Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.CC(C)([O-])C.[K+].[C:17]1(=[O:21])[O:20][CH2:19][CH2:18]1.Cl>O1CCCC1>[C:17]([CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1)([OH:21])=[O:20]
Reactant: Cc1cc(O)ccc1C=O
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OCCC(=O)O)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-hydroxy-2-methylbenzaldehyde (5 g) and potassium tert-butoxide (4.12 g) in tetrahydrofuran (60 mL) was added β-propiolactone (4.6 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in ethyl acetate (20 mL)—n-hexane (100 mL). The insoluble material was collected by filtration, and washed with n-hexane and dried under reduced pressure to give the title compound (7.2 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl>CN(C=O)C.CCOC(C)=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cccc(C)c1CCl
Reactant: CCOC(=O)c1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 3-hydroxy-2-methylbenzoate (Step A, 3.1 g, 17.22 mmol). K2CO3(3.09 g, 22.38 mmol) in dry DMF (15 ml) was added 2,6-Dimethylbenzyl chloride (3.19 g, 20.66 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours, diluted with EtOAc (40 ml), washed with water (20 ml) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.[CH3:17][S:18]([O:21]S(C)(=O)=O)(=[O:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:17][S:18]([O:21][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)(=[O:20])=[O:19]
Reactant: [O-][n+]1ccc(O)c2ccc(C(F)(F)F)cc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxy-7-trifluoromethyl-quinoline-1-oxide (2.0 g), methanesulphonic anhydride (1.7 g) and potassium carbonate (1.3 g) in dichloromethane (100 ml) was stirred at 0° for 2 hours. Further methanesulphonic anhydride (1.7 g) and potassium carbonate (1.3 g) were then added and the mixture was stirred at ambient temperature overnight. Water (50 ml) was added and the precipitated solid collected by filtration to give a first crop of the novel compound 4-hydroxy-7-trifluoromethylquinol-3-yl methanesulphonate, m.p. 220°. The dichloromethane layer of the filtrate was separated and the aqueous layer subsequently extracted with dichloromethane (2×25 ml). The combined dichloromethane layer and extracts were evaporated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (20:1) to give a second crop of 4-hydroxy-7-trifluoromethylquinol-3-yl methanesulphonate, m.p. 220°.
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>C(#N)C>[I:42][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: II
Reactant: CCOC(=O)CCCOc1ccc(CO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(CI)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the intermediate from step B (1 g, 4.24 mmol) in acetonitrile was added triphenyl phosphine (1.45 g, 5.5 mmol), imidazole (0.4 g, 5.93 mmol) and iodine (1.51 g, 5.94 mmol). After 20 minutes, the reaction was quenched with saturated Na2S2O3 solution. The resulting mixture was extracted with ethyl acetate washed with brine and dried over anhydrous Na2SO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography using 15% ethyl acetate-hexanes to give the desired product as an oil. 1H NMR (CDCl3, 500 MHz): 7.32 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.48 (s, 2H), 4.18 (q, J=6.1 Hz, 2H), 4.01 (t, J=6.1 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H), 2.14 (m, 2H), 1.29 (t, J=7.1 Hz, 3H). LC-MS=2.36 min; (M+23)=371.0.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C>C(O)C>[C:11]1([C:9]2[CH2:8][CH2:7][NH:5][N:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(C2=NNCC2)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Hydrazine monohydrate (6.2 g) was dissolved in ethanol (12 ml). Thereto was dropwise added a solution of 3-(N,N-dimethylamino)propiophenone (5.4 g) dissolved in ethanol (10 ml) in a nitrogen atmosphere at room temperature. The resulting mixture was refluxed for 3 hours with heating. The reaction mixture was poured into ice water. Extraction with chloroform was conducted, followed by drying and concentration, to obtain 4 g of a title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:12]3)=[CH:4][CH:3]=1.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[C:15]([N:11]1[CH2:10][C@@H:9]2[C@@H:13]([CH2:14][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:32])[F:33])=[CH:27][CH:26]=3)(=[O:30])=[O:29])=[CH:7][CH:6]=2)[CH2:12]1)(=[O:18])[CH2:16][CH3:17]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(N)cc3)[C@@H]2C1
Product: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)cc3)[C@@H]2C1
Yield: 86 %

Procedure:
Following a procedure analogous to the procedure described in example 1.5, but starting with 1-[(1R,5S,6R)-6-(4-aminophenyl)-3-aza-bicyclo[3.2.0]hept-3-yl]-propan-1-one and 4-trifluoromethoxybenzensulfonyl chloride, N-[4-((1R,5S,6R)-3-propionyl-3-azabicyclo[3.2.0]hept-6-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide (234 mg, yield 86%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[N:30]=[C:31]=[O:32])[N:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[N:25]=[C:24]2[CH3:43]>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32])[N:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[N:25]=[C:24]2[CH3:43]
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(N=C=O)cc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c3cc(Br)c(NC(=O)N4C=CC(=O)C[C@H]4c4ccc(F)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (58 mg, 0.30 mmol) was dissolved in 10 ml of THF and cooled to −40° C. n-BuLi (1.1 eq, 0.16 ml of a 2.5M soln) was added dropwise, forming a purple suspension. This mixture was allowed to stir for 30 minutes until the purple color changed to white. 5-Bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazole (1 eq, 146 mg) was added and the mixture was allowed to stir for 1 hour at −40° C., then warmed to warm to room temperature and stirred for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 1:1 hexanes/ethyl acetate) to give (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amide (140 mg, 65.1%) as a yellow foam.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].NC(N)=O>C(O)C>[C:6]1([CH2:5][CH2:2][CH:3]=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(Br)Cc1ccccc1
Agent: NC(N)=O
Solvent: CCO
Product: O=CCCc1ccccc1

Procedure:
5-Benzyl-thioxazol-2-ylamine A mixture of 2-bromo-3-phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated at reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was washed three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were brought to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid (5.2 g, 27 mmol, 27% from 3-phenyl-propionaldehyde). ESI-MS m/z calc. 190.1. found 191.2 (M+1)+; 1H NMR (CDCl3) δ 7.32-7.21 (m, 5H), 6.79 (s, 1H), 4.91 (bs, 2H), 3.95 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:29])[C:25]([O:27]C)=[O:26])[C:4]=12.C([O-])([O-])=O.[K+].[K+]>O.CO>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:29])[C:25]([OH:27])=[O:26])[C:4]=12
Reactant: COC(=O)C(=O)c1c[nH]c2c(-n3cnc(NC(=O)C(C)(C)C)n3)ncc(OC)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a mixture of methyl 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (40 mg, 0.100 mmol) in water (1 mL) and MeOH (1 mL) was added K2CO3 (83 mg, 0.599 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. MeOH was removed under reduced pressure. The water layer was acidified to PH=5-6 using 1N HCl and concentrated under reduced pressure. The resulting residue was washed with water, filtered and dried to give 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (30 mg, 78%) as white solid. LCMS: m/e 387.18 (M+H)+, ret time 2.46 min (method 4).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:53][CH:54]1[C:75](=[O:76])[N:56]2[C:57]([C:63]([O:65][CH2:66][C:67]3[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=3)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]12.Cl>ClCCl.N1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:53][C@@H:54]2[C:75](=[O:76])[N:56]3[C:57]([C:63]([O:65][CH2:66][C:67]4[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=4)=[O:64])=[C:58]([CH2:61][Cl:62])[CH2:59][S:60][C@H:55]23)=[O:29])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: CC(C)(C)OC(=O)C(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1cccnc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(C)(C)C)c4cccnc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
After 1.0 g (1.6 mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-[[(tert-butoxycarbonyl)(3-pyridyl)methoxy]imino]acetic acid and 0.37 g (1.77 mmol) of phosphorus pentachloride were added to 25 ml of dichloromethane, the mixture was stirred at 5° C. for 30 minutes. The resulting solution was dropwise added to a solution containing 0.65 g (1.6 mmol) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride and 1.3 ml of pyridine in 30 ml of dichloromethane. After stirring for an hour below -20° C., the solution was cooled to -40° C. After adding 50 ml of 1N hydrochloric acid, the temperature was reverted to room temperature. The dichloromethane layer was taken out, washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography. The column was eluted with dichloromethane-methanol (10:1) to give 0.90 g (57.7%) of p-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(tert-butoxycarbonyl)(3-pyridyl)methoxy]imino]acetamido]-3-chloromethyl-3-cephem-4-carboxylate.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7]1)=[O:5])C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl>[C:11]1([C:8]2[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCC(c2ccccc2)=N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 1L round bottomed flask with a stirring bar and an argon inlet was added 5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV-4-1 (4.84 g, 22.28 mmol), dry CH2Cl2 (220 mL) and DDQ (5.06 g, 22.28 mmol). This solution was stirred at ambient temperature 1 h. The solvent was removed in vacuo. Aqueous NaOH (10% w/v, 440 mL) was added and the mixture was heated at reflux 24 h. The cooled, black solution was poured onto crushed ice and the mixture was acidified with conc. HCl. This mixture was extracted with EtOAc (2×). The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 2.5% MeOH in EtOAc as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid AV-5-1 as an off white solid. 1H NMR (CDCl3) δ 6.59 (1H, dd, j=2.7, 3.9 Hz), 7.13 (1H, dd, j=2.7, 3.9 Hz), 7.34 (1H, m), 7.41 (2H, m), 7.59 (2H, m), 9.40 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:32](=O)N2CCN(CC3C=CC(OC)=CC=3)C(=O)C2=C[CH:14]=1.S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]2[C:13]([CH3:32])([CH3:14])[NH:11][C:9](=[O:10])[C:5]2=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)c(=O)[nH]1
Reactant: COc1ccc(CN2CCn3c(ccc(Cl)c3=O)C2=O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2ccc(Cl)c(=O)n21
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2, 1.4 g, 7.9 mmol) in 1,4-dioxane (20 mL), acetone (3, 4.6 g, 79 mmol) and concentrated sulfuric acid (0.038 g, 0.39 mmol) were added at room temperature and the reaction mixture was allowed to heat at 100° C. for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether and hexane, filtered and dried to afford 6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (4). Yield: 1.4 g, 83%; MS (ESI) m/z 213[M+1]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:29][CH2:30][CH2:31][N:32]4[C:40](=[O:41])[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:33]4=[O:42])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(CCCN5C(=O)c6ccccc6C5=O)CC4)c4cc(Cl)ccc43)c21
Temperature: 150 °C
Yield: 63.2 %

Procedure:
A mixture of (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (15 mg, 0.035 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (13 mg, 0.049 mmol), DIEA (0.018 mL, 0.11 mmol) and DMF (0.5 mL) was heated at about 150° C. in microwave for about 30 min. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 20:1) to give (R)-2-(3-(5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-yl)propyl)isoindoline-1,3-dione (12 mg, 63%). LCMS (APCI+) m/z 542, 544 [M+H]+; Rt=3.79 min.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][CH2:25][OH:26].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][CH2:25][O:26][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN1CCCC1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCCC1CCOc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 1-methyl-2-pyrrolidineethanol (79 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 55 mg (0.21 mmol, 53%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 267 (M+1)+, calc. 267 (M+1)+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([CH3:68])[C:55]([C:61]2[CH:66]=[CH:65][N:64]=[C:63]([Cl:67])[CH:62]=2)([OH:60])[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:69])[CH:49]=1>CN(C=O)C>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH:54]([CH3:68])[C:55]([C:61]3[CH:66]=[CH:65][N:64]=[C:63]([Cl:67])[CH:62]=3)([OH:60])[C:56]([F:57])([F:58])[F:59])=[C:50]([Cl:69])[CH:49]=2)=[O:7])[CH:3]=1
Reactant: CC(c1ccc(N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Nc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Monomethyl isophthalate (CAS Reg. No. 1877-71-0, 22 mg), HBTU (CAS Reg. No. 94790-37-1, 62 mg), and N,N-diisopropyl ethyl amine (0.06 ml) were added to a solution of 3-(4-amino-2-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (Example 60 step 4, 40 mg) in DMF (2 ml). The mixture was stirred overnight at room temperature, 1 h at 50° C., and then 1 h at 80° C. Additional monomethyl isophthalate (CAS Reg. No. 1877-71-0, 20 mg) and N,N-diisopropyl ethyl amine (0.02 ml) were added. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (13 mg) as a light yellow foam. MS (m/e)=527.0 [M+H+].
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:20][N:19]=[C:18]([C:21](=O)[CH2:22]Cl)[CH2:17]1)(=[O:4])=[O:3].[C:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=[S:27])[NH2:26].O>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:20][N:19]=[C:18]([C:21]2[N:26]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)[S:27][CH:22]=2)[CH2:17]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CS(=O)(=O)Oc1cc(C(F)(F)F)ccc1C1CC(C(=O)CCl)=NO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccc(C(F)(F)F)cc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of 2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-(trifluoromethyl)phenyl methanesulphonate (200 mg) and tert-butyl 4-carbamothioylpiperidine-1-carboxylate (108 mg) in tetrahydrofuran (2 ml) at room temperature was added tetrabutylammonium bromide. The reaction mixture was stirred at room temperature for 12 hours. Then water was added thereto, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave tert-butyl 4-[4-(5-{2-[(methylsulphonyl)oxy]-4-(trifluoromethyl)phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (168 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]=[O:15]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][NH:13][C:14]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)=[O:15])[CH3:21]
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1cc(C)nc2ccccc12
Temperature: -14 °C
Reaction time: 4 h

Procedure:
A suspension of 4-amino-2-methylchinoline (4.0 g, 25.3 mmol) in dry THF (80 mL) is cooled to −14° C. and ethyl isocyanatoacetate (3.3 mL, 27.4 mmol) is added dropwise under vigourous stirring. The reaction is warmed to room temperature and stirred for 4 h. Further ethyl isocyanatoacetate (0.6 mL, 5 mmol) is added and the reaction mixture stirred for 15 h. The solvent is evaporated and the residue crystallized from CHCl3-heptane (1/5) to provide the title compound.