Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH:19]=O)[C:11]=3[CH:12]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][NH2:23]>>[CH:1]1([NH:5][C:6]([C:8]2[O:9][C:10]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:19][NH:23][CH3:22])[C:11]=3[CH:12]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: COc1ccc(C=O)c2cc(C(=O)NC3CCC3)oc12
Agent: Cl
Product: CNCc1ccc(OC)c2oc(C(=O)NC3CCC3)cc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and cyclobutylamine to give N-Cyclobutyl-7-methoxybenzofuran-2-carboxamide (Compound 289a). Successively, it was formylated to give N-cyclobutyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 289b), then compound 289b was reacted with methylamine hydrochloride to give Compound 289 as a white solid.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH3:20][NH:21]C.[BH4-].[Na+].Cl>CO>[CH3:20][NH:21][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:13][CH:14]=1
Reactant: CNC
Reactant: O=Cc1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzaldehyde (76.2 mg, 0.3 mmol, 1.0 eq.) in MeOH (3.0 mL) was added dimethylamine (170 μL, 0.33 mmol, 1.1 eq.). The mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., NaBH4 (11.3 mg, 0.3 mmol, 1.0 eq.) was added in portions and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was carefully treated with dilute HCl (5 mL) and aqueous phase was extracted with EtOAc (3×10 mL). Combined organic extracts was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 5-(4-methylaminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol as a white solid. LCMS (m/z) 270 (M+H); 1H NMR (DMSO-d6) δ: 7.67-7.74 (m, 1H), 7.41-7.46 (m, J=8.5 Hz, 2H), 7.00-7.07 (m, 2H), 6.91-6.98 (m, 2H), 4.91 (s, 2H), 4.53 (s, 3H), 3.85 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 93.5 %

Procedure:
Beginning with 6.2 gm (31.6 mMol) 5-bromo-1H-indole and 4.7 gm (30.6 mMol) 4-piperidone monohydrate hydrochloride, 7.93 gm (93%) of the title compound were recovered as a solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>C(OCC)(=O)C>[OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC[C@@H](O)CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72 %

Procedure:
To a solution of (R)-3-hydroxytetradecanoic acid (36, see preparation below) (9.55 g, 39.1 mmol) and triethylamine (5.90 g, 58.6 mmol) in ethyl acetate (500 mL) was added 2-bromoacetophenone (7.90 g, 39.1 mmol) at room temperature. The mixture was stirred at room temperature for 14 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 50 min, 85 mL/min) to give the product 37 (10.2 g, 72% yield) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:19])=[CH:7][C:8]([Cl:18])=[C:9]([NH:11][C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])[CH:10]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:26](=[O:31])=[N:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:18][C:8]1[C:9]([N:11]2[C:28](=[O:29])[NH:27][C:26](=[O:31])[N:14]([CH2:15][C:16]#[CH:17])[C:12]2=[O:13])=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([F:19])[CH:7]=1
Reactant: C#CCNC(=O)Nc1cc(NC(C)=O)c(F)cc1Cl
Reactant: O=C=NC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(NC(C)=O)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-acetamido-2-chloro-4-fluorophenyl)-3-(2-propynyl)urea (4.50 g, 15.9 mmol), and pyridine (2.56 mL, 31.8 mmol) in methylene chloride is treated with N-(chlorocarbonyl) isocyanate (1.92 mL, 23.9 mmol), stirred at room temperature overnight, refluxed for 90 minutes, cooled to room temperature, treated with additional pyridine (1.30 mL) and N-(chlorocarbonyl) isocyanate (1.92 mL), stirred for 10 minutes, cooled to room temperature, and filtered to obtain a solid. The solid is washed sequentially with water and hexanes, and dried to give the title product as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:7][C:6]2[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid (2.03 g, 11.8 mmol), benzyl bromide (2.79 ml, 23.5 mmol) and potassium carbonate (4.87 g, 35.3 mmol) in DMF (20 ml) was stirred at room temperature overnight then heated at 60° C. for 1 hour. Cooled, diluted with water (150 ml) and extracted with ethyl acetate (×3). The organics were washed with water (×2) and brine, dried (MgSO4), and concentrated in vacuo to yield the crude title compound as a yellow oil which was used immediately without further purification.
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11]([CH3:33])[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.FC1C=CC([N+]([O-])=O)=CC=1C#[N:38]>>[NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:19][CH2:20]2)=[C:11]([C:33]#[N:38])[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Product: N#Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Yield: 12 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 2-fluoro-5-nitrobenzonitrile replacing 2-fluoro-5-nitrotoluene. A yellow solid is obtained (yield 12%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Na+].[I-:15]>O1CCOCC1.[Cu]I>[I:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Br)ccc1C
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(I)ccc1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of bromide 3 (39.0 g, 161 mmol) in 1,4-dioxane (150 mL) were added NaI (48.2 g, 321 mmol), CuI (1.6 g, 8.03 mmol) and N,N′-dimethylethyldiamine (1.8 mL, 16.1 mmol). The mixture was evacuated and backfilled with N2. The mixture was stirred at 110° C. for 15 h. The mixture was cooled to room temperature and filtered off through celite. The filtrated was evaporated under vacuum to remove solvent. The residue was diluted with EtOAc and washed with aq. 50% NH4Cl solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound 4 (41.3 g, 89%).
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(Cl)OCC
Reactant: Cl[Mg]CCc1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g,0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrlochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H)(9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH3:2].[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC.CC(O)=O>ClCCl>[OH:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([C:1]2([CH3:2])[S:21][CH2:18][CH2:19][S:20]2)[CH:9]=1
Reactant: SCCS
Reactant: CCOC(=O)CCc1ccc(O)cc1C(C)=O
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1C1(C)SCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed ethyl 3-(2-acetyl-4-hydroxyphenyl)propanoate (200 mg, 0.85 mmol, 1.00 equiv), dichloromethane (10 mL), ethane-1,2-dithiol (398 mg, 4.23 mmol, 5.00 equiv), BF3/Et2O (597 mg, 4.23 mmol, 5.00 equiv), AcOH (542 mg, 9.03 mmol, 8.00 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:2). This resulted in 150 mg (57%) of ethyl 3-[4-hydroxy-2-(2-methyl-1,3-dithiolan-2-yl)phenyl]propanoate as light yellow oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1F
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,4-difluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.78-6.86 (2H, m), 7.33 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.39-7.45 (1H, m), 7.51 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.62 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10F2N4O, 313; Found, 313.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH:41][C:3](=[O:4])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 2.5 h

Procedure:
Ac-L-proline (3.05 g, 19.41 mmol) was dissolved in dry tetrahydrofuran (100 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (2.13 ml, 19.41 mmol) was added followed by isobutylchloroformate (2.51 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-alanyl-L-proline benzyl ester hydrochloride (6.08 g, 19.41 mmol) in chloroform (70 ml) was added followed by a second portion of N-methylmorpholine (2.13 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was then allowed to slowly warm to room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to a small residue on a rotary evaporator, diluted with chloroform (500 ml) and poured into a separatory funnel where it was washed with 0.2 N hydrochloric acid (3×200 ml) and 5% sodium bicarbonate (200 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and chromatographed using methylene chloride-methanol as an eluent to give Ac-L-prolyl-L-alanyl-L-proline benzyl ester; Rf: 0.35 (CH3OH/CH2Cl2 --7:93).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(NC(C)C)(C)C.[Li].[N:16]1([C:20]2[C:29]3[C:24](=[N:25][C:26](Cl)=[C:27]([Cl:30])[N:28]=3)[N:23]=[C:22]([Cl:32])[N:21]=2)[CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[N:16]1([C:20]2[C:29]3[C:24](=[N:25][C:26]([O:1][CH:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[C:27]([Cl:30])[N:28]=3)[N:23]=[C:22]([Cl:32])[N:21]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCOCC1
Reactant: Clc1nc(N2CCC2)c2nc(Cl)c(Cl)nc2n1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(N2CCC2)c2nc(Cl)c(OC3CCOCC3)nc2n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
a)+b) 56 μl (0.59 mmol) 4-hydroxytetrahydropyran are dissolved in 2 ml of tetrahydrofuran and under protective gas at −10° C. mixed with 293 μl (0.59 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes at −10° C., then for one hour at ambient temperature. The mixture is cooled to −10° C. again and combined with a suspension of 170 mg (0.59 mmol) 4-azetidin-1-yl-2,6,7-trichloro-pteridine in 5 ml of tetrahydrofuran. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for approx. another 16 hours. The reaction mixture is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is purified by chromatography (reversed phase). 90 mg of 4-azetidin-1-yl-2,6-dichloro-7-(tetrahydropyran-4-yloxy)-pteridine are obtained, which is dissolved in 5 ml dioxane and slowly added dropwise to a solution of 109 mg (1.27 mmol) piperazine in 5 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. another 1 hour at 80° C., cooled to ambient temperature and the reaction mixture is combined with water. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. Yield 70 mg (68% of theoretical)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])[CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3cccc(F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Fluorobenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: C([SiH](CC)CC)C.[S:8]1[C:12]([CH:13]([C:15]2[CH:24]=[C:23]([Br:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)O)=[CH:11][C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]1=2.CO.O>C(Cl)Cl>[Br:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:13][C:12]2[S:8][C:9]3[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=3[CH:11]=2)[CH:24]=1
Reactant: OC(c1cc(Br)c2ccccc2c1)c1cc2ccccc2s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Brc1cc(Cc2cc3ccccc3s2)cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
In a nitrogen stream, triethylsilane (0.48 ml, 3.01 mmol) and a boron trifluoride-diethyl ether complex (0.34 ml, 2.71 mmol) were added dropwise to a solution of (benzo[b]-thiophen-2-yl)-(4-bromonaphthalen-2-yl)methanol (1.0 g, 2.71 mmol) in methylene chloride (30 mL) at 0° C. The reaction mixture was stirred at room temperature for three hours, and then a 50% methanol aqueous solution (1 ml) was added and further water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:40)] to obtain the title compound (0.82 g, 85.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](\[NH:13][C:14](=[O:16])[CH3:15])/[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2]>CO>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@H:6]([NH:13][C:14](=[O:16])[CH3:15])[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2].[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@H:6]([NH:13][C:14](=[O:16])[CH3:15])[C@H:7]([CH3:12])[C@H:8]([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)/C=C(\NC(C)=O)[C@H](C)[C@H](C)CC
Solvent: CO
Product: CCOC(=O)C[C@@H](NC(C)=O)[C@H](C)[C@H](C)CC
Product: CCOC(=O)C[C@H](NC(C)=O)[C@H](C)[C@H](C)CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ten mL ampoules were each charged with 20 mg of (4R,5R)-3-acetylamino-4,5-dimethyl-(Z)-hept-2-enoic acid ethyl ester (substrate), 2 mL of MeOH, and approximately 10 mg of catalyst. The ampoules were placed in a multi-reactor, purged with hydrogen, then pressurized to 20 psig with hydrogen and shaken at room temperature for 18 hours. For each ampoule following reaction, the solids were removed by filtration and the filtrate was analyzed by chiral GC (CHIRASIL-DEX CB, 140° C. isothermal). The table below provides conversion and ratio of (3R,4R,5R)-3-acetylamino-4,5-dimethyl-heptanoic acid ethyl ester (desired diastereoisomer) to (3S,4R,5R)-3-acetylamino-4,5-dimethyl-heptanoic acid ethyl ester (undesired diastereoisomer) for various hydrogenation catalysts.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[C:15]([CH2:16][C:17]#N)=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH2:19]>>[C:17]([CH2:16][C:15]1[C:7]([Cl:6])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([OH:2])=[O:19]
Reactant: O
Reactant: O=S(=O)(O)O
Reactant: N#CCc1cccc(C(=O)O)c1Cl
Product: O=C(O)Cc1cccc(C(=O)O)c1Cl
Temperature: 165 °C

Procedure:
Concentrated sulfuric acid (60 mL) was added dropwise to ice-cold water (75 mL) and the resulting solution was added to 2-chloro-3-(cyanomethyl)benzoic acid [Aromatic Intermediate 11, step b] (14 g). The resulting suspension was heated to reflux (165° C.) for 30 min during which the starting material dissolved and a new precipitate was observed. The reaction was allowed to cool and was diluted with water (250 mL) and extracted with ethyl acetate (3×500 mL). The combined organic phases were washed with water (250 mL) and brine (250 mL), then dried over magnesium sulphate and evaporated to give the subtitled compound as a white solid. Yield 13.7 g.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][N:9]1[C:13]([O:14][CH:15]([F:17])[F:16])=[C:12]([Cl:18])[C:11]([C:19]2[CH:24]=[C:23](N)[C:22]([Cl:26])=[CH:21][C:20]=2[F:27])=[N:10]1.[ClH:28].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31]>C(#N)C.[Cu](Cl)Cl>[Cl:28][CH:30]([CH2:31][C:23]1[CH:24]=[C:19]([C:11]2[C:12]([Cl:18])=[C:13]([O:14][CH:15]([F:17])[F:16])[N:9]([CH3:8])[N:10]=2)[C:20]([F:27])=[CH:21][C:22]=1[Cl:26])[C:29]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: Cl
Reactant: C=CC(=O)OCC
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)C(Cl)Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Temperature: 15 °C
Reaction time: 0.08 h

Procedure:
A mixture of 0.55 gram (0.004 mole) of copper(II) chloride and 0.6 mL (0.005 mole) of tert-butyl nitrite in 7.0 mL of ethyl acrylate and 10 mL of acetonitrile was stirred for five minutes, and cooled to 15° C. With continued stirring, a solution of 1.0 gram (0.003 mole) of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chloro-5-aminophenyl)pyrazole in about five mL of acetonitrile was added dropwise while maintaining the reaction mixture temperature below 30° C. Upon completion of addition the reaction mixture was stirred with continued cooling for ten minutes, then it was allowed to warm to ambient temperature where it stirred for 1.5 hours. After this time the reaction mixture was poured into 75 mL of aqueous 20% hydrochloric acid. The resultant mixture was extracted with two 50 mL portions of diethyl ether. The combined extracts were washed with one portion of aqueous 20% hydrochloric acid, then dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to an oil residue. The residue was subjected to column chromatography on silica gel using methylene chloride as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.9 gram of ethyl 2-chloro-3-[2-chloro-4-fluoro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)phenyl]propanoate. The NMR spectrum was consistent with the proposed structure.