Azzindani/Open_Reaction_Data huggingface dataset:
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.[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][C:16]=2[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:18][C:16]=2[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2c(s1)CCC(CO)C2
Product: Cc1ccc(S(=O)(=O)OCC2CCc3sc(C)nc3C2)cc1
Yield: 74 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above alcohol (IV), according to the procedure described in Example 1. M.p.=105°-106° C. Yield: 74%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:30]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O)[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH2:30][CH2:31][CH3:32])[CH:35]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCCOc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 99.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-propoxybenzaldehyde (623 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (804 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (412 mg) as yellow oil.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:20])([CH:17]([F:19])[F:18])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1>C1COCC1.O>[F:20][C:4]([F:3])([CH:17]([F:19])[F:18])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)C(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
Lithium hydroxide (469 mg, 19.6 mmol) is added to a solution of methyl 5-(2,2,3,3-tetrafluoropropoxyl)pyridine-2-carboxylate (1.047 mg, 3.92 mmol) in THF (7 mL) and water (7 mL). The reaction mixture is stirred for 1 hour at 60° C., cooled to ambient temperature, quenched with 1 M HCl (20 mL), diluted with brine and extracted with dichloromethane (3 times). The organic layers are combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (921 mg, 93%). ES/MS (m/e): 254.0 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[O:8]>CS(C)=O.O>[N:1]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[O:8])=[N+:2]=[N-:3]
Reactant: COc1ccccc1C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1C(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
Add sodium azide (2.14 g, 32.92 mmol) to a solution of 2-bromo-2′-methoxyacetophenone (5.01 g, 21.87 mmol) in 75 ml of DMSO. Stir the mixture at ambient temperature for 18 hours and dilute it with 250 ml of water. Extract the mixture with ether (3×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 3.54 g of 2-azido-1-(2-methoxyphenyl)-ethanone.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: O=CCOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Benzyloxy-acetaldehyde (3.0 g, 20 mmol) is dissolved in tetrahydrofuran (200 mL), cooled to −78° C. This solution is treated with phenylethylmagnesium chloride (1.0 M in tetrahydrofuran, 24 mL, 24 mmol), and stirred for one hour. The mixture is allowed to warm to room temperature and stirred for 4 h. The mixture is treated with hydrochloric acid (1 M, 40 mL) and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over sodium sulfate, and filtered. The filtrate is concentrated in vacuo to provide the title compound, 4.0 g (80%), as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)nc1)C(F)(F)F
Yield: 81.5 %

Procedure:
According to Reference Example 8-12, by use of 6-bromo-3-pyridinecarboxaldehyde (1.00 g, 5.37 mmol), (trifluoromethyl)trimethylsilane (935 μL, 6.45 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 537 μL, 0.537 mmol) and tetrahydrofuran (20 mL), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=19/1) was performed to give 2-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound DD) (1.12 g, yield: 81%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(methylamino)-5-oxopentanoate (Compound SP445) (13.3 g, crude product) was dissolved in a mixture of dichloromethane (140 ml) and trifluoroacetic acid (140 ml), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane and then dried in vacuo to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(methylamino)-5-oxopentanoic acid (Compound SP446) (5.84 g, 93%, two steps).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[BrH:11]>>[BrH:10].[NH2:1][C:2]1[C:7]([CH2:8][Br:11])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1CO
Agent: Br
Product: Nc1ncc(Br)cc1CBr

Procedure:
A solution of 2-amino-5-bromo-3-hydroxymethylpyridine (5.00 g, 24.6 mmole), from Preparation 14 (b), in 48% aqueous HBr (50 mL), was heated at reflux for 12 hrs. The reaction was concentrated and toluene was used to azeotrope the residual H2O. The resulting light brown solid was placed under high vacuum overnight and used directly.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[CH:15][C:14]=3[F:34])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:35][CH3:36].CS(O[CH2:42][CH2:43][CH2:44][C:45]1([OH:48])[CH2:47][CH2:46]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:48][C:45]1([CH2:44][CH2:43][CH2:42][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([N:19]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[CH:15][C:14]=4[F:34])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:35][CH3:36])[CH2:47][CH2:46]1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)cc3F)ccnc2cc1OCCCC1(O)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.616 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate (155 mg, 0.80 mmol), and Cs2CO3 (602.5 mg, 1.848 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (6:1 (v/v) EtOAc/n-hexane). The title compound was obtained as a white solid (263 mg, 73%).
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH:39]1([CH2:43]Br)[CH2:42][CH2:41][CH2:40]1>O>[ClH:1].[CH:39]1([CH2:43][N:19]2[CH2:18][CH2:17][C@:15]34[C:16]5[C:3]6[O:2][C@H:14]3[C:13](=[O:20])[CH2:12][CH2:11][C@@:10]4([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:31][CH3:32])[CH2:42][CH2:41][CH2:40]1
Reactant: BrCC1CCC1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)N(CC2CCC2)CC[C@]314
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (500 mg, 1.19 mmol), potassium carbonate (1.00 g, 7.24 mmol) and cyclobutylmethylbromide (0.6 ml, 5.43 mmol) in water-free N,N-dimethylformamide (7 ml) was stirred for 24 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 20 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 100 ml dichloromethane, washed with water (3×100 ml) and saturated sodium chloride solution (4×100 ml), dried over sodium sulphate and evaporated down. The evaporation residue (520 mg of brown oil) was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 10 ml ether and precipitated by the addition of etherial HCl. Yield: 0.40 g (69%) of the compound 2.HCl as colourless crystals. Fp. 128-133° C.; MS (CI): 488 (M++1); IR (KBr): 1728 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.48 (s, wide, HN+), 7.30-7.15 (m, 5 arom. H), 6.87 (d, 1 arom. H, J=8.4 Hz), 6.77 (d, 1 arom. H, J=8.4 Hz), 4.93 (s, CH-5), 3.81 (s, CH3O).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(Cl)(Cl)Cl>[CH2:17]([NH:19][C:20]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][N:13]=1)=[O:21])[CH3:18]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 76.3 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1 g, 4.5 mmol) in chloroform (5 mL), ethyl isocyanate (0.33 mL, 4.5 mmol) was added. The resulting mixture was microwaved at 110° C. for one hour and concentrated to give 1 g of product (white solid). MS (ESP): 292 (M+H+) for C14H22BN3O3; NMR (CDCl3): 1.22 (t, 3H), 1.32 (s, 2H), 3.41 (m, 2H), 6.82 (d, 1H), 7.90 (dd, 1H), 8.52 (s, 1H), 8.62 (s, 1H), 9.40 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=2[NH:13][C:12]1=[O:29])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:30]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH2:38]Br)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH2:38][N:13]1[C:14]2[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:17][CH:11]([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:12]1=[O:29])(=[O:32])[CH3:31]
Reactant: CC(=O)c1sccc1CBr
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1sccc1CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
To a suspension of sodium hydride (0.119 g of a 60% dispersion in mineral oil) in dry N,N-dimethylformamide (8 ml) was added dropwise a solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5- (2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (1.005 g) in dry N,N-dimethylformamide (5 ml) under stirring at cooling in an ice-bath. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1.5 hours. To the mixture was added a solution of 2-acetyl-3-bromomethylthiophen (0.82 g) in N,N-dimethylformamide (3 ml) under cooling in an ice-bath. The mixture was stirred under the same condition for 30 minutes and then at ambient temperature overnignt. The reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate and water. The organic layer seas washed with water and a brine, and dried over sodium sulfate. Removal of the solvent at reduced pressure gave a crude product. The crude product was purified by column chromatography on silica gel with chloroform as an eluent to give (3RS)-1-(2-acetylthiophen-3-yl)methyl-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (0.80 g).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1COCC1.C(OCC)(=O)C>[F:19][C:17]1[CH:18]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trifluoroethanol in 4 mL dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0° C. The resulting mixture was added dropwise to the solution of 2,4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 mL dry THF at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-fluoro-1-nitro-2-(2,2,2-trifluoro-ethoxy)-benzene.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[N:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:42][C:43]=1[CH3:44])[CH2:12][N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30](O)=[O:31])[C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>ClCCCl.CN(C)C=O>[CH3:44][C:43]1[O:42][C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:40][C:39]=1[CH2:38][O:37][C:36]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30]([Cl:4])=[O:31])[C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)Cl)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 mL of oxalyl chloride was added to the solution of 10.0 g of (±)-4-{9-[3-methoxy-4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-methyl-butyric acid prepared by the example 27 in 1,2-dichloroethane (100 mL), and then 5 drops of N,N-dimethylformamide was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was vacuum concentrated, and (±)-4-(9-(4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-3-methoxybenzyl)-9H-carbazole-4-yloxy)-2-methylbutanoyl chloride was prepared.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[CH2:32]([O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCc4ccccc4)cc3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
Compound 184 (100 mg, 0.29 mmol) obtained in Reference Example 181 was dissolved in 2 ml of dimethylformamide. To the solution were added 162 mg (1.17 mmol) of potassium carbonate and 0.28 ml (2.35 mmol) of benzyl bromide, and the mixture was stirred at 80° C. for 2.5 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give 67 mg (yield 53%) of Compound 185 as yellow needles.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ncoc1CSCCN
Product: Cc1ncoc1CSCCNC(=S)NC(=O)c1ccccc1

Procedure:
5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with benzoyl isothiocyanate by the procedure of Example 18 to give N-benzoyl-N'-[2-((4-methyl-5-oxazolyl)-methylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+:25]>C(O)C>[Na+:25].[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)[O-])c1
Reaction time: 1 h

Procedure:
The 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D, 5.5 g, 17.6 mmol) was dissolved in abs ethanol (20 ml) by warming gently followed by addition of NaOH (0.705 g) at 0° C. temperature. The reaction mixture was stirred for one hour, concentrated in vacuo and lyophilized to give as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31]S(C)(=O)=O)[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl.[CH:39]1([CH2:42]O)[CH2:41][CH2:40]1>>[CH:39]1([CH2:42][O:31][CH2:30][C:19]2[CH:18]=[C:17]([C:15]3[O:14][N:13]=[C:12]([C:10]4[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=4)[N:16]=3)[CH:22]=[CH:21][C:20]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:41][CH2:40]1
Reactant: OCC1CC1
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COS(C)(=O)=O)c3)n2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1COCC1CC1
Temperature: 130 °C

Procedure:
Methyl 2-fluoro-4-[5-(2′-methyl-2-{[(methylsulfonyl)oxy]methyl}biphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzoate, prepared as in example 58, step 1, (75 mg; 0.15 mmol) was dissolved in cyclopropylmethanol (5 mL). The solution was then heated in the microwave at 130° C. for 10 min. Sodium hydroxide (151.05 μL; 5 M; 0.76 mmol) was added and the mixture was heated at 60° C. for 10 min in the microwave. Hydrogen chloride (151.05 μL; 5 M; 0.76 mmol) was added and the mixture was evaporated to dryness. The crude was purified with MD Autoprep, to afford the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) 13.63 (br s, 1H), 8.35 (d, J=1.5 Hz, 1H), 8.18 (dd, J=7.8, 1.9 Hz, 1H), 8.13-8.08 (m, 1H), 8.04 (dd, J=8.0, 1.4 Hz, 1H), 7.96 (dd, J=11.1, 1.2 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 4.30-4.20 (m, 2H), 3.20-3.17 (m, 2H), 2.04 (s, 3H), 1-0.91 (m, 1H), 0.46-40 (m, 2H), 0.14-0.09 (m, 2H). LC/MS (Method B): 457.3 (M−H)−, 459.2 (M+H)+. HPLC (Method A) Rt 5.67 min (Purity: 98.5%).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])=[O:38])=[N:35][CH:36]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])=[N:35][CH:36]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c(-c2ccc(C(=O)NCCC(=O)O)nc2)c1
Temperature: 55 °C

Procedure:
A 1M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to a THF (1 mL) and MeOH (5 mL) solution of ethyl 3-(5-(2-((4′-chloro-[1,1′-biphenyl]-4-yl)carbamoyl)-5-methylphenyl)picolinamido)propanoate (50 mg, 0.09 mmol) and the resulting mixture was heated to 55° C. After 10 min the resulting mixture was neutralized with 2M aqueous HCl, concentrated and extracted with EtOAc. The combined extracts were concentrated and purified via column chromatography to yield the title compound.