Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O.Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1c(C=O)cccc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2cccc(OC)c2o1
Yield: 19.5 %

Procedure:
A solution of 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (2.00 g) and potassium tert-butoxide (963 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour under ice-cooling. Water was added to the reaction mixture, and the solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane:ethyl acetate=7:1, v/v) to give 2-ethoxycarbonyl-7-methoxybenzofuran (360 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.Cl.[OH:14][C:15]1[CH:26]=[C:25]2[C:18]([NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C(Cl)CCl.C(OCC)(=O)C>CCCCCC>[OH:14][C:15]1[CH:26]=[C:25]2[C:18](=[CH:17][CH:16]=1)[NH:19][CH:20]=[C:21]2[CH2:22][CH2:23][NH:24][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc(O)cc1)NCCc1c[nH]c2ccc(O)cc12

Procedure:
(E)-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-3-(4-hydroxyphenyl)acrylamide (2b) was synthesized according to by the condensation of 4-hydroxy cinnamic acid (150 mg, 0.914 mmol) and 5-hydroxy tryptamine hydrochloride (232 mg, 1.09 mmol) using standard EDC coupling method. 2b was isolated as reddish semi solid (182 mg 62%) by elution with 55% ethyl acetate in hexane. Rf: 0.58 (ethyl acetate);
Reaction SMILES: [Cl:1][CH:2]([F:14])[CH2:3][CH:4]([F:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[ClH:1].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH:2]([F:14])[CH2:3][CH:4]([F:13])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:6])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)Cl
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
A mixture of γ-chloro-2,4-difluorobutyrophenone (14.2 g), 4-(4-chlorophenyl)-4-hydroxypiperidine (13.8 g), anhydrous potassium carbonate (9.0 g), potassium iodide (0.5 g) and dimethylformamide (170 ml) was heated for 20 hours at 90° - 110°C. After cooling, the reaction mixture was diluted with water and extracted with ether. The ethereal extract was sufficiently washed with water, dried over anhydrous sodium sulfate, treated with hydrogen chloride and then concentrated. Trituration and recrystallization of the residue from methanol gave γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride. M.P. 245°C (decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cn2)CC1
Temperature: 80 °C
Yield: 10.1 %

Procedure:
A tube was charged with 2,5-dibromopyridine (0.24 g, 1.0 mmol), 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.1 mmol), di-isopropylethylamine (0.19 mL, 1.1 mmol) and N-methylpyrrolidinone (1.0 mL). The tube was sealed and the mixture was heated at 80° C. overnight. The temperature was increased to 120° C. and heated overnight. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 4-(5-bromo-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 10%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1[F:19].C(N(C(C)C)CC)(C)C>ClCCl>[F:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]([F:22])([F:23])[F:21])=[CH:14][C:13]=1[NH:12][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccc(C(=O)Cl)cc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1I
Temperature: 0 °C

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.0 g, 38.2 mmol) in thionyl chloride (30.0 mL) was heated at reflux for 3 hours. The resulting yellow solution was cooled to room temperature and concentrated under reduced pressure to afford 3-iodo-4-methylbenzoyl chloride. A solution of 3-iodo-4-methylbenzoyl chloride (1 g, 4 mmol) in dichloromethane (10 mL) was added slowly to a 0° C. solution of 3-amino-4-fluorobenzotrifluoride (0.7 ml, 4 mmol) and diisopropylethylamine (0.9 ml, 5 mmol) in dichloromethane (10 mL). The reaction stirred at 0° C. and warmed to room temperature over 20 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 100% ethyl acetate-hexane) to afford N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide 34 MS m/z found 423.9 [MH+]; calc. for C15H10F4INO=423.14.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](Br)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].O>O1CCOCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[CH:13]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Yield: 77.4 %

Procedure:
870 mg (2.78 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester, 53 mg (0.28 mmol) of copper (I) iodide, 1.126 g (5.5 mmol) of potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2-one are refluxed in 15 ml of dioxane for 8 hours. After water is added, the dioxane is distilled off in a vacuum, made alkaline with about 12% ammonia solution and shaken out several times with ethyl acetate. The collected ethyl acetate phase is washed, dried, filtered and concentrated by evaporation. As a residue, 700 mg (77% of theory) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH3:47])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4Cl)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((R)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)-2-methylpiperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.072 g, 0.12 mmol) in dichloromethane (1.5 mL) and the resulting solution was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the product as a white solid (0.007 g, 0.014 mmol, 12%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1 H), 7.66 (d, J=8.8 Hz, 1 H), 7.45 (d, J=1.6 Hz, 1 H), 7.14 (dd, J=1.6, 8.4 Hz, 1 H), 6.93 (d, J=8.4 Hz, 1 H), 6.85 (d, J=8.4 Hz, 1 H), 6.50 (d, J=2.0 Hz, 1 H), 5.89 (q, J=6.8 Hz, 1 H), 4.86-4.80 (m, 1 H), 4.56-4.85 (m, 1 H), 4.28-4.25 (m, 1 H), 3.99-3.94 (m, 1 H), 3.86-3.82 (m, 1 H), 3.73-3.70 (m, 1 H), 3.56-3.50 (m, 1 H), 3.44-3.31 (m, 2 H), 3.20-3.17 (m, 1H), 2.86-2.81 (m, 2 H), 2.71-2.66 (m, 1 H), 2.16-2.06 (m, 1 H), 1.96 (d, J=6.8 Hz, 3 H), 1.48-1.25 (m, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O [M+H]+486.2, found 486.4
Reaction SMILES: [C:1]1(=[O:16])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>ClC(Cl)C>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:7]1[N:6]([N:5]2[C:4](=[O:11])[C:3]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]3[C:1]2=[O:16])[CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(c1ccccc1F)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a mixture of N-phthalimidopyrrole (10 g, 47 mmole) and fused zinc chloride (10 g, 73 mmole) in 80 ml dichloroethane was added o-fluorobenzoyl chloride (7.5 g, 47 mmole). The reaction mixture was stirred at ambient temperature for twenty hours and at 80° for one hour. Thereafter, it was cooled, poured into water and extracted with dichloromethane. The organic extract was washed with water and with saturated sodium chloride solution, and dried over magnesium sulfate. The solution was filtered and evaporated to an oil which yielded a solid upon trituration with ethanol (yield 11 g, m.p. 180°-190°). This material was purified by column chromatography (silica gel, dichloromethane) to give 3 g solid. This material was recrystallized from isopropanol to give 2.6 g (17%) crystals, m.p. 202°-203°.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: COc1cccc(NC(=S)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)c1
Yield: 69 %

Procedure:
The compound of example 279 was prepared analogous to compound of example 257 by hydrolysis of compound of example 278.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([F:15])[CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(F)cc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2c(cc(F)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]3C=CC(F)=CC=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[C:24]([CH3:30])[CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(=O)C(OC)=C(C3C=CC(SC)=C(C)C=3)C=N2)C=CC=1.FC1C=CC([Mg]Br)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[C:24]([CH3:30])[CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1C
Agent: COc1c(-c2ccc(SC)c(C)c2)cnn(-c2cccc(Cl)c2)c1=O
Agent: Fc1ccc([Mg]Br)cc1
Product: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2C)cc1C

Procedure:
2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone, was prepared according to the method of Example 228, starting with 2-(3-chlorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting 4-fluorophenyl magnesium bromide in place of cyclohexylmagnesium chloride (yield: 180 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 2.25 (s, 3H), 2.56 (s, 3H), 7.28-7.45 (m, 6H), 7.58-7.63 (m, 1H), 7.71-7.74 (m, 1H), 7.82 (s, 1H). MS (APCI+) m/z 343 (M+H)+ and m/z 360 (M+NH4)+.
Reaction SMILES: C([N:11]1[CH2:15]C[C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)(OCC1C=CC=CC=1)=O.[C:23]([NH:30][C@H:31]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:32]([NH:34]N1CC(=O)C1)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:23]([NH:30][C@H:31]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:32]([NH:34][N:11]1[CH2:12][CH:13]([NH:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:15]1)=[O:33])([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(=O)C1
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC(NC2CCCCC2)C1

Procedure:
The title compound was prepared following the procedure described in Intermediate 2 using (2R)-2-(BOC-amino)-N-(3-oxo-azetidine-1-yl)-3-(4-chlorophenyl)propionamide prepared in Intermediate 201 and cyclohexylamines.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][S-:14].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: C[S-]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CSc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of the 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.50 g, 11.5 mmol) in THF (50 mL) in an ice bath under nitrogen was added zinc(II) chloride (1.0 M in ether, 13.8 mL, 13.8 mmol) dropwise. The mixture was stirred in the ice bath for two hours, then sodium methanethiolate (0.888 g, 12.7 mmol) was added. The mixture was stirred overnight, allowing the reaction to slowly come to room temperature. After 18 hours the reaction was quenched with 2 M HCl (15 mL), and the organics removed by evaporation under reduced pressure. The aqueous residue was diluted with brine (15 mL), and extracted with DCM (3×30 mL). The combined organic phases were dried (phase separator) and carefully evaporated to give a pale yellow oil. Chromatography (Biotage Isolera, 2×40 g silica cartridge, 0-20% DCM/n-hexane) followed by carefully evaporation of solvent (40° C.@400 mmHg then room temperature@200 mmHg) gave the title compound (I13) (2.149 g, 82% yield) as a colourless oil; 1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 2.61 (s, 3H). LCMS Method C: rt: 7.95 min; m/z 229.1[M+H]+. Note: I13 is volatile.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[CH3:9])[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([CH3:9])[N:5]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1sc(N)nc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCc1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C
Yield: 25 %

Procedure:
The title compound was prepared from 5-ethyl-4-methyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 42 mg (25% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0250).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)=[O:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:38]1C[O:41][CH2:40][CH2:39]1>>[CH2:11]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([C:36]#[N:37])=[CH:33][CH:34]=3)[C:29]([CH2:38][CH2:39][C:40]([O:5][CH3:4])=[O:41])=[CH:28]2)=[O:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc2c(ccn2CC(=O)N2CCC(Cc3ccccc3)CC2)c1
Reactant: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCc1cn(CC(=O)N2CCC(Cc3ccccc3)CC2)c2ccc(C#N)cc12
Reaction time: 3 h

Procedure:
To a stirred solution of DMF (15 mL) and POCl3 (256 mg, 1.7 mmol) at 0° C. was added 1-(4-benzylpiperidine-carbonyl)methyl-5-cyanoindole (199 mg, 0.56 mmol). After stirring 3 h, the reaction was quenched with 2N sodium hydroxide and stirred for 30 min. It was then extracted with chloroform, dried with sodium sulfate, filtered and concentrated in vacuo to afford product. LRMS (M+H)+ 386. The product was then refluxed in the presence of triphenyl phosphonium(methylenecarbomethoxy)ylide in THF under a nitrogen atmosphere for 18 h. The reaction was concentrated in vacuo and the residue purified via silica gel chromatography using 7% MeOH/CHCl3 as the eluant to afford 140 mg of product.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.Cl.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([CH2:10][NH:9][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Clc1cncc(Cl)n1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNc2cncc(Cl)n2)cc1
Temperature: 90 °C
Yield: 32 %

Procedure:
A stirred suspension of 2,6-dichloropyrazine (500 mg, 3.36 mmol), methyl 4-(aminomethyl)benzoate.HCl (744 mg, 3.69 mmol) and i-Pr2NEt (2.05 mL, 11.75 mmol) in a mixture of anhydrous THF/DMF (10 mL/2 mL) under nitrogen was heated at 90° C. for 24 h. The mixture was allowed to cool down to room temperature, was poured into saturated aqueous NH4Cl and extracted with AcOEt. The organic layer was washed with H2O and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (AcOEt/CH2Cl2: 20/80→30/70) to afford the title compound 62 (300 mg, 1.08 mmol, 32% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.18 (t, J=6.0 Hz, 1H), 7.97 (s, 1H), AB system (δA=7.95, δB=7.49, JAB=8.5 Hz, 4H), 7.75 (s, 1H), 4.58 (d, J=5.9 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(N)=O
Yield: 23 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)-imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 23% yield: mp 216-217° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.32 (s, 2H), 4.54 (s, 2H), 4.02 (dd, J=9.0, 7.3 Hz, 2H), 3.49 (dd, J=9.0, 7.3 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.5, 157.4, 155.2, 150.7, 141.5 (d, JC-F=1.2 Hz), 128.5, 128.1 (q, 2JC-F=31.6 Hz), 125.5 (q, 3JC-F=3.8 Hz), 124.3 (q, 1JC-F=272.2 Hz), 118.5, 46.5, 42.0, 41.8, 17.0; MS (ES+) m/z 384.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:20](Cl)(=O)[CH2:21][CH2:22][CH3:23].[OH-:26].[Na+].OO>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][C:20]([CH2:21][CH2:22][CH3:23])=[N:5][C:4]2=[O:26])([O-:12])=[O:11]
Reactant: [OH-]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCc1nc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 16.3 g (0.1 mol) of 2-amino-5-nitrobenzonitrile in 200 ml of CH2Cl2 at 0° C. was added 21 ml (0.15 mol) of triethyl amine followed by 0.3 g of DMAP and 11.71 g (0.11 mol) of butyryl chloride. The reaction mixture was warmed to room temperature and then heated over night at 50° C. The solution was washed with 1N HCl (1×20 ml), water (1×20 ml), saturated NaHCO3 (2×20 ml) and brine (1×20 ml) and dried over MgSO4. The solution was filtered and concentrated in vacuo. The residue was dissolved in 200 ml of MeOH to which was added 44 ml (0.22 mol) of 5M NaOH solution followed by the dropwise addition of 25 ml (0.22 mol) 30% H2O2 and 50 ml of water. The mixture was refuxed for 4 hours, cooled and filtered. The filtrate was acidified with 1N HCl and the resulting precipitate recovered by filtration. The residue was recrystalized from MeOH to provide the title compound.