Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Cl.[Cl:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:10].[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH2:11][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH3:3])[CH:17]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: Cc1ncc[nH]1
Reactant: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (17 mg of a 55% dispersion in mineral oil, 0.39 mmol) in DMF (5 ml) was added 2-methylimidazole (32 mg, 0.39 mmol). This mixture was stirred for 1.5 h at 20° C. Following this, 3-chloromethyl-5-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) (100 mg, 0.32 mmol) and triethylamine (78 mg, 0.78 mmol) were added and the mixture heated to 100° C. for 4 h. After cooling, the DMF was evaporated and the residue was directly chromatographed [silica, elution with CH2Cl2/(2M NH3 in MeOH)=85:15] to afford the free base of the title compound as a yellow oil. This material was dissolved in MeOH, cooled to 4° C. with stirring and treated with HCl/EtOH (1.46 M 1.1 eq) for 15 min. Evaporation of the solvent and drying under high vacuum at 50° C. for 2 h afforded the title compound (71 mg, 62%) as a light yellow solid. MS: m/e=317.1 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34]I)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Si:18]([O:31][CH2:32][CH:33]([F:36])[CH2:34][N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:13])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Reactant: CC(C)(C)[Si](OCC(F)CI)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(CC(F)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
7-Methoxyquinoxalin-2(1H)-one (synthesized with Reference to WO2009/1126; 1.50 g, 8.50 mmol) and tert-butyl(2-fluoro-3-iodopropoxy)diphenylsilane (Reference Example 29; 5.64 mmol, 12.75 mmol) were dissolved in N,N-dimethylformamide (60 ml). Cesium carbonate (3.88 g, 11.90 mmol) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 690 mg (17%) of the title compound in the form of a light brown solid.
Reaction SMILES: C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:11])(=O)=O)=CC=1.[CH2:21]([N:23]([CH2:36][CH3:37])[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([CH:34]=[O:35])[CH:28]=[CH:27]2)[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:36]([N:23]([CH2:21][CH3:22])[C:24]1[C:25]([F:11])=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([CH:34]=[O:35])[CH:28]=[CH:27]2)[CH3:37]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCN(CC)c1ccc2cc(C=O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc2cc(C=O)ccc2c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
N-fluorobenzenesulfonimide (57.0 milligrams, 0.18 millimole) was added to a solution of 6-diethylamino-naphthalene-2-carboxaldehyde (1, 40.0 milligrams, 0.18 millimole) in 5 milliliters of anhydrous N,N-dimethylformamide under argon at −40° C. The mixture was allowed to warm up to room temperature slowly. After 3 hours, 10 milliliters of 10% K2CO3 aqueous solution was added and the product was extracted with ethyl acetate (3×50 milliliters). Solvent was removed by rotary evaporation and the residue was purified by chromatography (SiO2, 1:1 hexane/CH2Cl2) to give 2 as yellow needles (35.0 milligrams, 79%). Rf (silica gel, 1:1 Hex/CH2Cl2)=0.74; 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J=7.0 Hz, 6 H), 3.45 (q, J=7.0 Hz, 4 H), 7.25 (t, J=8.8 Hz, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.89 (dd, J=1.2 Hz, 8.8 Hz, 1 H), 8.00 (d, J=8.8 Hz, 1 H), 8.19 (s, 1 H), 10.06 (s, 1 H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=O.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[OH:13][N:12]=[CH:1][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: O=Cc1ncn2ccsc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1ncn2ccsc12
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
7-Formylimidazo[5,1-b]thiazole (249 mg) was suspended in 10 ml of ethanol. Hydroxylamine hydrochloride (137 mg) and 2.0 ml of a 1 N aqueous sodium hydroxide solution were added under ice cooling to the suspension. The mixture was stirred at the same temperature for 1.5 hr, and then stirred at room temperature for 3 hr. The reaction solution was concentrated under the reduced pressure until the volume of the reaction solution was reduced to approximately the half of the original volume. The concentrate was adjusted to pH 12 by the addition of a potassium carbonate solution, followed by extraction three times with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=1:2). Of two main components, the fraction, which had been eluted earlier, was collected to give 160 mg of 7-hydroxyiminomethylimidazo[5,1-b]thiazole (a low-polarity geometrical isomer).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10])[OH:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(C(C)=O)C(C)C>[OH:8][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[O:10][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccccc1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCCCCOc1ccccc1O
Yield: 56.5 %

Procedure:
95.1 g (0.69 mol) of potassium carbonate and 321.2 g of methyl isobutyl ketone were added to 137.64 g (1.25 mol) of pyrocatechol and 188.63 g (1.25 mol) of 1-bromopentane, and the mixture was then refluxed for 23 hours. The mixture was cooled, after which the potassium carbonate was filtered off and the methyl isobutyl ketone was distilled off under reduced pressure. The oily residue was then subjected to fractional distillation over a short column under reduced pressure from an oil pump. 127.3 g of 1-hydroxy-2-pentoxybenzene were obtained at 5 bar and a boiling point of 88°-92° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[SH:19].[Br-].C(=O)([O-])[O-].[Na+].[Na+].CN1[CH2:32][CH2:31][CH2:30][C:29]1=O>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[S:19][CH2:29][C@H:30]1[CH2:14][CH2:15][C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:32][CH2:31]1
Reactant: CN1CCCC1=O
Reactant: Nc1c(S)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Product: CCCCC[C@H]1CC[C@H](CSc2cc(O)c3c(c2N)C(=O)c2ccccc2C3=O)CC1
Temperature: 0 °C

Procedure:
To 30 ml of N-methylpyrrolidone, 1 g of 1-amino-2-mercapto-4-hydroxyanthraquinone, 1.2 g of trans-4-n-penthylcyclohexylmethyl bromide and 0.6 g of sodium carbonate were added. The resulting mixture was heated at 120° to 125° C. for 7 hours. After cooling to 60° to 70° C., the mixture was poured on 100 g of ice, followed by separation of the product and washing with water until neutral was obtained. The product thus obtained was dried and purified by column chromatography using silica gel as carrier and chloroform as separating solvent to give 0.7 g of 1-amino-2-(trans-4-n-pentylcyclohexylmethylmercapto)-4-hydroxyanthraquinone having a melting point of 129°-130° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cccnc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromo-3-methylpyridine
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[CH:23]=[N:22][C:21]([C:24](O)=[O:25])=[N:20]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([C:21]2[N:22]=[CH:23][NH:19][N:20]=2)=[O:25])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)c1nc[nH]n1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2nc[nH]n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), 1H-1,2,4-triazole-3-carboxylic acid (0.12 g, 1.08 mmol), triethylamine (0.22 g, 2.16 mmol), EDCI (0.21 g, 1.08 mmol) and HOBt (0.17 g, 1.08 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water, and the suspension of white precipitate in ethyl acetate was washed with 10% sodium hydrogen carbonate solution, water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford white solid. This solid was triturated with diisopropyl ether to give the title compound (0.18 g, 56%) as a white solid, mp 295° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:21]([O:20][P:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[CH:4][CH:3]=1)(=[O:19])[O:23][CH2:24][CH3:25])[CH3:22]
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(F)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A solution of 1-bromo-4-fluoronaphthalene (500 mg, 2.22 mmol) in tetrahydrofuran (5 mL) was added dropwise to stirred solution of t-BuLi (1.4 M in pentane, 3.17 mL, 4.44 mmol) in tetrahydrofuran (5 mL) at −78° C. The reaction mixture was stirred for 1 hour at −78° C., after which diethyl chlorophosphate (0.96 mL, 6.66 mmol) was added dropwise. The reaction mixture was left to warm to rt and concentrated. The residue was suspended in 2 M NaOH (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated to give crude (4-fluoronaphthalen-1-yl)phosphonic acid diethyl ester (139MBT60-8C, 512 mg, 60% pure by NMR) as a yellow oil. 139MBT60-8C (200 mg, 0.425 mmol) was dissolved in pyrrolidine (0.5 mL) and stirred 2 hours at rt. The reaction mixture was concentrated and re-dissolved in dichloromethane (20 mL). The organic phase was washed with 2 M NaOH (20 mL) and dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (0-5% methanol in dichloromethane) to give the title compound (89 mg, 30%) as a white solid.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1cccnc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of N'-t-butyl-N-benzoylhydrazine (2.0 g) and nicotinoyl chloride hydrochloride in 20 ml of methylene chloride at 23° C. was treated dropwise with triethylamine (4 ml). The reaction mixture was stirred at 23° C. for 0.5 hours. Solids were removed by filtration. The filtrate was diluted with 10N HCl and ether. The layers were separated and the organic layer was washed with 10N HCl. The aqueous layer was neutralized with solid sodium bicarbonate and extracted with ether. The ether extracts were treated with charcoal and then dried with magnesium sulfate. Evaporation of solvents afforded a yellow oil which was chromatographed on silica gel using as eluant a mixture of 10% CH3OH, 40% CH2Cl2, 50% Et2O to afford N'-t-butyl-N-benzoyl-N'-nicotinoylhydrazine as a yellow foam: m.p. 60°-63° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:63][NH:64][CH2:65][CH:66]4[CH2:68][CH2:67]4)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:63][NH:64][CH2:65][CH:66]4[CH2:68][CH2:67]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNCC3CC3)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=493, obsd.=493).
Reaction SMILES: Cl.C([O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=O)C1C=CC=CC=1>CO>[O:10]=[C:11]1[NH:16][CH:15]=[C:14]([C:17]2([NH:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:13]=[CH:12]1
Reactant: O=C(NC1(c2ccc(OC(=O)c3ccccc3)nc2)CCCCC1)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(NC1(c2ccc(=O)[nH]c2)CCCCC1)c1ccccc1
Yield: 27.1 %

Procedure:
A solution of N-[1-[6-(benzoyloxy)-3-pyridinyl]cyclohexyl]benzamide hydrochloride (10.4 g) was heated in 75 ml of refluxing methanol for 1 hour. The solution was cooled, and the solvent was removed in vacuo. The residual oil was triturated with a mixture of ethyl acetate and hexanes, affording 5.9 g of crude product as a solid. Recrystallization from isopropyl alcohol gave 1.91 g of a flocculent solid, m.p. 223°-224° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@@H:9]1[C:21](=[O:40])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:25][C:24]=1[F:39])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:39][C:24]1[CH:25]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH3:38])(=[O:36])=[O:37])[CH:27]=[CH:28][C:23]=1[NH:22][C:21]([C@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]1)=[O:40]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)[C@H]2C[C@@H](O)CN2)c(F)c1

Procedure:
(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 1.35 mmol) was dissolved in 30 mL DCM, added 10 mL trifluoroacetic acid and stirred reaction at ambient temperature for 90 minutes. Solution was concentrated to yield title compound as an amber oil. (100% crude yield) APCI (AP−): 434.1 (M−H)−.
Reaction SMILES: Br[C:2]([CH3:10])([CH2:8][Br:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[Br:9]/[CH:8]=[C:2](\[CH3:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(Br)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(C)=C/Br
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 37.7 g (137 mmol) of ethyl 2,3-dibromo-2-methylpropanoate in 176 ml of THF was added 25 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and refluxed for 2 hours. After cooling to room temperature, to the mixture was added 1N HCl and extracted with tert-butyl methyl ether. The organic layer was washed sequentially with a saturated NaHCO3 solution and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated under vacuum to obtain 23.8 g of (E)-ethyl 3-bromo-2-methyl-2-propenoate.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:31].[Li+]>C(COC)OC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:31])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(F)c2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cccc(F)c1)C(=O)O

Procedure:
Analogously to Example 1i), 3.7 g (8.95 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(m-fluorophenylmethyl)-dihydrofuran-2-(3H)-one in 140 ml of dimethoxyethane are hydrolysed with 35.8 ml of 1M lithium hydroxide solution. Extraction of the evaporation residue of the reaction mixture from a mixture of ice, 120 ml of sat. ammonium chloride solution and 240 ml of 10% citric acid solution with a large amount of methylene chloride (solubility!) yields the title compound: tRet (I)=14.6 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[C:28]([O:31][CH2:32][CH2:33][NH:34][C:35]([C@@H:37]1[CH2:42][O:41][CH2:40][CH2:39][NH:38]1)=[O:36])(=[O:30])[CH3:29]>>[C:28]([O:31][CH2:32][CH2:33][NH:34][C:35]([C@H:37]1[N:38]([CH2:20][C:13]2[NH:12][C:11]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:39][CH2:40][O:41][CH2:42]1)=[O:36])(=[O:30])[CH3:29]
Reactant: CC(=O)OCCNC(=O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NCCOC(C)=O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 26.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with (S)-2-(morpholine-3-carboxamido)ethyl acetate hydrochloride (0.3 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.2 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](Cl)=[O:6].FC1C=C(F)C(F)=CC=1C(O)=[O:18]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:18])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F

Procedure:
A process for the preparation of 3-chloro-2,4,5-trifluorobenzoyl chloride, which comprises chlorinating 2,4,5-trifluorobenzoic acid to give 3-chloro-2,4,5-trifluorobenzoic acid, and reacting the latter with thionyl chloride.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]([C:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:12]([O:14]CC)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OS([O-])(=O)=O.[K+]>O.CO>[CH2:24]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]([C:17]1([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:12]([OH:14])=[O:13])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCCCC1
Temperature: 60 °C

Procedure:
KOH (1.44 g, 25.6 mmol, Eq: 6) in H2O (20 mL) was added to as solution of ethyl 2-(dibenzylamino)-2-(1-hydroxycyclohexyl)acetate (1.63 g, 4.27 mmol, Eq: 1.00) in MeOH (60 mL) and the mixture was heated to 60° C. After 18 h the reaction was cooled to RT and diluted with 100 mL H2O. The pH of the reaction was adjusted to about 4 using sat. KHSO4, and extracted with EtOAc. The combined extracts were washed with H2O, dried over Na2SO4 and concentrated the title compound as a white foam (1.44 g, 95%) which was used without purification. MS m/e 354.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[NH2:6])[CH3:2].[C:15]([O:19][C:20](=[O:24])[CH:21](Br)[CH3:22])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:22])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCCCSC[C@H](N)C(=O)OCC
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 20 ml of HMPA were dissolved 8.6 g of S-pentyl-L-cysteine ethyl ester and 8.2 g of 2-bromopropionic acid t-butyl ester. To the solution was added 5.5 ml of triethylamine. The solution was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was sufficiently washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (a 1:2 mixture of ether and n-hexane as an eluent), producing the α-isomer of the title compound as a colorless oil from the first eluate. Yield 3.9 g.