Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:3]=1[NH2:15].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:22]=[C:21]([NH:15][C:3]2[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1c(F)cc(F)cc1N1CCOCC1
Product: Fc1cc(F)c(Nc2nc(Cl)ncc2Cl)c(N2CCOCC2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-6-morpholin-4-yl-phenyl)-amine was prepared from 2,4-Difluoro-6-morpholin-4-yl-phenylamine and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. Title compound was isolated as an off-white foam (337 mg, 57%) HPLC 97% purity, LCMS 363.10 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 6.90 (s, 1H), 6.72 (dd, 1H), 6.64 (d, J=9.6 Hz, 1H), 3.79-3.77 (m, 4H), 2.90-2.87 (m, 4H).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.C[O:12][C:13]([CH2:15][CH2:16][C:17]1[C:21]([CH3:22])=[CH:20][NH:19][CH:18]=1)=[O:14]>ClC(Cl)C>[C:13]([CH2:15][CH2:16][C:17]1[C:21]([CH3:22])=[C:20]([CH:3]=[O:4])[NH:19][CH:18]=1)([OH:12])=[O:14]
Reactant: CN(C)C=O
Reactant: COC(=O)CCc1c[nH]cc1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1c(CCC(=O)O)c[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 90.2 %

Procedure:
Dimethylformamide was charged to a 500 mL, 3 neck round bottom flask equipped with mechanical stirring, a thermometer and a dropping funnel and maintained under a nitrogen atmosphere. The flask was cooled to 0° C. and 58.4 mL of phosphorus oxychloride was added dropwise over 80 minutes. Dichloroethane (280 mL) was added and the mixture allowed to warm to room temperature and then cooled to −10° C. 3-(2-methoxycarbonyl-ethyl)-4-methylpyrrole (55.7 g) dissolved in 80 mL dichloroethane was added dropwise over 1 hour and the mixture stirred for another 35 minutes. The mixture was rotary evaporated at <30° C. The fluid residue was poured into 2700 mL of ice-cold 2 N sodium hydroxide solution. The resulting solution was heated to 88° C. over 20 minutes and then maintained at this temperature for an additional 30 minutes. The solution was cooled to ambient temperature and extracted with 200 mL of ethyl ether. The aqueous solution was cooled to 0° C. and acidified to pH 3:5 by slowly adding about 1350 mL of 5 N hydrochloric acid. The yellow precipitate was collected by vacuum filtration, washed four times with 100 mL of water, and dried in a vacuum oven at ambient temperature to give 54.4 g (90.2% yield) of crude 4-(2-carboxyethyl)-2-formyl-3-methylpyrrole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 54 h
Yield: 82.1 %

Procedure:
N-t-Butyloxycarbonyl-β-alanine (2.0 g, 10.6 mmol) in methylene chloride (50 mL) was treated with benzyl alcohol (1.66 mL, 26.0 mmol), N,N-dicyclohexylcarbodiimide (2.39 g, 11.6 mmol) and N,N-dimethylaminopyridine (1.42 g, 11.6 mmol) and the subsequent reaction mixture was stirred at room temperature for 54 h. The reaction mixture was filtered and evaporated at reduced pressure. The residue was purified using flash chromatography (silica gel, 50% ethyl acetate/hexane) to yield the title compound (25) (2.43 g, 82%). 1H NMR (CDCl3) ε 1.47 (s, 9H), 2.61 (t, 2H, J=6 Hz), 3.45 (q, 2H, J=7.5 Hz), 5.15 (br s, 1H), 5.27 (s, 2H), 7.43 (s, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20]([OH:22])=O)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].Cl.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH2:34])[CH2:31]2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:20]([C:14]1[CH:13]=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=3)[C:15]=1[S:16][CH2:17][CH2:18][CH3:19])=[O:22])[CH2:31]2
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(C(=O)OC)cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 18 h

Procedure:
1-(4-methoxycarbonylphenyl)-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate #7) (160 mg, 0.5 mmol), 2-adamantylamine hydrochloride (94 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (261 μL, 1.5 mmol) were dissolved in DMF (5 mL) and treated at ambient temperature with EDCI (115 mg, 0.6 mmol). The mixture was stirred at ambient for 18 h and then diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and brine, dried (MgSO4) and evaporated to leave a white solid, which was purified by chromatography on silica gel, (12 g silica 0-50% EtOAc/isohexane) to give the title compound as a white solid. (203 mg, 92%)
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[CH3:3].Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.ClCCl>[CH3:1][N:2]([CH3:3])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)C(=O)CCl
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)C(=O)COc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-N,N-dimethylamino phenol (69) (3.43 g, 25 mmol) and 2-chloro N,N-dimethylacetamide (3.66 g, 30 mmol) in DMSO (30 mL) was added K2CO3 (6.7 g, 50 mmol) and the resulting suspension was stirred at room temperature for 16 h. The reaction was then diluted with dichloromethane (125 mL), and washed with water (2×100 mL), and brine (100 mL), and dried, and filtered, and the solvent was removed under vacuum. The crude product, Compound 70, was obtained as purple, thick oil that was used in the next step without additional purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[CH:20][C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:33](=O)=O.C([O-])(O)=O.[Na+]>C(O)=O>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([CH:20]=1)[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: O=C=O
Reactant: O=C(Nc1cccnc1)c1cc(OC[C@@H]2CCCN2)ccc1OCc1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC[C@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
2-[(Phenylmethyl)oxy]-N-3-pyridinyl-5-{[(2S)-2-pyrrolidinylmethyl]oxy}benzamide (may be prepared as described in Example 46; 80 mg, 0.20 mmol) was added to formic acid (4 ml) at 5° C., followed by aqueous formaldehyde (40%, 2.0 ml). When the initial evolution of carbon dioxide had subsided, the mixture was refluxed for 2 h. After the solution was cooled, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, waters X-Bridge 5 μm, 100*19 mm; A: 0.04% NH3.H2O/water, B: CH3CN; 0-7.2 min, 40%-50%; 7.2-7.5 min, 50%-95%; 7.5-11.5 min, 95%, RT=4.0 min) to yield the title compound as a white solid. 68 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:17][CH:18](Br)[CH3:19].C(OCC)(=O)C>CN(C=O)C.O>[Br:17][CH2:18][CH2:19][N:6]1[C:7]([CH2:9][OH:10])=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A mixture of 296a (345 mg, 2.41 mmol), and cesium carbonate (965 mg, 2.96 mmol) in DMF (5 mL) was cooled to 0° C. using an ice/acetone bath and dibromoethane (4.48 g, 24.1 mmol) was added portion-wise (no exotherm). The reaction was stirred at 0° C. for 1 h and room temperature for 4 h. After this time ethyl acetate (20 mL) and water (15 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by silica-gel column chromatography eluting with 6:1 petroleum ether/ethyl acetate to afford 296b (300 mg, 50%). MS-ESI: [M+H]+ 250
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([Cl:17])[N:6]=[CH:5]2
Reactant: COc1cc2nc(O)ncc2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2nc(Cl)ncc2cc1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 6-bromo-7-methoxyquinazolin-2-ol (3.0 g, 11.8 mmol) in phosphoryl trichloride (30 mL) was refluxed at 130° C. for 5 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and most of phosphoryl trichloride was evaporated. The residue was dropwise added to ice water (100 mL), and the resulting precipitate was collected via filtration to give the title compound as a yellow solid (2.4 g, 75%). MS (ES+) C9H6BrClN2O requires: 272, 274. Found: 273, 275 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C)=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2
Reactant: COC(=O)Cn1ccc2cc(OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of methyl 2-(5-methoxy-1H-indol-1-yl)acetate (745 mg, 3.40 mmol) in MeOH (20 ml), aqueous 4N sodium hydroxide (935 μl, 3.74 mmol) was slowly added and the reaction was stirred at room temperature for 1 hour. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous phase was acidified with 2.5M HCl and extracted with ethyl acetate. This organic phase was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (510 mg, 2.485 mmol, 73% yield). MS/ESI+ 206.1 [MH]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:14]C(=O)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=1.[ClH:18]>>[ClH:18].[NH2:14][C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=1)[CH2:2][OH:1]
Reactant: CC(=O)N[C@@H](CO)Cc1cccc(C(=O)O)c1
Agent: Cl
Product: N[C@@H](CO)Cc1cccc(C(=O)O)c1
Temperature: 100 °C

Procedure:
The process is performed as in Example 2, starting with 1.96 g of N-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]acetamide in 14 cm3 of aqueous 6N hydrochloric acid heated at a temperature in the region of 100° C. for 17 hours. After an identical work-up, 2.16 g of (2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride are obtained in the form of a white solid melting at 194° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28]>>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: O=C(O)c1cc(F)cc(S(F)(F)(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(F)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 100 mg (0.346 mmol) of the compound of Example 6A and 97 mg (0.363 mmol) of 3-fluoro-5-(pentafluoro-λ6-sulphanyl)benzoic acid (JRD Fluorochemicals Ltd., United Kingdom) gave 165 mg (89% of theory) of the title compound. In this case, the reaction time was about 15 h.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38](Br)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].[CH2:42]([OH:46])[CH2:43][CH:44]=[CH2:45].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38](/[CH:45]=[CH:44]/[CH2:43][CH2:42][OH:46])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: C=CCCO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(/C=C/CCO)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 71.9 %

Procedure:
Combine [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-bromophenyl)methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.67 mmol), 3-buten-1-ol (5 mmol), triethylamine (35.8 mmol), and acetonitrile (10 mL) and purge with nitrogen for 10 minutes. To this mixture add palladium acetate (0.17 mmol) and tri-o-tolylphosphine (0.33 mmol). Heat this mixture at 80° C. for 2 hours, then cool to room temperature. Dilute with ethyl acetate (50 mL) and water (50 mL). Separate and wash the organic phase with brine (50 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure. Purify by flash chromatography (40 g silica gel cartridge) eluting with 5-80% ethyl acetate in dichloromethane to yield the title compound as a tan foam (0.8 g, 1.2 mmol): MS (m/z): 622.0 (M+H).
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]1[S:9][C:8]([Si:7]([CH3:14])([CH3:13])[CH3:6])=[N:12][CH:11]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C)(C)C)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of n-BuLi (2.5M in hexane, 6.0 mL, 15 mmol) in ether (60 mL) at −78° C. is added a solution of 2-(trimethylsilyl)thiazole (2.0 mL, 12.5 mmol) in ether (20 mL) dropwise. The mixture is stirred at −78° C. for 1 h then tributyltin chloride (4.04 mL, 15 mmol) in ether (25 mL) is added dropwise and stirring is continued at −78° C. for 1 h. The reaction mixture is washed with saturated NaHCO3, dried over anhydrous MgSO4 and concentrated to afford the title compound as a yellow oil which used in the next step without further purification: 1H NMR (CDCl3) δ 0.41 (s, 9H), 0.90 (t, J=8 Hz, 9H), 1.14 (q, 6H), 1.13 (q, 6H), 1.54 (m, 6H), 8.06 (s, 1H); (M+1)+=447.
Reaction SMILES: [OH:1][C@H:2]([CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C([CH2:18][C:19]([O-])=[O:20])=C>O1CCCC1>[C:19]([O:14][CH2:13][C@@H:12]([OH:15])[CH2:11][C@@H:2]([OH:1])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])(=[O:20])[CH3:18]
Reactant: C=CCC(=O)[O-]
Reactant: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred 11 round bottom flask 700 ml tetrahydrofuran and 70.7 g (0.32 mol) of (3R,5S) t-butyl 3,5,6-trihydroxyhexanoate, 41 ml (0.46 mol) vinylacetate and 6.3 g of the supported lipase Chirazyme L2′ were charged. After 3 hours stirring at ambient temperature the lipase was removed by screening and the volatiles removed by distillation under vacuum. The mass of crude oil was 78.7 g and the major component was determined to be (3R,5S) t-butyl 6-acetoxy-3,5-dihydroxyhexanoate. This material was used directly in the next stage.
Reaction SMILES: CO.O.[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[N:14]1[C:18](=[O:19])[NH:17][C:16]([CH:20]([C:37]2[C:38]([F:49])=[C:39]3[C:44](=[C:45]([O:47][CH3:48])[CH:46]=2)[O:43][CH2:42][CH2:41][CH2:40]3)[NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=C(C(F)(F)F)O[N:29]=3)=[CH:24][CH:23]=2)=[N:15]1)=[O:8])[CH3:5]>[Fe].C(O)(=O)C>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[N:14]1[C:18](=[O:19])[NH:17][C:16]([CH:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:32])=[CH:24][CH:23]=2)[C:37]2[C:38]([F:49])=[C:39]3[C:44](=[C:45]([O:47][CH3:48])[CH:46]=2)[O:43][CH2:42][CH2:41][CH2:40]3)=[N:15]1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.8 %

Procedure:
Iron powder (64 mg) was added to 6 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 74 mg of 5-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. The resulting mixture was stirred at 60° C. for 20 hours under a nitrogen atmosphere. After filtration, the reaction mixture was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 22 mg of 5-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][C:4]1=[O:10])[CH3:2].[CH:11]([O-])([O-])[O:12][CH3:13]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[C:5](=[CH:11][O:12][CH3:13])[C:4]1=[O:10])[CH3:2]
Reactant: CCN1CCC(=O)CC1=O
Reactant: COC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCN1CCC(=O)C(=COC)C1=O
Yield: 25.1 %

Procedure:
Added to 8.3 g of 1-ethylpiperidine-2,4-dione were 11 g of methyl orthoformate and 20 ml of acetic anhydride. The resultant mixture was refluxed for 7 hours. After allowing the reaction mixture to cool down, excess methyl orthoformate and acetic anydride were distilled off under reduced pressure. The brown residue was distilled under reduced pressure in a Kugelroll apparatus (0.5 mmHg; bath temperature: 200°-250° C.) to obtain 2.7 g of 1-ethyl-3-methoxymethylenepiperidine-2,4-dione as crystals (yield: 25%). The crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to obtain needles.
Reaction SMILES: [CH2:1]([S:4]([N:7]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][C:28]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:27]3)=[O:23])[C:15]=1[F:40])S(CCC)(=O)=O)(=[O:6])=[O:5])[CH2:2][CH3:3].[OH-].[Na+]>CO>[F:40][C:15]1[C:16]([C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][C:28]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[N:27]3)=[O:23])=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=1[NH:7][S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of N-(propylsulfonyl)-N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (41 mg, 0.068 mmol, 1.0 eq.) in MeOH/THE (10 mL/10 mL) was added 1 N NaOH (0.15 mmol, 2.2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (23 mg, 68.9%). LRMS (M+H+) m/z calculated 495.1, found 495.1. 1H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1 H), 7.98-8.03 (m, 3 H), 7.66-7.73 (m, 1 H), 6.72 (s, 1 H), 3.78-3.88 (m, 8H), 3.12-3.16 (t, 2 H), 1.87-1.92 (q, 2 H), 1.05-1.09 (t, 3 H).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][CH2:8][N:9]([CH2:25][C:26]1[S:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[C:10]1[S:11][CH:12]=[C:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[N:14]=1)(C)(C)C.[OH-].[Na+]>>[CH3:31][C:28]1[S:27][C:26]([CH2:25][N:9]([C:10]2[S:11][CH:12]=[C:13]([CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20]3)[N:14]=2)[CH2:8][CH2:7][C:6]([OH:32])=[O:5])=[CH:30][CH:29]=1
Reactant: Cc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc(C3CC(C)(C)CC(C)(C)C3)cs2)s1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(CN(CCC(=O)O)c2nc(C3CC(C)(C)CC(C)(C)C3)cs2)s1
Temperature: 50 °C
Yield: 49.5 %

Procedure:
3-{(5-methyl-thiophen-2-ylmethyl)-[4-(3,3,5,5-tetramethyl-cyclohexyl)-thiazol-2-yl]-amino}-propionic acid tert-butyl ester (60 mg, 0.12 mmol) was treated with NaOH (2N NaOH: 1 mL; MeOH: 1 mL; THF: 1 mL) and the reaction was heated at 50° C. for 3 hrs following a method analogous to General Procedure G1 to produce 3-{(5-methyl-thiophen-2-ylmethyl)-[4-(3,3,5,5-tetramethyl-cyclohexyl)-thiazol-2-yl]-amino}-propionic acid (25 mg) after workup and purification. LC-MS m/z: 421 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.81 (d, 1H), 6.60 (d, 1H), 6.12 (s, 1H), 4.60 (S, 2H), 3.75-3.80 (m, 2H), 2.92 (m, 1H), 2.68-2.73 (m, 2H), 2.44 (s, 3H), 1.73 (d, 2H), 1.27-1.32 (m, 1H), 1.00-1.17 (m, 3H), 1.07 (s, 6H), 0.93 (s, 6H). The sodium carboxylate salt of the title compound could be prepared from this acid using a method analogous to General Procedure H.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]2[S:14]C=NC=2C(O)=O)=[CH:7][CH:6]=[CH:5][N:4]=1.CC1N=C(N)C=CC=1.COC1C(N)=CC=CN=1>>[N:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)=[C:10]=[S:14]
Reactant: COc1ncccc1Nc1scnc1C(=O)O
Agent: COc1ncccc1N
Agent: Cc1cccc(N)n1
Product: COc1ncccc1N=C=S

Procedure:
The title compound, MS (ISP): m/e=342.1 (M+H+), was prepared as for example 1, steps A to C. Step A was performed using 3-isothiocyanato-2-methoxy-pyridine and yielded 5-(2-methoxy-pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester. This was hydrolized in step B to 5-(2-methoxy-pyridin-3-ylamino)-thiazole-4-carboxylic acid, which was reacted with 6-methyl-pyridin-2-ylamine in step C. 3-Isothiocyanato-2-methoxy-pyridine was prepared as in example 96, starting from 2-methoxy-pyridin-3-ylamine.