Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][C:20]1([CH3:28])[CH2:24][NH:23][CH:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C:20]([CH3:28])([CH3:19])[CH2:21][CH:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CNC(C(N)=O)C1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC1(C)CC(C(N)=O)N(C(=O)c2ccc(C3CC3)c(OCC3CC3)n2)C1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 4,4-dimethyl-pyrrolidine-2-carboxylic acid amide hydrochloride (84.3 mg, 472 μmol) as starting materials and isolated (145 mg, 95%) as white foam; LC-MS (UV peak area, ESI) 100%, 358.2124 [MH+].
Reaction SMILES: CN1CCOCC1.Cl.Cl.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1.[CH3:24][O:25][C:26]([NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:39]([O-])=[O:40])=[CH:36][C:35]=2[CH:42]=1)=[NH:30])=[O:27].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:24][O:25][C:26]([NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:39]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]3)=[O:40])=[CH:36][C:35]=2[CH:42]=1)=[NH:30])=[O:27]
Reactant: CCOC(=O)CCN1CCC(N)CC1
Reactant: COC(=O)NC(=N)c1ccc2oc(C(=O)[O-])cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCC(NC(=O)c2cc3cc(C(=N)NC(=O)OC)ccc3o2)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
N,N-Dimethylformamide (14 ml) and N-methylmorpholine (0.57 ml, 5.20 mmol) were added to ethyl 3-(4-aminopiperidino)propionate dihydrochloride (567 mg, 2.08 mmol) and the mixture was stirred at 60° C. for 20 minutes under a nitrogen atmosphere. This solution was added to a mixture of 5-(methoxycarbonylamidino)-2-benzofurancarboxylate acid (364 mg, 1.39 mmol), 1-hydroxy-1H-benzotriazole (207 mg, 1.54 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (294 mg, 1.54 mmol) added to N,N-dimethylformamide (15 ml). The mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by column chromatography (chloroform/methanol=10/1) to give 338 mg of compound (187) as a yellow solid (55%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:22]([O-])=O)=[C:16]([CH2:18][C:19](O)=[O:20])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CO.C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[NH:22][C:19](=[O:20])[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Cc2cc(OCCOCc3ccccc3)ccc2N1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A mixture of [5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-acetic acid (0.58 g, 1751 mmol), 5% palladium on carbon (0.05 g) and triethylamine (0.37 ml, 2.66 mmol) in methanol (35 ml) was stirred under a hydrogen atmosphere (1 atm) for 3 h. After removal of the catalyst by filtration, the filtrate was evaporated to give a yellow oil. The oil was dissolved in 10 ml of acetic acid and the solution was stirred at 80° C. under argon for 3 h. The acetic acid was removed on a rotavap. The residue was dissolved in a small amount of methylene chloride and chromatographed on silica gel eluted with 30% ethyl acetate in methylene chloride to give 5-(2-benzyloxy-ethoxy)-1,3-dihydro-indol-2-one (0.39 g, 79%) as a white solid. Analysis calculated for C17H17NO3 : C, 72.07; H, 6.05; N, 4.85. Found: C, 72.09; H, 6.01; N, 4.85.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=2)=[O:31])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cc(C(=O)O)n(C)n1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)nn2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=450.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)[CH:5]=[C:4]([CH3:26])[C:3]=1[OH:27].[F-].[Cs+].[CH2:30]1[O:32][C@H:31]1[CH2:33][OH:34]>CN(C=O)C>[CH3:26][C:4]1[CH:5]=[C:6]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)[CH:7]=[C:2]([CH3:1])[C:3]=1[O:27][CH2:30][C@@H:31]([OH:32])[CH2:33][OH:34]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1O
Reactant: OC[C@H]1CO1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1OC[C@@H](O)CO
Temperature: 80 °C

Procedure:
A mixture of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenol (36.7 mg, 99 μmol) and cesium fluoride (1.5 mg, 9.9 μmol) in anhydrous DMF (0.5 mL) was stirred at 25° C. for 1 h. (S)-(−)-glycidol (14 μl, 207 μmol) was then added, and the resulting mixture was heated under argon at 80° C. for 7 d. The reaction mixture was subsequently cooled to 25° C., filtered through Celite, diluted with DMSO (1.5 mL), and purified by rpHPLC (10-100% CH3CN/water+0.1% TFA) to provide (S)-3-(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)phenoxy)-propane-1,2-diol as a light yellow solid. MS (ESI) m/z: Calculated: 446.2; Observed: 447.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][O:8][CH3:9])[CH:3]=1.[OH-].[K+].[CH3:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([CH3:25])[C:17]=1[CH2:26][O:27][CH3:28])(=[O:15])=[O:14].[CH:29](Cl)(Cl)Cl>>[CH3:12][S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([O:1][C:2]2[N:6]([CH3:29])[N:5]=[C:4]([CH2:7][O:8][CH3:9])[CH:3]=2)=[O:21])=[C:18]([CH3:25])[C:17]=1[CH2:26][O:27][CH3:28])(=[O:15])=[O:14]
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Reactant: ClC(Cl)Cl
Reactant: COCc1cc(O)[nH]n1
Agent: [K+]
Agent: [OH-]
Product: COCc1cc(OC(=O)c2ccc(S(C)(=O)=O)c(COC)c2C)n(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.9 g of 5-hydroxy-3-methoxymethylpyrazol was added to a mixture consisting of 8 ml of an aqueous solution containing 0.5 g of potassium hydroxide (85%) and 12 ml of chloroform, and then 4-methanesulfonyl-3-methoxymethyl-2-methylbenzoyl chloride was added thereto. The mixture was stirred for 3 hours at room temperature. Then, the reaction mixture was extracted with chloroform. The chloroform solution was washed with water and dried to obtain the desired product substantially quantitatively as an oily substance.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:27][S:28][C:29]1[N:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=1.N1C=CC=CC=1>CN(C)C=O.C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:35][C:32]2[CH:31]=[N:30][C:29]([S:28][CH3:27])=[CH:34][N:33]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: CSc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-propionic acid (prepared as in Example 3, 1.21 g, 4.07 mmol) and N,N-dimethylformamide (5 drops) in methylene chloride (10 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (0.53 mL, 6.10 mmol), and the resulting reaction mixture was stirred at 0° C. for 1 h. The solution was then concentrated in vacuo, and the orange-brown gel was dissolved in methylene chloride. The resulting solution was added dropwise via an addition funnel at 0° C. to a solution of 5-methylsulfanyl-pyrazin-2-ylamine (prepared as in Example 4, 0.58 g, 4.07 mmol) in methylene chloride (10 mL) and pyridine (0.36 mL, 4.48 mmol). The reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 3 h. The reaction mixture was quenched with a 1N aqueous citric acid solution (10 mL) and was stirred for 15 min. The reaction was then diluted with ethyl acetate (75 mL) and a 1N aqueous citric acid solution (50 mL). The layers were separated, and the organic layer was then washed with a saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamide (0.864 g, 51%) as a white foam: mp 71–77° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H25N3O3S2 (M+H)+ 420.1410, found 420.1415.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.CCOCC>[CH3:27][S:28]([O:1][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)(=[O:30])=[O:29]
Reactant: OCC1COc2ccc(Oc3ccccc3)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCC1COc2ccc(Oc3ccccc3)cc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxymethyl-7-phenoxy-1,4-benzodioxane (1.42 g, 5.50 mmol) and triethylamine (1.11 g, 11.0 mmol) are dissolved in methylene chloride (50 mL) and treated with methanesulfonyl chloride (0.94 g, 8.26 mmol) at 0° C. The mixture is stirred at 0° C. for 30 minutes, and diluted with ether. This is washed with aqueous sodium bicarbonate, aqueous 1N hydrochloric acid and saturated aqueous ammonium chloride, dried over magnesium sulfate and evaporated to give 2-methanesulfonyloxymethyl-7-phenoxy-1,4-benzodioxane. The crude oil is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C=C(C=C(C(F)(F)F)C=1)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: CC(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Product: CC(=O)c1cc(Br)cc(C(F)(F)F)c1
Yield: 85 %

Procedure:
The title compound was prepared from 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (Reference Example 40) by a procedure similar to the one described for 3-chloro-5-(trifluoromethyl)benzaldehyde (Reference Example 31) to provide 1-(3-bromo-5-(trifluoromethyl)-phenyl)ethanone (17.94 g, 85%) as a pale yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1([CH2:19][C:20](=[O:24])[C:21](O)=[O:22])[CH2:18][CH2:17]1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:31](=[O:32])[O:30][CH2:29]2.Cl>CC(N(C)C)=O.C(OCC)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[C:16]1([CH2:19][C:20](=[O:24])[C:21]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:31](=[O:32])[O:30][CH2:29]3)=[O:22])[CH2:17][CH2:18]1
Reactant: O=C(O)C(=O)CC1(c2cc(C(F)(F)F)ccc2F)CC1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(CC1(c2cc(C(F)(F)F)ccc2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At −10° C., 0.84 ml of thionyl chloride are added to 2.9 g of 3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionic acid in 15 ml dimethylacetamide. The mixture is stirred for 30 min. at −10° C. and for 1 hour at 0° C. and then added to 1.95 g of 5-aminophthalide (or, vice versa, 5-aminophthalide may be added to the mixture). After 16 hours at ambient temperature, 2 M hydrochloric acid and ethyl acetate are added, the organic phase is washed to neutral with water, dried over sodium sulfate and concentrated. After chromatography on silica gel (hexane/ethyl acetate: 1+1) and recrystallization from diisopropyl ether, 2.4 g of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionylamino}-phthalide (m.p. 168° C.) are obtained.
Reaction SMILES: S(Cl)(Cl)=O.S1C=CC=C1CC(O)=O.S1C=CC=C1CC(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52]>C1(C)C=CC=CC=1.C(O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)=[S:55])=[CH:40][CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cc1cccs1)N=C=S
Agent: O=C(Cl)Cc1cccs1
Agent: O=C(O)Cc1cccs1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4cccs4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-thienyl)acetic acid (40 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-thienyl)ethanoyl isothiocyanate was prepared using the resultant 2-(2-thienyl)ethanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-thienyl)ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 54%).
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:22]=[C:21]([C:4]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=2[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reactant: N#Cc1cccc(Br)c1
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1cccc(C#N)c1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (iv) and 3-bromobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([F:33])=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D146) (320 mg) in isopropanol (7 mL) and water (7.00 mL) was added NaOH (6.78 mL, 0.5 M aqueous solution) at room temperature. The reaction suspension was stirred at 90° C. for 2 hours, and the solution turned clear. Isopropanol was removed in vacuo and water (8 mL) was added to the residue. The aqueous solution was acidified to pH=1 and extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over sodium sulphate. The organic solution was concentrated and the residue was purified by MDAP to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoic acid (E103) (140 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.31 (6H, d), 2.56 (2H, t), 2.92 (2H, t), 4.85 (1H, m), 7.03 (1H, m), 7.22 (1H, s), 7.39 (1H, d), 7.74 (1H, m), 8.21 (1H, dd), 8.47 (1H, d), 11.01 (1H, s), 12.07 (1H, s). MS (ES): C22H19ClFN3O4 requires 443; found 444.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)(c1nc(OC)cc(OC)n1)C(C)C
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)Nc1ccccc1Cl)(c1nc(OC)cc(OC)n1)C(C)C
Yield: 88.6 %

Procedure:
A solution of ethyl 2-amino-3-methyl-2-(4,6-dimethoxypyrimidin-2-yl)butanoate (0.556 g) and 2-chlorophenylisocyanate (0.306 g) in ethyl acetate (30 ml) was refluxed for 5 hours, evaporated to dryness, and flash chromatographed on silica gel, eluting with ethyl acetate/60°-80° petroleum ether (1:2). The residual gum was triturated with 60°-80° petroleum ether, to give 0.76 g of the desired product as a white solid, mp 84°-87° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:24]1([C:28]([C:30]2[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>CC(N(C)C)=O.C(OCC)(=O)C>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Yield: 66.8 %

Procedure:
A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (2.48 g, 12.6 mmol) in DMA (25 mL) was heated at 120° C. for 2 hours. The solution was diluted with ethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (2.8 g). 1H NMR δ (CDCl3): 2.13-2.29 (m, 2H), 2.34-2.41 (m, 2H), 3.88-4.04 (m, 4H), 3.90 (s, 3H), 4.25 (t, 2H), 4.68 (t, 2H), 4.96-5.00 (m, 1H), 6.91 (t, 1H), 7.43 (d, 2H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 386 (M+H)+, 384 (M−H)−
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4].COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:16]\[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:18]#[N:19])=[C:6]3[O:5][CH2:1][CH2:2][CH2:3][CH3:4])/[C:36](=[O:37])[N:38]=1
Reactant: CCCCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-butoxy-6-formyl-quinoline-3-carbonitrile (example 79b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-butoxy-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Product: CNc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 12.8 %

Procedure:
In a similar fashion using route 48 general procedure 114, N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (80 mg, 0.25 mmol), methyl amine (2M in THF; 1.23 ml, 2.50 mmol) at 100° C. for 48 h gave the title compound (10 mg, 13%) after purification by column chromatography with chloroform/MeOH (1 drop NH3) (98:2) as the eluent followed by recrystallisation from MeOH/DCM.