Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[S:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[S:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=S)c1cnc(C)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C(O)=S)cc1OC1CCCC1
Reaction time: 6 h
Yield: 73.7 %

Procedure:
A solution of potassium hydroxide (582 mg) in water (6 mL) is added to a stirred solution of methyl 5-cyclopentyloxy-6methylthionicotinoate (920 mg) in methanol at room temperature and the mixture stirred for 6 hours. After concentrating in vacuo the mixture is diluted with water and acidified to pH 1 with aqueous 2 M hydrochloric acid. The product is extracted into ethyl acetate, the extracts treated with decolourising charcoal, dried (MgSO4) and evaporated. The residue is triturated with n-pentane to give 5-cyclopentyloxy-6-methylthionicotinic acid (640 mg) as a white solid, m.p. 177-8° C. [Elemental analysis: C, 56.90; H, 6.02; N, 5.52%. calculated: C, 56.90; H, 5.97; N, 5.53%.].
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([OH:22])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40]>>[C:1]([O:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)O)C(C)C
Yield: 82.1 %

Procedure:
Starting from 2-hexadecanoyloxyhexadecanoic acid (2.55 g) prepared by the method described in Preparation A-3 and L-valine (2.34 g), N-(2-hexadecanoyloxyhexadecanoyl)-L-valine (2.5 g) was obtained as crystals according to a similar manner to that of Preparation B-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[OH:11])=O)=[CH:4][CH:3]=1.[CH:19]([NH2:21])=O.P(Cl)(Cl)(Cl)=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:21]=[CH:19][O:11][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)C(O)c2ccc(C)cc2)cc1
Reactant: NC=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ncoc2-c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
4,4'-Dimethylbenzoin (25.0 g), formamide (230 ml) and phosphorus oxychloride (16.0 ml) was mixed and stirred under reflux for 5.5 hours. The reaction mixture was cooled to room temperature and poured into water, and then extracted with diethyl ether twice. The collected organic phases were washed with brine and dried over magnesium sulfate and activated carbon. The mixture was filtered and evaporated in vacuo, and then purified by column chromatography on silica. The solvent was evaporated to afford 4,5-bis(4-methylphenyl)oxazole (15.41 g) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:24]2[CH2:23][CH2:22][N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=3)[CH2:26][CH2:25]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzenesulfonyl chloride, 1-(m-chlorophenyl)piperazine, and triethylamine are stirred at reflux to give 1-[(p-nitrophenyl)sulfonyl]-4-(m-chlorophenyl)piperazine.
Reaction SMILES: ClC1C=NC=C(Cl)C=1.[CH3:9][O-:10].[Na+].O.Cl[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1>CS(C)=O.C(OCC)C>[CH3:9][O:10][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: C[O-]
Reactant: COc1cncc(Cl)c1
Agent: Clc1cncc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cncc(OC)c1

Procedure:
50 g of 3,5-dichloro-pyridine are dissolved in 250 ml dimethylsulfoxide. 15 g sodium methylate are added to this solution under stirring. It is stirred under exclusion of moisture at 60°-80° C. 15 g sodium methylate are further added after each of 8 and 16 hours. After a total of 72 hours' stirring, the reaction mixture is reacted with a little water and shaked out with diethylether. The ether phase, after drying, is distilled in a vacuum, resulting in 24 g (51% of theoretical amount) of 3,5-dimethoxy-pyridine in the boiling range 90°-120° C. at 1.6·103Pa. The product is polluted with a small amount of 3-chloro-5-methoxypyridine. It can, however, be employed directly in the next stage for nitrification, since the chloro-compound is not dinitrified and therefore can easily be removed upon crystallization of the 3,5-dimethoxy-2,6-dinitro-pyridine.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:10]=2[C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[CH2:29][N:30](CC)CC.Br[CH:36]([CH3:40])[C:37](Br)=[O:38].CN>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH3:29][NH:30][CH:36]([CH3:40])[C:37]([NH:15][C:13]1[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=1)=[O:38]
Reactant: CC(Br)C(=O)Br
Reactant: CCN(CC)CC
Reactant: Nc1cc(-c2ccncc2)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CNC(C)C(=O)Nc1cc(-c2ccncc2)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6-(2-phenylethynyl)-4-(pyridin-4-yl)-5-(pyrimidin-5-yl)pyridin-2-amine G9 (72 mg, 0.21 mmol), DMAP (0.05 mg, 4 μmol) and Et3N (43 μl, 0.31 mmol) in dioxane (4.3 ml) is stirred at 0° C. for 15 minutes. 2-bromo-propionyl bromide (33 μl, 0.31 mmol) is added dropwise and the mixture stirred at RT for 1 h. The mixture is heated to 90° C. and stirred for 16 h. Et3N (43 μl, 0.31 mmol) and 2-Bromo-propionyl bromide (33 μl, 0.31 mmol) is added and the mixture stirred for another 3 h. The mixture is cooled to RT, methylamine (2 mol/l solution in THF, 1.03 ml, 2.06 mmol) is added and the mixture stirred for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 7.6 mg (9%). HPLC-MS: M+H=435; tR=.2.75 min (METHOD—6).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3C(F)(F)F)C2=O)cn1
Yield: 37 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-(trifluoromethyl)benzene. Yield: 37%. MS M+H calculated 434.1. Found 434.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.2 uM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1.[H-].[Na+].Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]2)=[CH:4][C:5]([O:9][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(=O)C(C)Br
Reactant: Cc1cc(Cl)c(-n2nc(C)n(C(F)F)c2=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Yield: 98.5 %

Procedure:
In a manner similar to Example 2, Step G, the reaction of 3.0 g (0.01 mole) of 1-(2-chloro-4-methyl-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.25 g (0.01 mole) of sodium hydride and 1.75 g (0.01 mole) of methyl 2-bromopropionate in 100 mL of N,N-dimethylformamide produced 3.7 g of methyl 2-[4-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-2-methylphenoxy]propionate as an oil, Compound 4.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)([O-:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N+:2]([O-:4])=[O:3])[N:12]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3[N+](=O)[O-])cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(2-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.47 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted twice with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid and boiling there separated, upon cooling, 0.58 g of 4-methyl-N-[4-(2-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellow crystals.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:16][N:15]=2)=[CH:9][CH:8]=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:35](=[O:38])[CH2:36][CH2:37][N:15]3[N:16]=[C:17](/[CH:19]=[CH:20]/[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[N:18]=[C:14]23)=[CH:11][CH:12]=1
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: C=CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc3n(n2)CCC(=O)N3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (3 mL) and TEA (0.06 mL) were added to (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162 (44 mg), and the reaction solution was stirred at room temperature for 10 minutes. Acrylic acid chloride (0.01 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour and at 60° C. for two hours. TEA (0.03 mL) and acrylic acid chloride (0.01 mL) were added to the reaction solution at 60° C., and the reaction solution was stirred at 60° C. for four hours. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) and further purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH2:23][CH2:24][C:25](O)=[O:26])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:3]1=[O:32]>O1CCCC1>[CH3:12][CH2:10][CH2:9][CH:6]([CH3:7])[CH3:5].[OH:26][CH2:25][CH2:24][CH2:23][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:32])[N:4]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(CCC(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CCCO)c(Cc3ccccc3C(F)(F)F)sc21
Product: CCCC(C)C
Temperature: 55 °C
Yield: 119.9 %

Procedure:
The product of Example 28 (674 mg) was dissolved in tetrahydrofuran (20 ml) and LiA1H(OtBu)3 (4 ml of 1M solution in tetrahydrofuran) was added. The mixture was heated at 55° C. under an atmosphere of nitrogen for 17 hrs. The reaction was quenched with water, concentrated in vacuo and purified via chromatography, eluting with 1:1 diethyl ether:isohexane to give the title compound (392 mg).
Reaction SMILES: Cl.C[N:3]([CH2:10][CH2:11][Cl:12])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[C:13](=O)(O)[O-].[Na+]>O>[ClH:12].[CH3:13][O:9][C:7]([CH:4]1[CH2:5][S:6][CH2:11][CH2:10][NH:3]1)=[O:8]
Reactant: O=C([O-])O
Reactant: CN(CCCl)[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C1CSCCN1
Temperature: 25 °C
Reaction time: 120 h
Yield: 53 %

Procedure:
20 g (0.085 mol) methyl 2-chloroethyl cysteine hydrochloride was dissolved with 200 ml water, and a solution of 7.2 g (0.085 mol) sodium bicarbonate dissolved in 120 ml water was added dropwise to the above-obtained solution under ice bath condition, and then the mixed solution was allowed to react by keeping a constant temperature in the bath ice for 1 hour. The obtained reaction product was extracted with ethyl acetate (100 ml×3), and the resulting ester layers were combined, and dried with anhydrous sodium sulfate for 4 hours. The solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved with 400 ml anhydrous methanol, and reacted with stirring at room temperature for 5 days, followed by removing solvent by evaporation under reduced pressure. The resulting residue was recrystallized with anhydrous methanol/ethyl acetate, obtaining 8.9 g of a white crystal, yield 49.2%.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C)C=O.[Cu]>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 4-hydroxybenzoate (25.3 g, 111 mmol) in N,N-dimethylformamide (60 ml) was added potassium tert-butoxide (12.4 g, 111 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure and 2-bromopyridine (24.5 g, 155 mmol), a copper powder (1.76 g, 27.7 mmol) and N,N-imethylformamide (80 ml) were added. The mixture was stirred at 120° C. for 8 hrs. The reaction solution was filtered with celite, and the filtrate was evaporated under reduced pressure. To the residue was added water (500 ml), and the mixture was extracted with ethyl acetate (500 ml). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1). Recrystallization from ethyl acetate-hexane gave the objective substance (25.5 g, 73%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37](=[O:43])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:17]=[CH:18][C:19]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69]O>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:41][C:40](=[O:42])[CH2:39][CH2:38][C:37]([NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:16]1[CH:17]=[CH:18][C:19]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[C:14]([Cl:13])[CH:15]=1)=[O:43]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Reactant: COCCOCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOCCOC(=O)CCC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Reaction time: 48 h

Procedure:
A solution of diethylazodicarboxylate (40% in toluene, 229 μL, 0.5 mmol) was slowly added to a mixture of N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (200 mg, 0.46 mmol) (disclosed in WO 01/05746), triphenylphosphine (132 mg, 0.50 mmol), and 2-(2-methoxyethoxy)ethanol (55 mg, 0.46 mmol) in dry toluene (2.5 ml). The reaction mixture was stirred for 48 h and then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:14]1.[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[N:12]=[C:13]1[S:17][CH2:16][C:15]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: Cc1ccc([N+](=O)[O-])c(N=C2NC3(CCCC3)CS2)c1C
Reactant: CC(C)CBr
Product: Cc1ccc([N+](=O)[O-])c(N=C2SCC3(CCCC3)N2CC(C)C)c1C

Procedure:
2,3-Dimethylaniline was converted to 2,3-dimethyl-6-nitroaniline according to Method A4a. The aniline was converted to 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method A2d. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2,3-dimethyl-6-nitrophenyl isothiocyanate according to Method C1e to give 2-(2,3-dimethyl-6-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2b to afford 2-(2,3-dimethyl-6-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:31][CH2:29][CH3:30])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCNCc1c(C(=O)OCC)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
5-Fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1.) was reacted with ethyl amine as described in Example 86.1. to give 3-ethylaminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was reacted with methyl chloroformate as described in Example 77.1. to give 3-[(ethyl-methoxycarbonyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 3-[(ethyl-methoxycarbonyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid as an off-white solid. MS: 433.5 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[Br:15]Br>C1COCC1>[Br:15][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1Br
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The 3-fluoro anisole (15 g, 119 mmol) was placed in THF (300 mL) and cooled to about −78° C., and then n-BuLi (89 mL 1.6 M in hexanes) was added while maintaining the temperature at around −70° C. The mixture was stirred for about 15 minutes, and bromine (18.9 g, 119 mmol) was added over 10 minutes. The mixture was warmed to r.t. and stirred overnight. The mixture was quenched with water, diluted with ether (500 mL) and partitioned between water/ether (1/1 300 mL). The water layer was back extracted with ether (250 mL), and the combined organic fractions were dried, filtered and concentrated. The dark residue was distilled under house vacuum (product 115–130° C.) to recover about 13.8 g of the product as a gray oil (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.FC(F)(F)C1C=CC=C(C=C)C=1.[H-].[Na+].Cl[CH2:39][C:40]1[N:44]=[C:43]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[O:42][N:41]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=3)[CH2:11][N:10]([CH2:39][C:40]3[N:44]=[C:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)[O:42][N:41]=3)[C:9]2=[O:23])=[CH:4][CH:3]=1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Cl)cc1
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Agent: C=Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN3C[C@H](c4cccc(C(F)(F)F)c4)N(c4ccc(Cl)cc4)C3=O)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-1-(4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (40 mg, 0.117 mmol, prepared by following the same procedure as described in example 151 using 1-(trifluoromethyl)-3-vinylbenzene as the starting material.) in anhydrous DMF (2 mL) is cooled down to 0° C. in an ice bath when NaH (17 mg, 60% in mineral oil, 0.423 mmol) is added into the solution portion wise. After the addition, the mixture is stirred at 0° C. for 10 min when a solution of 3-(chloromethyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole (31.6 mg, 0.141 mmol) in DMF (1 mL) is added into the mixture. The resulted mixture is allowed to warm up to room temperature and stir for 1 h. The residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CD3OD, 400 MHz) δ 7.95 (d, J=9.2 Hz, 2H), 7.62 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.48-7.39 (m, 2H), 7.31 (d, J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 5.50 (dd, J=9.2, 6.0 Hz, 1H), 4.68 (m, 2H), 4.07 (t, J=9.2 Hz, 1H), 3.78 (s, 3H), 3.41 (dd, J=9.0, 6.0 Hz, 1H); HPLC-MS calculated for C26H21ClF3N4O3 (M+H+) 529.1, found 529.0.