Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([O-])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:54]([O:58][C:59](=[O:62])[CH2:60][NH2:61])([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([NH:61][CH2:60][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:62])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)[O-])C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
More specifically, a dried methylene chloride solution containing 394 mg (1 mmol) of 1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylate, 309 mg (1.5 mmol) of dicyclohexylcarbodiimide and 134 mg (1.1 mmol) of dimethylaminopyridine was stirred for one hour. To this reaction mixture, 157 mg (1.2 mmol) of glycine t-butyl ester was added and the reaction mixture was refluxed for 2 hours. Insoluble components were removed from the reaction mixture by filtration and the reaction mixture was chromatographed on a silica gel column for purification, whereby 508 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][CH:9]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:12])[NH:28][CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)c1ccc(C(=O)O)s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cccc3ccccc23)s1
Reaction time: 0.17 h

Procedure:
1.9 g Thiophene-2,5-dicarboxylic acid monomethyl ester and 1.2 mL N-methylmorpholine is dissolved in 20 mL of CH2Cl2 at −10° C. To this solution is added 1.5 mL isobutyl chloroformate. After 10 min of stirring, 1.7 mL 1-(aminomethyl)-naphthalene in 5 mL of CH2Cl2 is added. The cooling bath is removed and the reaction mixture is allowed to reach rt. After 90 min, 10 mL of water and 10 mL 2N HCl are added. The phases are separated, and the organic phase is washed with water. After evaporation of the solvent there is obtained 4.4 g crude 5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (1b) which is purified by recrystalisation from ethylacetate, petrol ether, yielding 58%, mp 125° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:28])[C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:25]([C:24]2[C:23]([Cl:28])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:18])=[O:26])[NH2:17])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NN(C(=O)c1c(Cl)cncc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 96 %

Procedure:
Triethylamine (1.40 mL, 1.02 g, 10.1 mmol) was added to a suspension of 4-chlorophenylhydrazine hydrochloride (1.83 g, 98%, 10.0 mmol) in THF (75 mL). The mixture was stirred under nitrogen at room temperature for 2.75 h. More triethylamine (3.0 mL, 21.6 mmol) was added followed by dropwise addition of a solution of freshly-prepared 3,5-dichloropyridine-4-carbonyl chloride (10.0 mmol) in THF (20 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The layers were shaken together and allowed to separate. The organic phase was dried (Na2SO4) and concentrated, leaving 3.04 g of a tan solid, mp 201-203.5° C. Recrystallized from ethyl acetate/cyclohexane and then from ethanol furnished crystals which melted at 206-207.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40]O)([CH3:35])([CH3:34])[CH3:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:32]([O:36][C:37](=[O:42])[NH:38][CH2:39][CH2:40][O:12][C:3]1[C:4]([F:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[F:1])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a solution of 2,6-difluoro-3-nitrophenol (248 mg, 1.416 mmol) and triphenylphosphine (558 mg, 2.127 mmol) in THF (10 mL) was added a solution of (2-hydroxyethyl)carbamic acid tert-butyl ester (274 mg, 1.70 mmol) in THF (2 mL). The mixture was cooled in an ice bath and a solution of diethyl azodicarboxylate (372 mg, 2.127 mmol) in THF (2 mL) was added over 5 min. The reaction was removed from the ice bath after 5 min and stirred at RT for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 30-40% EtOAc in cyclohexane) affording the title compound as a colourless gum (483 mg, quantitative). 1H NMR (CDCl3, 300 MHz): 7.84 (1H, ddd, J=9.5, 7.8, 5.3 Hz), 7.05 (1H, dt, J=9.9, 2.2 Hz), 5.05 (1H, bs), 4.26 (2H, t, J=5.0 Hz), 3.52 (2H, q, J=5.4 Hz), 1.45 (9H, s)
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:29])[CH2:8][C:9]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)(O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([F:22])[CH:13]=1)[C:3]([O:5]C)=[O:4].CCCC[Sn](Cl)(O[Sn](Cl)(CCCC)CCCC)CCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:4])[O:5][C:9]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([F:22])[CH:13]=2)[CH2:8][C:7]=1[OH:29]
Reactant: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC(C)C)c(F)c1)C1CCCC1
Agent: CCCC[Sn](Cl)(CCCC)O[Sn](Cl)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1F
Yield: 49.2 %

Procedure:
A solution of methyl 2-chloro-5-cyclopentyl-7-(3-fluoro-4-isopropoxyphenyl)-5-hydroxy-3-oxoheptanoate (1.74 g, 4.1 mmol), and bis(dibutylchlorotin)oxide (1.38 g, 2.5 mmol), dissolved in toluene (20 mL) were heated at reflux for 30 mins. The resulting mixture was concentrated and purified by silica gel chromatography to give the title compound (0.80 g, 50% yield, two Steps).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:26]=[CH:25][C:18]2[C:19](=O)[O:20]C(=O)[NH:22][C:17]=2[CH:16]=1>CCCCCC.O1CCCC1>[NH2:22][C:17]1[CH:16]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:26]=[CH:25][C:18]=1[C:19](=[O:20])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2c(=O)o1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(=O)c1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 11.1 ml) was added during 2 minutes to a stirred solution of 1,5-dimethyltetrazole (2.94 g) in dry tetrahydrofuran (100 ml) at -10° to -5°. After stirring for 15 minutes, 7-trifluoromethyl-1H-3,1-benzoxazine-2,4-dione (2.3 g) was added during 5 minutes at -10° to -5°. The reaction mixture was stirred at ambient temperature for 1 hour. Industrial methylated spirit (2 ml) was added and the mixture kept at ambient temperature for 1.5 hours. The mixture was evaporated to one quarter volume, then poured on to ice. The mixture was acidified to pH 2 with hydrochloric acid (5N). The solid product was collected, dried and recrystallised from ethyl acetate:diethyl ether to give the novel compound 1-(2-amino-4-trifluoromethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 200°-201°.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2cccs2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-thiophene carboxaldehyde (12.5 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Thiophen-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 8 as a colorless oil (25.2 mg, 82%). LRMS 343.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:20](Cl)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C([O-])(O)=O.[Na+]>>[N:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:2][CH2:3]2)=[CH:12][CH:11]=1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 10 mL round bottom flask was charged with piperidine 32 (500 mg, 3.08 mmol), and then triethylamine (314 mg, 3.10 mmol), and then CbzCl (529 mg, 3.10 mmol), and the reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was then poured into 50 mL of an aqueous solution saturated with NaHCO3 and extracted with 3×50 mL of methylene chloride. The organic fractions were pooled, dried over Na2SO4, filtered, concentrated under reduced pressure, and not purified further. Crude yield of 33: 900 mg (99%). 1H NMR (500 MHz, CDCl3) δ 1.87 (m, 2H), 2.30 (m, 2H), 2.69 (m, 1H), 2.91 (bs, 2H), 4.37 (bs, 2H), 5.17 (m, 2H), 7.13 (d, J=6.3 Hz, 2H), 7.39 (m, 5H), 8.54 (d, J=6.3 Hz, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:22][C:23]([NH2:25])=[O:24]>CN(C)C=O>[C:23]([CH2:22][N:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][CH:5]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=[O:24])[NH2:25]
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC2C=CC(I)=CN2CC(N)=O)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product (1.60 g, 4.27 mmol) from Step A in 8.0 mL of dry N,N-dimethylformamide was added sodium hydride (188 mg of 60 weight % dispersion in mineral oil, 4.44 mmol). After 15 min, the solution was warmed to 60° C. for 10 min, and was then cooled to room temperature. Chloroacetamide (420 mg) was added in one portion, and the solution was then warmed to 100° C. After 2.5 h, the solution was cooled to room temperature and poured into 70 mL of ice-water. The resultant precipitate was collected, washed with water and air-dried overnight. The crude product was subsequently stirred with 20 mL of methanol for several minutes, and the product was collected by filtration to afford the title compound as a white powder. LC/MS 414.9 (M+1-H2O).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:11][S:12](=[O:15])(=[O:14])[NH2:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:16][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][S:12]([NH2:13])(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)NC(CCS(N)(=O)=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC(CCS(N)(=O)=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
Hydrogen chloride (4M in dioxan, 1.0 mL, 4.00 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-sulfamoylpropylcarbamate (Intermediate 103) (38 mg, 0.11 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 24 hours. The mixture was evaporated to dryness and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford 3-amino-3-(4-chlorophenyl)propane-1-sulfonamide (20.00 mg, 73.8%) as a colourless gum.
Reaction SMILES: [C:1]([NH:11][NH2:12])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[O:10])=[CH:7][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: c1ccncc1
Product: CCCC(=O)NNC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.25 mol of anisohydrazide is dissolved in 300 ml of pyridine. At room temperature, 0.25 mol of butyryl chloride is added dropwise, and the mixture is stirred for a further 11/2 hours. The mixture is subsequently poured into 1.5 1 of ice/water, and the crystals are filtered off with suction and washed with water. The N-(4-methoxybenzoyl)-N'-butyrylhydrazine obtained is recrystallized from toluene. 0.1 mol of this compound and 0.1 mol of Lawesson's reagent are refluxed for 10 hours in 200 ml of THF. 2/3 of the solvent are removed by distillation, the residue is poured into 500 ml of water and 50 ml of 32% sodium hydroxide solution, and the precipitate is filtered off with suction and recrystallized from ethanol/activated charcoal, to give 2-(p-methoxyphenyl)-5-propyl-1,3,4-thiadiazole, m.p. 54°, C 0°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.Cl.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:22]=[CH:23][C:24]([C@H:27]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[C@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[CH:5]=[CH:4][N:3]=2)[CH3:28])=[CH:25][CH:26]=1.[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:22]=[CH:23][C:24]([C@@H:27]([NH:29][C:2]2[N:7]=[C:6]([N:8]3[C@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[CH:5]=[CH:4][N:3]=2)[CH3:28])=[CH:25][CH:26]=1
Reactant: CC(N)c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC[C@@H](c2ccccc2)N1c1ccnc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](Nc1nccc(N2C(=O)OC[C@H]2c2ccccc2)n1)c1ccc(-c2ccccc2)cc1
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@H]2c2ccccc2)n1)c1ccc(-c2ccccc2)cc1

Procedure:
A solution of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (97 mg, 0.35 mmol), 1-(biphenyl-4-yl)ethanamine hydrochloride (304 mg, 1.30 mmol, 3.7 equiv) and iPr2NEt (0.307 mL, 1.76 mmol, 5.0 equiv) in DMSO (1 mL) was heated at 110° C. for 1½ h and at 130° C. for 20 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (R)-3-(2-((R)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one and (R)-3-(2-((S)-1-(biphenyl-4-yl)ethylamino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[O:15][C:16]=1[CH3:17])[CH:5]=[O:6].C(O)C.[BH4-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[N:13]=[C:14]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[O:15][C:16]=1[CH3:17]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzaldehyde (4.93 g) in tetrahydrofuran (100 mL)-ethanol (50 mL) was gradually added sodium borohydride (0.51 g) at 0° C. After stirring at room temperature for 2 hrs, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol as colorless crystals (4.40 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [C:1]12(C)[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:20]([O:19][C:12]1([O:16][CH2:17][CH3:18])[CH2:7][CH:1]2[C:8]([CH3:10])([CH3:9])[C:5]1([CH3:6])[CH2:4][CH2:2]2)[CH3:21]
Reactant: CC12CCC(CC1=O)C2(C)C
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC1(OCC)CC2CCC1(C)C2(C)C

Procedure:
To a flask with reflux condenser, (25 g) camphor and 50 ml absolute ethanol was taken. (36.45 g) (1.5 eq.) triethyl orthoformate and crystals of p-toluenesulfonic acid was added into the reaction mixture. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled and concentrated on rotavapour and was washed with 10% potassium hydroxide solution. Extract it with dichloromethane and concentrated the organic layer on rotavapour, yellow colored liquid product was obtained. 38. g (Quantitative)
Reaction SMILES: C(Cl)Cl.[C:4]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27]C)[CH:16]=2)[CH:5]=1.B(Br)(Br)Br>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:4]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([OH:27])[CH:16]=2)[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cn(-c2ccc(/C=C/C(=O)NCc3cccc(-c4ccccc4)c3)cc2O)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.1 %

Procedure:
To a methylene chloride solution (3 mL) of (E)-N-biphenyl-3-ylmethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid amide (100 mg) obtained in Example 121, boron tribromide (1M pentane solution, 1.18 mL) was added dropwise at −78° C. and the reaction solution was agitated at room temperature for 6 hours. The reaction solution was diluted with a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: chloroform-methanol system), and 16.5 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([NH:12][C:13](=[O:29])[CH2:14][C:15]2[CH:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:18]=[CH:19][C:20]=2[CH3:21])([C:8](OC)=[O:9])[CH2:4][CH2:3]1.CN(C)C(=O)C.CC(C)([O-])C.[K+].Cl>O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][C:5]2([NH:12][C:13](=[O:29])[C:14]([C:15]3[CH:16]=[C:17]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH:18]=[CH:19][C:20]=3[CH3:21])=[C:8]2[OH:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(F)cc3)ccc2C)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2ccc(F)cc2)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.80 g (5.94 mmol) of the compound from Example 7A were initially charged in a solution of 8 ml of DMA (N,N-dimethylacetamide), a solution of 5 ml of DMA and 1.75 g (2.5 eq.) of potassium tert-butoxide was added dropwise at 20° C. and the mixture was stirred at room temperature for 4 h. The mixture was poured into 200 ml of water and the reaction was adjusted to pH 2 using concentrated aqueous hydrochloric acid, and the resulting residue was filtered off with suction. Purification by flash column chromatography (silica gel; ethyl acetate/n-hexane 1:1) gave 1.07 g (44% of theory) of the title compound.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13]([C:26]([O:28]CC)=[O:27])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13]([C:26]([OH:28])=[O:27])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(COc2nc(N3CCc4ccccc43)ncc2C(=O)O)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a suspension of ethyl 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-5-pyrimidinecarboxylate (5.5 g, 13.6 mmol) in ethanol (50 mL) were added 10% aqueous sodium hydroxide solution (30 mL) and tetrahydrofuran (30 mL) and the mixture was heated under reflux for 30 min. The reaction mixture was allowed to cool to room temperature and 1N hydrochloric acid was added to adjust the reaction mixture to pH 5. The precipitated crystals were collected by filtration, washed several times with water, and dried with heating under vacuum to give 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-5-pyrimidinecarboxylic acid (4.9 g, 96%) as crystals. A suspension of the obtained carboxylic acid (564 mg, 1.5 mmol), L-α-amino-ε-caprolactam (384 mg, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (612 mg, 3.0 mmol) and 1-hydroxybenzotriazole (408 mg, 3.0 mmol) in dichloromethane (2 mL) was stirred at room temperature for 18 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (650 mg, 89%).