Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Oc2cccc(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.6 %

Procedure:
3-Hydroxybenzaldehyde (1.0 g, 8.2 mmol) was dissolved in dichloromethane (50 mL). (4-Methylphenyl)boronic acid (2.2 g, 16.4 mmol), triethylamine (5.7 mL, 41.0 mmol) and copper acetate(II) (1.5 g, 8.2 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 days. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (324 mg, yield 19%).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[CH:16]([O:21][CH3:22])([O:19][CH3:20])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:22][O:21][CH:16]([O:19][CH3:20])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1ccc(OC)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1ccc(OC)c(C(OC)OC)c1
Yield: 97 %

Procedure:
Ethyl 3-formyl-4-methoxybenzoate (500 mg) obtained in step C of Example 1-2-1 was dissolved in 10 mL of methanol. Trimethyl orthoformate (263 μL) and 41 mg of p-toluenesulfonic acid monohydrate were added to the solution, and then the mixture was heated for 2 hours under reflux. After the reaction solution was cooled, 5 mL of a saturated aqueous solution of sodium bicarbonate was added, and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with purified water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, whereafter the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 596 mg (97%) of ethyl 3-dimethoxymethyl-4-methoxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[C:3]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1sc2cccc(F)c2c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To an ice-cold suspension of 3-chloro-4-fluoro-benzo[b]thiophene-2-carbonyl chloride (5.46 g, 23.6 mmol) in THF (120 mL) was added lithium aluminum hydride (11.8 mL of a 1.0 M solution in THF, 11.8 mmol) dropwise. The mixture was stirred for 2 h then quenched with NaOH (0.35 N solution in H2O). The mixture was diluted with Et2O and the solution filtered. The filtrate was dried (Na2SO4) and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 8:2) gave the title compound (4.52 g, 96%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.1 Hz, 1H), 7.31 (ddd, J=8.0, 8.0, 4.7 Hz, 1H), 7.06 (dd, J=11.3, 8.0 Hz, 1H), 4.97 (d, J=6.2 Hz, 2H), 2.04 (t, J=6.2 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1.[OH-].[Na+].O>CN(C=O)C>[Br:22][C:20]1[CH:21]=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:17]=[N:18][CH:19]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: Nc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Nc2ncnc3[se]c4c(c23)CCCC4)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 66.6 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (500 mg, 1.84 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 3-amino-5-bromopyridine (380 mg, 2.19 mmol) and powdered NaOH (220 mg, 5.5 mmol) at rt and the mixture was stirred at rt for 36 h. The mixture was poured into ice cooled water and stirred for 10 min. The precipitated solid was filtered, washed with water and dried. The crude solid was chromatographed over silica gel column using hexane-EtOAc (70:30) as eluents to give the product as an off-white color solid (500 mg, 67%), which was recrystallized from acetonitrile, mp 170-172° C. 1H NMR (400 MHz, CDCl3): δ 8.66 (1H, t, J=2.0 Hz), 8.56 (1H, d, J=2.4 Hz), 8.49 (1H, s), 8.39 (1H, d, J=1.6 Hz), 7.24 (1H, s, exchangeable with D2O), 3.08 (2H, t, J=6.2 Hz), 2.96 (2H, t, J=6.0 Hz), 2.00-2.06 (2H, m), 1.92-1.98 (2H, m); 13C NMR (100 MHz, CDCl3): δ 171.7, 154.7, 151.6, 145.3, 140.8, 140.0, 136.4, 130.3, 126.4, 120.5, 120.0, 28.4, 28.1, 22.7, 22.3; LC-MS (positive ion mode): m/z 407, 409, 411 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34](I)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:16][CH:15]=2)(=[O:12])=[O:13])[CH:6]=[CH:5]3)[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(I)ccc21
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(ccn3S(=O)(=O)c3ccc(-c4cnco4)cc3)c2)C1

Procedure:
This compound was prepared from 5-Iodo-1-(4-oxazol-5-yl-benzenesulfonyl)-1H-indole and 3-iodoazetidin-1-carboxylic acid tert-butyl ester by the method outlined under 1.b). ESI-MS [m/z]: 380.05 [M-Boc-+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][OH:26])[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:21][CH:20]2[OH:34])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([C:41]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)Cl)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][O:26][C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:23][N:22]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:21][CH:20]2[OH:34])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(CO)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
In an analogous manner to that described in Example 22 (h), by reacting tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate with triphenylchloromethane in pyridine there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxy-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 731 (M+NH4)+ ], as a colourless foam, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 62 (h) gave tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, [MS: 871 (M+NH4)+ ], as a colourless foam. Subsequent selective cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) yielded tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 612 (M+H)+. Subsequent alkylation with methyl iodide analogously to Example 62 (h) gave tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 626 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:15][CH3:16])[NH:9][C:10](=[O:14])[C:11]=1[O:12][CH3:13])=[O:5])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:15][CH3:16])[N:9]([CH3:20])[C:10](=[O:14])[C:11]=1[O:12][CH3:13])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(SC)n(C)c(=O)c1OC
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A solution of 5-methoxy-2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.442 g, 1.81 mmol) in dry N,N-dimethylformamide (5 ml) was treated at 10° C. with sodium hydride (0.080 g of a 60% dispersion in mineral oil, 2.0 mmol) and the resulting mixture was stirred for 10 min. Then iodomethane (0.123 ml, 2.0 mmol) was added and the mixture was stirred for another 1 h. The solvent was then evaporated in vacuo and the residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 9:1) gave 0.419 g (89% yield) of the title ester as white needles; mp 74.5–76° C. (ether-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.41 (3H, t, J=7.1 Hz, CH3), 2.62 (3H, s, SCH3), 3.55 (3H, s, NCH3), 3.95 (3H, s, OCH3), 4.43 (2H, q, J=7.1 Hz, CH2). Anal. Calcd for C10H14N2O4S: C 46.50, H 5.46; N, 10.85. Found: C 46.73; H, 5.21; N, 10.93.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N#C[Cu]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 170 °C
Yield: 15933 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.60 mmol) in N,N-dimethylformamide (4.01 mL) was treated with copper(I) cyanide (144 mg, 1.60 mmol). The mixture was heated at 170° C. for 1 h. At this time, the reaction was cooled to 25° C. and poured into aqueous ammonium hydroxide (5 mL). The solution was diluted with water (25 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.6 g, 15.8%) as a clear oil: EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:15]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]4[N:22]=[CH:23][CH:24]=[CH:25][N:26]=4)[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: COC(OC)c1cccc(Oc2ncccn2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ncccn2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(2-pyrimidinyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9- [3-(2-pyrimidinyloxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale yellow crystalline solid of melting point 220-221° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].C1(C)C=CC(S(O[CH2:28][C@H:29]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=O)=O)=CC=1.O>CN(C)C=O>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][C@@H:29]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:28][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][CH:11]=2)[CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)OC(=O)c2ccccc2)cc1
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-c2ccc(OC[C@@H](CCc3cccnc3)OC(=O)c3ccccc3)cc2)c1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Solid 3'-cyanobiphenyl-4-ol (0.20 g, Example 36b)) was added to a suspension of sodium hydride (60%, 0.049 g) in dimethylformamide (5 ml) and the resulting solution stirred for 30 minutes. Solid (2R)-2-benzoyloxy-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.43 g) was then added and the mixture stirred at 60° C. for 2 hours. The mixture was cooled, poured into water (50 ml) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as an oil (0.34 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:54][C:55]([F:64])([F:63])[C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][CH:62]=1)[NH2:59]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:59][C:58]4[CH:60]=[CH:61][CH:62]=[C:56]([C:55]([F:54])([F:63])[F:64])[CH:57]=4)=[O:18])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc2c(n1)CCN(c1ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
A mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 1.0 mL DMF was stirred at room temperature for 10 minutes. Then 3-(trifluoromethyl)aniline (0.025 mL, 0.20 mmol) was added and the reaction heated at 55° C. for 18 hours and then 90° C. for 2 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with dilute aqueous HCl, aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with CHCl3, then gradient 2% to 5% MeOH/CHCl3 to give the title compound as a brownish-tan solid (3 mg, 8%). 1H NMR (CDCl3) δ: 8.15 (s, 1H), 7.93 (s, 1H), 7.80-7.89 (m, 4H), 7.44-7.51 (m, 1H), 7.35-7.40 (m, 1H), 6.94-7.00 (m, 2H), 5.00 (br. s., 2H), 4.39 (s, 2H), 3.73 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H)
Reaction SMILES: Cl[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:21][S-:22].[Na+]>CO.CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([S:22][CH3:21])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: C[S-]
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2ncc(C(F)(F)F)cc2SC)ccc1Cl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
3.0 g (9.3 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 0.7 g (10 mmol) of sodium thiomethoxide in a mixture of 50 ml of methanol and 20 ml of dimethylformamide were stirred at 80° C. for 7 h and then at 23° C. for 72 h. The mixture was then poured into 500 ml of ice-water, which was then extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulfate and concentrated.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH:11][C:33](=[O:34])[C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:26][N:25]=4)=[CH:32][CH:31]=3)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1
Reactant: Cc1c(C2CCOC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Product: Cc1c(C2CCOC2)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3)cn12

Procedure:
Conducting the operations similar to those of Example 1 using 3-methyl-6-nitro-2-tetrahydro-3-furanylimidazo[1,2-a]pyridine and 4-[5-(trifluoromethyl)-2-pyridyl]benzenecarboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:35]([CH3:44])([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(benzyloxy)carbonyl]-L-tyrosinate (1.00 g) in N,N-dimethylformamide (10.0 mL) were added potassium carbonate (2.71 g) and tert-butyl 2-bromo-2-methylpropanoate (2.01 mL), followed by stirring at 90° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[(benzyloxy)carbonyl]-O-(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)-L-tyrosinate (1.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[C:32](#N)[CH3:33].Cl[Si](C)(C)C.C(I)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[CH2:32][CH3:33])[C:8]([OH:10])=[O:9]
Reactant: CC#N
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCI
Product: CCN1CCc2ccccc2[C@@]1(c1ccccc1)[C@H](Oc1cc(OC)cc(OC)c1)C(=O)O
Temperature: 55 °C
Yield: 27.2 %

Procedure:
To a suspension of (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (200 mg, 0.477 mmol, Example 1) in acetonitrile (5 ml) Hünig's base (327 μl, 1.91 mmol) followed by chlorotrimethylsilane (72 μl, 0.572 mmol) is added. The mixture is stirred at 55° C. for 3 h before ethyliodide (95 μl, 1.19 mmol) is added. Stirring at 55° C. is continued for another 16 h before water is added (about 200 μl). The solvent is removed under reduced pressure and the crude product is purified by prep. HPLC on Rp-C18 silica gel to furnish (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-2-ethyl-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (58 mg) as a white solid. LC-MS2: tR=4.20 min, [M+1]+=448.39, [M−1]−=446.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@@H:12]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:29][C:28]4=[CH:30][N:31]=[C:32]([CH3:33])[N:27]4[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:14][S:15][CH3:16])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C@@H:12]([C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:29][C:28]4=[CH:30][N:31]=[C:32]([CH3:33])[N:27]4[C:26]3=[O:34])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:14][S:15]([CH3:16])=[O:43])=[O:10])=[CH:6][CH:7]=1
Reactant: CSCC[C@@H](NC(=O)Nc1ccc(Cl)cc1)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)[C@@H](CCS(C)=O)NC(=O)Nc3ccc(Cl)cc3)CC1)C2
Yield: 55.4 %

Procedure:
To a solution of N—(4-chlorophenyl)—N′—((1R)-1-((4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)-3-(methylthio)propyl)urea (0.21 g) obtained in Example 65 in dichloromethane (15 ml) was added 3-chloroperbenzoic acid (0.10 g), and mixed at 0° C. for 20 minutes. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=10/1). The product was recrystallized from ethanol-diethyl ether to obtain the title compound as colorless powder (0.12 g, 54%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([N+:41]([O-:43])=[O:42])=[C:38]([OH:40])[CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([N+:41]([O-:43])=[O:42])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc([N+](=O)[O-])c(O)c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc([N+](=O)[O-])c(O)c3)n2)c1

Procedure:
Intermediate 4 was coupled with 5-(2-amino-ethyl)-2-nitro-phenol and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 501. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 8.1 (m, 2H) 7.8 (m, 4H) 7.6 (s, 1H) 7.3 (m, 1H) 7.1 (s, 1H) 6.9 (d, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.6 (s, 1H) 3.2 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.7 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([OH:23])[C:18]([O:20]CC)=O)=[CH:11][C:10]=1[O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:27][C:28]#[N:29].[K+]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]2[O:23][C:28](=[O:27])[NH:29][C:18]2=[O:20])=[CH:11][C:10]=1[O:24][CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)C(O)CCc1ccc(OCc2ccccc2)c(OCC)c1
Agent: [K+]
Product: CCOc1cc(CCC2OC(=O)NC2=O)ccc1OCc1ccccc1

Procedure:
In substantially the same manner as in Working Example 34, ethyl 4-(4-benzyloxy-3-ethoxyphenyl)-2-hydroxybutanoate was reacted with potassium cyanate (KCNO) to obtain 5-[2-(4-benzyloxy-3-ethoxyphenyl)ethyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.143-144° C.