Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: O=C(O)c1cccc(Cl)c1

Procedure:
A solution of (e3) (0.3 g) in water (10 ml) was treated with solid m-chloroperbenzoic acid (0.17 g). A white precipitate of m-chlorobenzoic acid was rapidly formed, and after 10 minutes was filtered off. The remaining solution was neutralised to pH 7 with sodium bicarbonate and then chromatographed on QAE sephadex A 25 eluting with NaCl--phosphate buffer. The product was desalted on Amberlite XAD 4 using distilled water to elute, and then freeze-dried to afford a mixture of sulphoxides (1.2:1) (e4) as a white solid (0.176 g, 57%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(O[C:12](=[O:14])[CH3:13])(=O)C.[OH-].[Na+]>CCOCC.O>[C:12]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CNCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(=O)N(C)CCN(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
N-Acetyl-N,N',N'-trimethylethylenediamine intermediate was prepared in the following manner. N,N,N'-Trimethylethylenediamine (24.5 g, 0.24 mol) was added to acetic anhydride (38 mL, 0.40 mol) over 1.5 hours with cooling in an ice-water bath. After stirring another 22 hours at ambient temperature, the reaction mixture was diluted with 50 mL of ether and 25 mL of water, and then cooled in an ice-water bath. A solution of 25 percent aqueous NaOH was added until the pH was approximately 10 and the phases were separated. The aqueous phase was extracted two more times with ether and the combined organic phase was concentrated on the rotary evaporator (50°,>100 mm Hg). Yield=2.4 g. The aqueous phase was saturated with NaCl and extracted again with methylene chloride (3×25 mL). After evaporation, it gave a total of 33.4 g of yellow liquid. Distillation through a 1×8 cm Vigreux column afforded 23.53 g of colorless liquid, bp 90°-1°/7 mm Hg (68 percent yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:35][C:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH3:36]
Reactant: CC(C)(N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2-amino-2-(2-pyridyl)-propane (47 mg, 0.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 50 mg of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:13]C(=O)C(F)(F)F)[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([OH:13])[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:6]=2[CH:27]=1
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1OC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1O
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A suspension of 9.5 g (0.021 mole) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-one in a mixture of 130 ml ethanol and 130 ml aqueous 5% sodium bicarbonate was stirred at 25° for 18 hr. The suspended solid was collected on a filter, washed with water, dried in air, and recrystallized from ethanol to give 4.54 g (62%) 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 196°-198°; 19F nmr (DMSO-d6) δ -113.5 ppm (m); 1H nmr (DMSO-d6) δ 4.88 ppm (s, 1H), 6.35 ppm (s, OH), 7.0-7.9 ppm (m, 7H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[OH:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([N:15]2[CH2:16][CH2:17][CH:13]([OH:12])[CH2:14]2)=[CH:5][CH:4]=1
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: OC1CCN(c2ccc(C(F)(F)F)cc2)C1
Yield: 55 %

Procedure:
The title compound (2.71 g, yield 55%) was obtained from 4-(trifluoromethyl)phenyl bromide and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: OC(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(OCC(F)(F)F)nc1)C(F)(F)F

Procedure:
2.75 g (0.01 mol) of 2-(2,2,2-trifluoroethoxy)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 30 ml of methylene chloride at room temperature. 22 ml (0.036 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 10 minutes with vigorous stirring and the mixture is stirred for a further 4.5 hours during which the reaction temperature rises to 25° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 100°-120° C. bath temperature), 2.48 g (90% of theory) of 2-(2,2,2-trifluoroethoxy)-5-trifluoroacetylpyridine are obtained, which, according to GC, is 96% pure. nD20 : 1.4312.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc3c2C=C(CC2CCCCC2)C3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
82.3 g (229 mmole) 7-(4′-tert-Butyl-phenyl)-2-cyclohexylmethyl-indan-1-one were dissolved in 292 ml toluene in a 1 l-roundbottom flask equipped with a reflux condenser. 9.5 g (1.1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 3 h at 50° C. An additional 1 g of sodium borohydride and 5 ml methanol were added and the mixture was stirred another 2 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 800 ml ethanol afforded 67.3 g (86%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.45, 7.33, 7.25, 7.14 (4×m, 7H, aromatic), 6.69 (s, 1H, ═CH), 3.35 (s, 2H, benzylic), 2.34 (d, 2H, aliphatic), 1.71-1.50 (m, 6H, aliphatic), 1.39 (s, 9H, C(CH3)3), 1.24-0.87 (m, 5H, aliphatic) ppm.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CON(C)[C:39]([CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)C1CCOCC1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C3CCOCC3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([OH:13])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1>C1C2C(=CC=CC=2)CCC1.[Cr].[Cu]>[CH3:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([CH3:11])[CH:8]=1)[O:4][CH2:3][C:2](=[O:13])[CH3:1]
Reactant: Cc1cc(C)cc(OCC(C)O)c1
Agent: [Cr]
Agent: [Cu]
Solvent: c1ccc2c(c1)CCCC2
Product: CC(=O)COc1cc(C)cc(C)c1
Yield: 68.3 %

Procedure:
5.0 Grams (28 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethanol was dissolved in 10 ml of tetralin, and 0.5 g of a copper-chromium catalyst (203 SD, supplied by Nikki Chemical Co., Ltd.) was added. The resultant mixture was stirred under a nitrogen current (0.1 liter/minute) at 210° C. for 8 hours. The catalyst was removed by filtration, and the filtrate was distilled under reduced pressure to give 3.41 g of 1-(3,5-dimethylphenoxy)-2-propanone (boiling point: 88° C./0.35 mmHg, yield 69%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CCOCC>[C:22]([C:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:27][CH:26]=1)([OH:24])=[O:23]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)O)cc2)CC1
Yield: 11.3 %

Procedure:
To a solution of tert-butyl 1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine-1-carboxylate (2.63 g, 7.9 mmol, reference example 76) in dimethdxyethane (21 mL) is added 4-carboxybenzeneboronic acid (1.44 g, 8.7 mmol), 2M aqueous sodium carbonate (17.4 mL) and lithium chloride (0.99 g, 24 mmol). The mixture is degassed and then tetrakis(triphenylphosphine)palladium (450 mg, 0.4 mmol) added, the reaction is degassed again and then heated at reflux 6 h. The reaction is filtered and the solid washed with EtOAc. The organic phase is washed with 0.5 N HCl, dried (MgSO4), concentrated and purified by column chromatography (silica, 3% MeOH/CH2Cl2/0.1%HOAc) providing a semi-purified product. This material is titurated with ether and a small amount of CH2Cl2 to provide 0.27 g of the title compound as a white solid: m.p. 200-209 (dec); 1H NMR (300 MHz, CDCl3) d 8.07 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.20 (bs, 1H), 4.15-4.00 (m, 2H), 3.66 (t, J=5.6 Hz, 2H), 2.60-2.52 (m, 2H), 1.50 (s, 9H); MS (ion spray) m/z 304 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:16]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (1.092 g, 4.0 mmol) was added dichloromethane (10 mL), oxalyl chloride (2.8 mL) and one small drop of N,N-dimethylformamide. The mixture was stirred at room temperature overnight. The mixture was then concentrated to give 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoyl chloride which was used without additional purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.36 g (0.01 mol) of 7β-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 4 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6 N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is treated with Amberlite IR-120H ionexchange resin and lyophilized to give the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:9][CH:10]=1)(=O)C.[CH3:25]O>Cl>[NH2:4][C:5]1[CH:6]=[C:7]([C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:25])=[O:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1cccc(C(=CCCCC(=O)O)c2cccnc2)c1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1

Procedure:
65 g of 6-(3-acetylaminophenyl)-6-(3-pyridyl)hex-5-enoic acid are refluxed for 4 hours in a mixture of 400 ml of methanol and 200 ml of methanolic hydrochloric acid. The solvent is removed and the residue is taken up in water. The aqueous phase is washed with ethyl acetate and adjusted to pH 8-9 by the addition of 4N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The organic phase is washed, dried and evaporated down.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:12])[C@@:4]1([CH3:11])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>CCOCC>[CH3:10][C:6]1([CH3:9])[O:5][C@@:4]([CH3:11])([C:3]([Cl:12])=[N:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][O:7]1
Reactant: CC1(C)OC[C@](C)(C(Cl)=NO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@](C)(C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(R)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (6.4 g, 33.1 mmol) was dissolved in Et2O (150 mL) and methanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine (3.96 ml, 28.4 mmol) was added dropwise and the reaction stirred at ambient temperature for 1 hour. The resulting solids were filtered and the filtrate was concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (R)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (5.8 g, 21.3 mmol, 64.6% yield) as an amber oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][NH:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]([CH3:33])[CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CNCc1cccnc1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(Cc1cccnc1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-pyridin-3-ylmethyl-amino)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and Methyl-pyridin-3-ylmethyl-amine following General Procedure B.
Reaction SMILES: BrC1[C:7]2[O:8]CC[O:11][C:6]=2C(NC(=O)C)=CC=1.C(C1C2CCCCC=2C(NC(=O)C)=CC=1)#N.[OH:32][C@H:33]1[C@@H:40]2[N:36]([C:37](=[O:54])[N:38]([C:42]3[C:51]4CCCC[C:46]=4[C:45]([C:52]#[N:53])=[CH:44][CH:43]=3)[C:39]2=[O:41])[CH2:35][CH2:34]1.C(O)(C)C>CCCCCC>[OH:32][C@H:33]1[C@@H:40]2[N:36]([C:37](=[O:54])[N:38]([C:42]3[C:51]4[O:8][CH2:7][CH2:6][O:11][C:46]=4[C:45]([C:52]#[N:53])=[CH:44][CH:43]=3)[C:39]2=[O:41])[CH2:35][CH2:34]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: CC(=O)Nc1ccc(Br)c2c1OCCO2
Agent: CC(=O)Nc1ccc(C#N)c2c1CCCC2
Solvent: CC(C)O
Solvent: CCCCCC
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1OCCO2

Procedure:
The title compound (32 mg) was prepared from compound 8D and isolated as a white solid by procedures analogous to those described in Example 2 (2C to 2F). mp196-197° C.; HPLC: 99% at 12.31 min (retention time) (CHIRALPAK® OD column 4.6×250 mm; 25% isopropanol in hexane over 30 min, 1 mL/min, UV detection at 220 nm); MS (ES) m/z 322 [M+1]+.
Reaction SMILES: C(OC[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:17]=[C:12]2[C:11]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:10]1)(=O)C(C)(C)C.[OH-].[K+].Cl>O1CCOCC1.O>[C:33]([NH:32][C:31]([C:11]1[C:12]2[C:13](=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]([CH3:28])[CH3:29])[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:17]=2)[NH:9][CH:10]=1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)c1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COC(=O)C(C)(C)C)nn2C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)NC(C)(C)C)c3n1)nn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a stirred solution of (7-(tert-butylcarbamoyl)-2-(5-isopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (0.2 g, crude) in dioxane/water (5 mL/10 mL) was added KOH (0.23 g, 4.1 mmol). The mixture was stirred at room temperature for 3 hours. Then the reaction mixture treated with 1N HCl to pH=3-4. The solvent was removed under reduced pressure and the residue triturated with water (15 mL) and dried to give a crude product which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 62% acetonitrile/38% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 64% acetonitrile/36% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give N-tert-butyl-2-(5-isopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.05 g) as a yellow solid. LCMS: (M+H)+=391; 1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.61 (d, 1H, J=8.7 Hz), 7.48 (dd, 1H, J1=8.7 Hz, J2=1.5 Hz), 4.18 (s, 3H), 3.19-3.02 (m, 1H), 1.58 (s, 9H), 1.35 (d, 6H, J=6.6 Hz).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=1.[CH2:53]([O:55][C:56](=[O:69])[C@@H:57]([O:66][CH2:67][CH3:68])[CH2:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1)[CH3:54]>ClCCl>[CH2:53]([O:55][C:56](=[O:69])[C@@H:57]([O:66][CH2:67][CH3:68])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[CH:49]([CH3:50])[CH3:51])=[CH:43][CH:42]=2)=[CH:61][CH:60]=1)[CH3:54]
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1)OCC
Reaction time: 24 h
Yield: 87.3 %

Procedure:
Azodicarbonyl dipiperidine (0.99 g; 3.93 mmole) and triphenylphosphine (1.03 g; 3.93 mmole) were added to a solution of N-[4-(2-hydroxyethyl)phenyl]isobutyramide (described in Example 68a) (0.79 g; 3.93 mmole) and (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 40h) (0.78 g; 3.27 mmole) in dry dichloromethane (25 ml). After stirring at room temperature over night more N-[4-(2-hydroxyethyl)phenyl]isobutyramide, azodicarbonyl dipiperidine (0.16 g; 0.65 mmole) and triphenylphosphine (0.17 g; 0.65 mmole) were added. After stirring for 24 hours the reaction mixture was filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (2:1) as eluant gave 1.22 g (yield 87%) of (S)-2-ethoxy-3-{4-[2-(4-isobutyrylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.