Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][CH:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl>CO.[Pd]>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][CH:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[N:14]1)([CH3:27])([CH3:28])[CH3:26]
Reactant: CC(Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
A mixture of the product from Step A (10.6 g, 27 mmol) and palladium-on-carbon (10%, 0.26 g) in methanol (250 mL) was stirred under an atmosphere of hydrogen for 6 h, dichloromethane (100 mL) was added and the mixture filtered. Evaporation of the filtrate gave an off-white solid (7.0 g, 85%): mp 169-174° C.; LC/MS (+APCI) m/z 307 (M+H).
Reaction SMILES: C([NH:4][C:5]1[NH:27][C:26](=[O:28])[C:25]2[C:7](=[N:8][CH:9]=[C:10]([N:24]=2)[CH2:11][NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)[N:6]=1)(=O)C.Cl>[OH-].[Na+]>[C:17]([OH:19])(=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([NH:12][CH2:11][C:10]2[N:24]=[C:25]3[C:7]([N:6]=[C:5]([NH:27][C:26]3=[O:28])[NH2:4])=[N:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(NCc2cnc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ncc(CNc3ccc(C(=O)O)cc3)nc2c(=O)[nH]1
Temperature: 20 °C

Procedure:
The ester (2.64 g) is hydrolyzed by heating with 350 ml of 0.1 N sodium hydroxide at 100° C for 30 minutes (under nitrogen and protected from light). The solution is cooled to 20° C and adjusted to pH 3 with concentrated hydrochloric acid. The precipitate is collected by centrifugation at 300 rpm. After washing twice with water and freeze drying, the product pteroic acid is obtained.
Reaction SMILES: [CH2:1]1[O:16][C:4]([CH3:15])([CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:3][CH2:2]1>[Rh].N>[CH2:2]1[O:3][C:4]([CH3:15])([CH:5]([CH2:11][CH2:12][CH2:13][NH2:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:16][CH2:1]1
Reactant: CCOC(=O)C(CCC#N)C1(C)OCCO1
Agent: [Rh]
Agent: N
Product: CCOC(=O)C(CCCN)C1(C)OCCO1

Procedure:
The above ketal was hydrogenated over a rhodium-on-alumina catalyst as follows: After dissolving 16 g of ethyl 2-(2-cyanoethyl)acetoacetate ethyleneketal in 90 ml of 10% ethanolic ammonia, 2 g of 5% rhodium-on-alumina were added, and the mixture hydrogenated at low pressure. The catalyst was separated by filtration, and the solvent removed from the filtrate to yield, as a residue, ethyl 2-(3-aminopropyl)acetoacetate ethyleneketal formed in the above hydrogenation. NMR indicated a mixture of the expected ketal plus some cyclized product produced by the next reaction step. The crude product from the above reaction was therefore heated in toluene solution for about 2 hours to convert the amino derivative to 3-acetyl-2-piperidone ethyleneketal. NMR showed the reaction being incomplete at this point; heating in toluene was therefore continued for 7 more hours. NMR again showed incomplete reaction; so heating was continued overnight. After a total of 24 hours of heating under reflux, the reaction mixture was cooled, and the solvent was removed in vacuo.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:24][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(CO)cc(OCOC)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(CO)c(Br)c(OCOC)c1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of (3,5-bis-methoxymethoxy-phenyl)-methanol (9.16 g, 40.2 mmol) in DMF (40 mL) was treated with NBS (7.51 g, 42.2 mmol) at room temperature and the mixture was stirred at same temperature for 30 min. The residue was diluted with ethyl acetate and washed with brine. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=1:1) to afford the title compound (10.2 g, 83%). 1H NMR (300 MHz, CDCl3) δ 6.91 (s, 1H), 6.81 (s, 1H), 5.24 (s, 2H), 5.17 (s, 2H), 4.72 (d, J=6.3 Hz, 2H), 3.52 (s, 3H), 3.47 (s, 3H), 2.05 (t, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CS(O[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)(=O)=O>CN(C=O)C>[CH2:1]([CH:3]1[C:4](=[O:9])[N:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[C:6](=[O:8])[NH:7]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CCC1NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1NC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 100 °C

Procedure:
To a solution of 5-ethylimidazoline-2,4-dione (1 g) in DMF (40 ml) was added potassium carbonate (2.16 g) followed by tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (2.18 g) and the resulting mixture was heated to 100° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and then was partitioned between dichloromethane and water. The organic layer was collected, dried and evaporated to dryness. The residue was purified by chromatography on silica eluting with a gradient of isohexane to ethyl acetate/isohexane (1:1) to give tert-butyl 4(4-ethyl-2,5-dioxoimidazolidin-1-yl)piperidine-1-carboxylate as a solid. Yield 1.12 g. NMR (CDCl3): 0.95 (t, 3H), 1.5 (s, 9H), 1.9 (m, 2H), 2.35 (m, 2H), 2.7 (m, 2H), 3.8-4.0 (m, 3H), 4.1 (q, 2H), 5.6 (bs, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:26]([O-])=O)[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=3[O:24][CH3:25])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:29].O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl>C(OCC)(=O)C>[NH2:26][C:6]1[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[O:24][CH3:25])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:3]([CH3:29])[N:2]2[CH3:1]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2[N+](=O)[O-])c(OC)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2N)c(OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 3.2 (35 mg, 0.088 mmol) and tin chloride dihydrate (159 mg, 0.70 mmol) dissolved in ethyl acetate (5 mL) was heated to 80° C. overnight. Alter 18 h, HPLC indicated no 3.2 remained and the reaction was poured into aqueous 5% hydrochloric acid solution. The resulting emulsion was filtered through a pad of Celite to remove fine solids, rinsing the solids with ethyl acetate and water. The biphasic filtrate was separated and the organic layer washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark brown, foamy solid.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[N:7]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:2]1([O:1][C:13]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[O:14])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: On1ccnc1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(On1ccnc1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxyimidazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by preparative HPLC (water-acetonitrile-0.1% TFA) (36%, crystals).
Reaction SMILES: [C:1](Cl)([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.[Br:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.CC(C)([O-])C.[K+]>CN(C=O)C.O>[Br:21][C:22]1[CH:23]=[N:24][N:25]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 28 °C
Reaction time: 12 h

Procedure:
Ph3CCl (10.4 g, 37 mmol) was added to a mixture of 4-bromopyrazole (5.0 g, 34 mmol) and potassium tert-butoxide (4.58 g, 41 mmol) in DMF (15 mL) at 0° C. then the mixture was stirred at 28° C. for 12 hours. The mixture was diluted with water and extracted with ethyl acetate, filtrated and recrystallized. The solid was dried under reduced pressure to afford 4-bromo-1-trityl-1H-pyrazole. MS ESI calc'd. for C22H18BrN2 [M+H]+389 and 391. found 389 and 391. 1H NMR (400 MHz, DMSO-d6): δ 7.74 (s, 1H), 7.50 (s, 1H), 7.38-7.34 (m, 10H), 7.04-7.01 (m, 5H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8])[NH:5][CH:6]=1>C(#N)C>[I:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[NH:9][CH2:10][CH:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]2[CH:6]=1
Reactant: CCOC(=O)/C=C/CNC(=O)c1cc(I)c[nH]1
Solvent: CC#N
Product: CCOC(=O)CC1CNC(=O)c2cc(I)cn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Diaza(1,3)bicyclo[5.4.0]undecane (DBU) (0.04 mL, 0.3 mmol) was added to a solution of ethyl (2E)-4-{[(4-iodo-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (X, where R1=OCH2CH3) (0.45 g, 1.3 mmol) in acetonitrile (8 mL) and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1) to obtain compound ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XII, where R1=OCH2CH3) as an off-white solid (0.35 g, 79% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([OH:10])[C:6]=2[CH:11]=1.Cl.Cl[CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:11]=1
Reactant: Oc1noc2ccc(Br)cc12
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2onc(OCc3ncccn3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
5-bromobenzo[d]isoxazol-3-ol (200 mg, 0.93 mmol), 2-(chloromethyl)pyrimidine hydrochloride (200 mg, 1.21 mmol) and cesium carbonate (1 g) were combined in 10 mL DMF and stirred at ambient temperature for two days. The reaction mixture was diluted with 60 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-100% ethyl acetate in hexane gave O-alkylated product 5-bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (120 mg, 0.39 mmol).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:19][C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Fc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Reactant: CC(=O)Nc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Nc2nccc3nc(-c4c(F)cccc4Cl)sc23)ncn1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a microwave tube was added 4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5 mmol), N-(6-aminopyrimidin-4-yl)acetamide (0.034 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration and the filtrate was concentrated under reduced pressure. The residue was purified with reverse phase column chromatography eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a yellow solid (0.018 g, 27% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.67 (s, 1H), 8.48-8.25 (m, 3H), 7.85-7.51 (m, 4H), 2.12 (s, 3H). LCMS (Method A): RT=5.04 min, m/z: 415.0 [M+H+].
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1.[C:11]([O:15][C:16]([NH:18][C@H:19]([CH:25]([CH3:27])[CH3:26])[CH2:20][CH2:21][C:22]([OH:24])=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:17])[NH:18][C@@H:19]([CH2:20][CH2:21][C:22](=[O:24])[N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]#[N:10])[CH2:5][CH2:4]1)[CH3:1])[CH:25]([CH3:27])[CH3:26])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC1CCC(C#N)CC1
Product: CC(C)[C@H](CCC(=O)N(C)C1CCC(C#N)CC1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure as described in Example 25, STEP E, 4-methyamino-cyclohexanecarbonitrile and 4-(S)-tert-butoxycarbonylamino-5-methyl-hexanoic acid were reacted to yield (1-{2-[(4-cyano-cyclohexyl)-methyl-carbamoyl]-ethyl}-2-methyl-(S)-propyl)-carbamic tert-butyl ester as a lightly colored oil was prepared.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[Mg].[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH:23]=[O:24]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([CH:23]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[CH3:16])[OH:24])=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1ccncc1C=O
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)c2cnccc2C)cc1
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
Under an atmosphere of nitrogen, a solution of 900 mg of 4-bromobenzaldehyde diethylacetal in 1.8 ml of tetrahydrofuran was added dropwise to 83 mg of magnesium at 50° to 60° C., and the mixture was stirred at that temperature for 10 minutes, and then diluted with 2 ml of tetrahydrofuran. The solution, thus obtained, was added dropwise to a solution of 280 mg of 4-methyl-3-formylpyridine [prepared as described in J. Org. Chem., 25, 560(1960)] in 7 ml of tetrahydrofuran at 0° C., and the mixture was stirred at the same temperature for one hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (7:3) a eluent to give 406 mg of the title compound having the following physical characteristics:
Reaction SMILES: C([O:4][C:5](=[O:66])[C@@H:6]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:7][C:8]1[CH:57]=[CH:56][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28]([NH:30][C@H:31]([C:53]([NH2:55])=[O:54])[CH2:32][S:33][C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:28]([NH:30][C@H:31]([C:53]([NH2:55])=[O:54])[CH2:32][S:33][C:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH2:18][CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH:58][C:59]([O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[O:60])[C:5]([OH:66])=[O:4])=[CH:57][CH:56]=1)=[O:14])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
3.06 g (2.33 mmol) of the compound from example 10A was dissolved in 46 ml tetrahydrofuran. 1.63 ml (11.6 mmol) triethylamine, 0.44 ml (11.6 mmol) formic acid and 0.265 g (0.233 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 50 ml water and twice extracted with approx. 50 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 500 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 40/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.40 g raw product of 86% purity. The product was further purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 2 fractions: 0.93 g product (45% of theory).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28])=[O:9]
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (1S,2S)-2-amino-cyclohexanol as starting materials, MS (ISP) 465.1, 467.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]
Reactant: [H][H]
Reactant: C=Cc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC)c(NC(=O)OC(C)C)cc1C(F)(F)F
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Add 10% palladium on carbon (4.06 g, 12.22 mmol) to a solution of 2-isopropoxycarbonylamino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (40.48 g, 122.19 mmol) in methanol (350 mL) in a Parr bottle. Subject the mixture to a hydrogen atmosphere at a pressure of 30 psi at room temperature with shaking on a Parr shaker apparatus for 2 h. Filter the mixture through Celite and remove the solvent under reduced pressure to provide the title compound as a white solid (39.07 g, 96%): TLC Rf 0.62 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.13-1.42 (m, 9H), 2.71-2.80 (m, 2H), 3.89 (s, 3H), 5.21-5.27 (m, 1H), 7.98 (s, 1H), 8.81 (s, 1H), 10.23 (bs, 1H).
Reaction SMILES: [C:1]1([S:10]([NH:13][C:14](=[O:17])[CH2:15][NH2:16])(=[O:12])=[O:11])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22].O>CN(C)C=O>[C:1]1([S:10]([NH:13][C:14](=[O:17])[CH2:15][NH:16][C:21]([O:23][CH3:24])=[O:22])(=[O:11])=[O:12])[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)Cl
Reactant: NCC(=O)NS(=O)(=O)c1scc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)NCC(=O)NS(=O)(=O)c1scc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product obtained in Step 1 (0.45 g) in N,N-dimethylformamide (5 ml) was added slowly 60% sodium hydride (75 mg) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. Methyl chloroformate (0.14 ml) was added to the above-mentioned mixture followed by stirring for 20 minutes at room temperature. 60% sodium hydride (75 mg) was added to the solution, and the mixture was stirred for 1.5 hours at room temperature, then 15 minutes at 70° C. After cooling to room temperature, water (20 ml) was added to the resultant mixture and this aqueous solution was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water, then saturated aqueous NaCl solution. After drying over anhydrous magnesium sulfate, ethyl acetate was removed in vacuo and the residue was purified by silica-gel columun chromatography to give 0.18 g of the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C@@H:7]([OH:9])[CH3:8])[NH:4][N:3]=1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[OH:9][C@H:7]([C:5]1[NH:4][N:3]=[C:2]([O:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:6]=1)[CH3:8]
Reactant: C[C@H](O)c1cc(O)n[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc([C@H](C)O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a stirred solution of (S)-3-hydroxy-5-(1-hydroxyethyl)-1H-pyrazole (0.5056 g, 3.95 mmol) in anhydrous dichloromethane (20 ml) under nitrogen was added p-toluenesulfonyl chloride (0.8276 g, 4.34 mmol) then, dropwise, triethylamine (0.66 ml, 4.74 mmol). The mixture was stirred at room temperature for 3 h, then washed with saturated NaCl (15 ml). The aqueous layer was further extracted with dichloromethane (2×25 ml) and the combined organic extracts were dried (NaSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 0.8770 g (79%) of the title compound as an orange oil: 1H NMR (400 MHz, DMSO-d6) δ 1.31 (3H, d, J=6.5 Hz), 2.42 (3H, s), 4.67 (1H, m), 5.40 (1H, d, J=5.1 Hz), 5.79 (1H, d, J=2.1 Hz), 7.47 (2H, d, J=8.1 Hz), 7.77 (2H, d, J=8.4 Hz), 12.48 (1H, s); MS (ES+) m/e 283 [M+H]+, 265 [M−OH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.CN([CH:39]=[O:40])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:39]([OH:40])[N:10]([C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:8]2=[O:9]
Reactant: CN(C)C=O
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C(OC)OC
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C(OC)OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 76 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-4-dimethoxymethyl-N-(1-methyl-1-phenylethyl)benzamide (3.61 g, 9.67 mmol) was dissolved in THF (100 mL), and the solution was treated with TMEDA (4.70 mL, 31.0 mmol), sec-butyl lithium-hexane solution (1.03 mol/L, 30.0 mL, 30.9 mmol) and DMF (1.65 mL, 21.3 mmol), followed by purification by slurry using chloroform and hexane to obtain 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.95 g, yield 85%).