), 1.98 (s, 3H), 1.78-1.57 (m, 12H); MS (ES+) m/z 482.2 (M+1), 484.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].CC(O)=O.C1(C)C=CC=CC=1>C1COCC1.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([O:19][C@H:17]3[CH2:16][NH:15][C@H:14]([C:12]([NH:11][C@:6]4([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]4[CH:9]=[CH2:10])=[O:13])[CH2:18]3)=[CH:21][C:22]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.5 %

Procedure:
To a solution of compound 6 (0.067 mmol) in THF-MeOH 2:3 (2 ml) was added 1M LiOH 10 equiv. The solution was kept at 50° C. for 2.5 hrs. After cooling to RT, HOAc 20 eq. was added followed by toluene (2 ml) and then concentrated to dryness. The residue was taken up in DCM and filtered form the salts which gave the title compound (0.07 mmol). Purity >95% by HPLC M+H+ 474.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([F:43])[CH:37]=2)([C:33](O)=[O:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:30]2([C:33]([N:16]3[CH2:15][CH2:14][N:13]([C:11]4[C:12]5[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=5[N:8]=[CH:9][N:10]=4)[CH2:18][CH2:17]3)=[O:34])[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:32][CH2:31]2)=[CH:37][C:38]=1[F:43]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)c(F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)c(F)c5)CCN(C(=O)OC(C)(C)C)CC4)CC3)c21
Reaction time: 4 h
Yield: 22.9 %

Procedure:
(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (35.0 mg, 0.114 mmol) and 1-(tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid (40.8 mg, 0.114 mmol) were dissolved in DCM (1.1 mL) and treated with DIEA (0.0595 ml, 0.342 mmol) at ambient temperature. The mixture was allowed to homogenize before the HBTU (47.5 mg, 0.125 mmol) was added in one lot. The reaction was allowed to stir for four hours to completion by LCMS analysis of the crude. The reaction was diluted with DCM, washed with diluted NaHCO3 solution, washed with water, washed with brine, and separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 5% methanol in ethyl acetate) to afford the pure tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate (15.0 mg, 22.9% yield) as a pale yellow oil. MS (APCI+) [M+H] +574; Rf: 2.92.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]([OH:40])([C@H:32]([S:34][CH:35]([CH2:38]O)[CH2:36][OH:37])[CH3:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:40])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@H:32]([S:34][C@@H:35]1[CH2:36][O:37][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[S:11][CH:12]=[CH:13][N:14]=3)=[O:8])=[CH:15][CH:16]=2)[O:2][CH2:38]1)[CH3:33]
Reactant: O=Cc1ccc(C(=O)Nc2nccs2)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3nccs3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 1(2), a reaction was carried out using 4-formyl-N-(2-thiazolyl)benzamide, obtained in Example 27(1) (200 mg, 0.86 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (270 mg, 0.75 mmol) and p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol) and the reaction mixture was treated using a similar procedure to that described in Example 1(2) to afford the trans isomer of the title compound (64 mg, yield 15%) as a white oil and the cis isomer (29 mg, yield 7%) as a colorless oil. The trans isomer was recrystallized from tetrahydrofuran-hexane to give white powdery crystals.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.[Cl-].[NH4+].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30]>O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:30]1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Oc1ccc(-c2nn(-c3ccccc3Cl)c3cc(O)ccc23)c(O)c1
Yield: 0.1 %

Procedure:
A mixture of 2,2′,4,4′-tetrahydroxybenzophenone (0.246 g, 1.0 mmol), ammonium chloride (0.16 g, 3 mmol) and 2-chlorophenyl hydrazine hydrochloride (0.535 g, 3 mmol) in 10 mL H2O was heated at reflux for 4 hours. The reaction mixture was cooled and the solids formed were filtered washed with H2O and dried to give 0.296 mg of the intermediate hydrazone. The hydrazone was heated to 200° C. under argon for 2 hours. The residue was purified by flash chromatography (hexane-EtOAc, 2:1) to give 0.055 g of product as a tan solid