Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22](OC)[O:23]C)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+].[C-:50]#[N:51].[Na+]>CC(C)=O.O.C(OCC)(=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]([C:50]#[N:51])[OH:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COC(OC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(O)C#N)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
A solution of 2-(R)-(3-chloro-4-methanesulfonylphenyl)-3-cyclopentyl-N-(5-dimethoxymethylpyrazin-2-yl)-propionamide (prepared as in Example 21, 740 mg, 1.53 mmol) and p-toluenesulfonic acid monohydrate (80 mg, 0.41 mmol) in acetone/water (20 mL, 9:1) was heated at 60° C. for 30 min. The mixture was cooled and then diluted with ethyl acetate (100 mL). The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (1×30 mL), water (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a pale yellow foam. The resulting material was dissolved in a mixture of ethyl acetate/water (1:1, 10 mL), cooled to 0° C., and then treated with sodium bisulfite (69 mg, 1.5 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min. At this time, the reaction was treated with sodium cyanide (73 mg, 1.5 mmol), and the reaction was stirred at 0° C. for 30 min. At this time, the mixture was partitioned between a saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with a saturated ammonium chloride solution (1×30 mL), a saturated aqueous sodium bicarbonate solution (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(cyano-hydroxy-methyl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (230 mg, 32%) as a yellow foam: (ES)+-HRMS m/e calcd for C21H23ClN4O4S (M+H)+ 463.1208, found 463.1202.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CO[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.3 mL, 18.4 mmol) was added dropwise to a solution of methyl 4-(hydroxymethyl)benzoate (2.0 g, 12.0 mmol) and triethylamine (3.3 mL, 23.7 mmol) in anhydrous THF (80 ml) cooled to 0° C. A precipitate formed and the stirring was continued at 0° C. for 1 h. The mixture was diluted with hexanes (50 mL) and precipitates eliminated by vacuum filtration through a sintered funnel. Volatiles were removed by rotary evaporation. The residue was purified by flash chromatography (DCM:Hex 1:1+1% TEA) through a short silica column providing methyl 4-[(trimethylsiloxy)methyl]benzoate as a clear liquid in a yield of 2.5 g (87%). 1H-NMR (500 MHz, CDCl3): δ=0.16 ppm (s, 9H), 3.90 ppm (s, 3H), 4.74 ppm (s, 2H), 7.38 ppm (d, J=8.0 Hz, 2H), 8.00 ppm (d, J=8.0 Hz, 2H); 13C-NMR (500 MHz, CDCl3): δ=−0.41, 52.09, 64.12, 126.08, 128.90, 129.68, 146.39, 167.10 ppm. HRMS [+Scan]; calculated m/z for C12H19O3Si 239.1098; observed mass: 239.1095.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][OH:9].[Mn]([O-])(=O)(=O)=[O:17].[K+].S([O-])(O)=O.[Na+].Cl>O>[CH3:6][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:17])=[O:9]
Reactant: CCCCCCC(C)CO
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: O
Product: CCCCCCC(C)C(=O)O
Temperature: 0 °C
Yield: 65.8 %

Procedure:
After 46.4 g of concentrated sulfuric acid and 21.2 g (147 mmol) of (-)-2-methyloctanol were added to 330 ml of water, 63.4 g (401 mmol) of potassium permanganate was added dropwise over 7.3 hours while the reaction temperature was held at 21°~28° C. The thus obtained reaction mixture was poured into 270 ml of ice water, added with 52 g of sodium hydrogen sulfite, adjusted to pH of not more than 1 with hydrochloric acid, extracted with ether and then extracted with a 10% aqueous solution of sodium hydroxide. This extract was added with hydrochloric acid to adjust pH to not more than 1 and again extracted with chloroform. The extract was washed with water, dried, concentrated and distilled under a reduced pressure (0.28 mmHg, 91°~94° C.) to obtain 15.3 g (yield 64%) of (+)-2-methyl octanoic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:30]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:25]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 149.2° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](Cl)=[O:27]>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:27]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4(R)-phenyl-2-oxazolidinone (340 g, 2.08 mol) in THF (8000 mL), is added n-BuLi (2.5 M, 920 mL, 1.1 eq). The reaction mixture is stirred for 20 minutes and 2-fluorobenzeneacetyl chloride (358 g, 2.08 mol) is added. After 2 hours the reaction mixture is quenched with saturated NH4Cl solution (1×1000 mL). The organic layer is separated, washed with H2O (1×1000 mL), saturated NaCl solution (2×1000 mL) and then concentrated in vacuo. This procedure yields 3-[(2-fluorophenyl)-acetyl]-4(R)-phenyl-2-oxazolidinone.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH2:4](O)C(N)(CO)CO.Cl.OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[NH2:37][C@H:38]([C:45]([OH:47])=[O:46])[CH2:39][C:40]1N=CN[CH:41]=1>>[NH2:37][C@H:38]([C:45]([OH:47])=[O:46])[CH2:39][CH:40]([CH3:4])[CH3:41]
Reactant: NC(CO)(CO)CO
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
The starting yeast is Saccharomyces cerevisiae AH22 [a leu 2 his4 can 1 (Cir+)], which has been deposited at Fermentation Research Institute, Agency of Industrial Science and Technology, Japan under Budapest Treaty as "FERM BP-312". The starting yeast is inoculated in YPD medium (100 ml) containing 2% polypeptone, 1% yeast extract and 2% glucose, and the mixture is incubated at 30° C. overnight, and thereafter, the cells are collected by centrifugation. The cells are washed with sterilized water (20 ml) and suspended in a solution (5 ml) of 1.2M sorbitol and 100 μg/ml zymolyase-60,000 (manufactured by Seikagaku Kogyo K. K., Japan), and the suspension is allowed to stand at 30° C. for about 30 minutes to give spheroplast. The spheroplast thus prepared is washed with 1.2M sorbitol solution three times, and then suspended in a solution (0.6 ml) of 2M sorbitol, 10 mM CaCl2 and 10 mM Tris-HCl (pH 7.5). The suspension thus prepared is divided into a small test tube in a volume of 60 μl. To the suspension is added the recombinant plasmid pONY-S1 (5 μg) as prepared in the above (3). After mixing well, 0.1M CaCl2 (3 μl) is added thereto in a final concentration of 10 mM CaCl2, and the mixture is allowed to stand at room temperature for 5 to 10 minutes. To the resulting mixture is added each 1 ml of 20% polyethylene glycol 4,000, 10 mM CaCl2 and 10 mM Tris-HCl (pH 7.5), and the mixture is allowed to stand at room temperature for about 20 minutes. The resulting mixture (each 0.2 ml) is added to a medium (10 ml) [which consists of 22% sorbitol, 2% glucose, 0.7% yeast nitrogen base amino acid, 2% YPD, 20 μg/ml histidine, and 3% agar], which is kept at a constant temperature of 45° C. After gently mixing, the mixture is added in a layer onto a plate of minimal medium containing 1.2M sorbitol which is previously prepared and consists of 0.7% yeast nitrogen base amino acid, 2% glucose, 20 μg/ml histidine and 2% agar and is set thereon. The plate is incubated at 30° C. to give colony of a leucine-non-requiring yeast. The colony is incubated in a Burkholder minimal medium supplemented with histidine (20 μg/ml) [cf. Tohe, A. et al., J. Bacteriol., 113, 727-738 (1973)] to give the desired transformed yeast: Saccharomyces cerevisiae YpONY-S1.
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[C:6]([O:9][CH3:10])[C:5]([Br:11])=[CH:4][C:3]=1[NH:12][C:13]([NH:15]C(=O)OCC)=[S:14].C(N)C>>[Br:1][C:2]1[C:7]([Br:8])=[C:6]([O:9][CH3:10])[C:5]([Br:11])=[CH:4][C:3]=1[NH:12][C:13]([NH2:15])=[S:14]
Reactant: CCOC(=O)NC(=S)Nc1cc(Br)c(OC)c(Br)c1Br
Agent: CCN
Product: COc1c(Br)cc(NC(N)=S)c(Br)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl N-[(2,3,5-tribromo-4-methoxy-phenyl)carbamothioyl]carbamate (500 mg, 1.02 mmol) was dissolved in ethylamine solution (5.09 mL, 10.18 mmol, 2 M in THF) and stirred at rt overnight. The mixture was concentrated to dryness under reduced pressure to give the desired compound as an off white solid. The mixture was used with no further purification in the next step. m/z: 416.83/418.84/420.83/422.83 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:16][CH:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CC([O-])(C)C.[K+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:14][CH:15]([CH2:17][N:38]4[CH2:39][CH2:40][N:35]([C:30]5[N:29]=[CH:34][CH:33]=[CH:32][N:31]=5)[CH2:36][CH2:37]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(c3ccc(CN4CCCC4)cc3)C2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CC3CC(c4ccc(CN5CCCC5)cc4)C3)CC2)nc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a stirring solution of toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester (159.9 mg, 0.40 mmol) prepared above (Example 4, General Procedure A, Step G) in 2 mL of THF was added 1-(2-pyrimidyl)piperizine (136.2 mg, 0.8 mmol) followed by a solution of KOtBu (136 uL, 0.8 mmol, 1M THF). The reaction was heated to 70 □C (oil bath). After 1 hour DMF (1 mL) was added along with K2CO3 (2 eq). The reaction was then heated to 100 □C. After 3 hours the reaction was cooled to rt and concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2, quenched with a saturated aqueous solution of NaHCO3. The two layers were separated and the aqueous layer was back extracted with 3:1 chloroform:isopropyl alcohol. The combined organic layers were dried over MgSO4, filtered through a fritted funnel and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a 10 g ISCO column, eluting with a gradient of 5%, 10%, 20% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (70.0 mg, 44%) as a colorless oil, and a mixture of cis:trans isomers. The bis-HCl salt was generated by dissolving the title compound in EtOAc and then a solution of HCl (2 eq, 1M HCl, THF) was added. The colorless solid was collected and dried under reduced pressure.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br>S(=O)(=O)(O)O.C(Cl)(Cl)(Cl)Cl.S([O-])([O-])(=O)=O.[Ag+2]>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH:3]=[N:4]2
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cnc2cc(Br)ccc2[nH]1
Temperature: 50 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
The quinoxalin-2(1H)-one (14.6 g, 0.1 mol, Aldrich, cat. no. 260517) and silver sulphate (15.6 g, 0.05 mol) were dissolved in conc. Sulfuric acid (100 ml) at 20° C. Bromine (5.2 ml, 0.1 mol) was added and the reaction mixture was stirred vigorously for 24 hours. The reaction mass was then diluted with carbon tetrachloride (100 mL), and this was heated at 50° C. The reaction mass was then filtered and the filtrate was poured into ice cold water and stirred for 30 minutes to obtain a precipitate. The precipitate was filtered and the solid material was dried in vacuo to afford the title product (9.0 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[CH:16](OCC)=[O:17].[Na]>CCOCC>[CH:16]([CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1cccc(OC)c1
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A mixture of ethyl 3-(3-methoxyphenyl)propionate (100 g) and ethyl formate (37 g) was added dropwise to a mixture of sodium wire (11 g) in stirred ether (500 ml) at 0°. The mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was dissolved in water and extracted with ether, the extracted aqueous phase was adjusted to pH 4 with hydrochloric acid and was extracted with ether and the ether extract was evaporated to dryness to give ethyl 2-formyl-3-(3-methoxyphenyl)propionate (46.05 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH2:29]([C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1)[CH3:30].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:37][C:34]3[CH:35]=[CH:36][C:31]([CH2:29][CH3:30])=[CH:32][CH:33]=3)=[CH:3][C:4]=2[F:28])=[CH:9][CH:10]=1)([CH2:17][OH:18])[CH2:21][OH:20]
Reactant: CCc1ccc(S)cc1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 39.5 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 4-ethylbenzenethiol (69 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 8 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (4 mL). Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (84 mg) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O>CO.Cl.[Fe]>[NH2:1][C:4]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[C:9]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Temperature: 30 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Iron powder (15.80 g, 283.0 mmol) was added in small portions over 5 min to a stirred suspension of finely grinded 2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile from step 3 (19.93 g, 63.4 mmol) in MeOH (32 mL) and conc. HCl (40 mL) with water bath cooling keeping the internal temperature at 25-35° C. The resulting mixture was stirred for further 1 h at ca. 30° C. and then poured into ice cold H2O (400 mL). The precipitate was filtered, washed with water, dried, and dissolved in boiling EtOH (400 mL), activated carbon (ca. 10 g) was added, the mixture was refluxed for 45 min, the hot solution was filtered and evaporated to dryness to leave a dark green solid (15.96 g, 84%), which was further purified by silica gel column chromatography with heptane/EtOAc 4:1 to give the title compound as a yellow solid (14.56 g, 81%). MS (ISN) 283 [M−H].
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:28])[CH3:27])[C@@H:21]([CH3:29])[CH2:20][N:19]4[C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32](C4CCCCO4)[N:31]=3)[CH:13]=[N:12]2)[CH2:10][CH2:9]1>ClCCl>[CH:8]1([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:28])[CH3:27])[C@@H:21]([CH3:29])[CH2:20][N:19]4[C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][N:31]=3)[CH:13]=[N:12]2)[CH2:9][CH2:10]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2nn(C3CCCCO3)c3ccccc23)C[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2n[nH]c3ccccc23)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of 1-((2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.048 g, 0.097 mmol) in dichloromethane (2.0 mL) and the mixture stirred at rt for 4 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(1H-indazol-3-yl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (0.039 g, 98%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.76-1.04 (m, 4 H), 1.09-1.33 (m, 3 H), 2.23 (s, 3 H), 3.54-3.77 (m, 2 H), 3.78-3.99 (m, 1 H), 4.36 (br s, 1 H), 6.67-6.85 (m, 1 H), 6.87-7.14 (m, 2 H), 7.26-7.46 (m, 4 H), 7.53 (d, J=8.50 Hz, 1 H), 7.87 (s, 1 H), 12.70-12.87 (m, 1 H). MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+].[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH4-].[Na+]>C1COCC1.CO>[ClH:1].[CH2:39]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:33])[C@H:14]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:8][CH:7]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)OCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of N-[4-(trans-2-aminocyclopropyl)phenyl]-Nα-[(benzyloxy)carbonyl]-L-phenylalaninamide hydrochloride (100 mg) described in a document (J. Am. Chem. Soc. 2010, 132, 6827.), sodium hydrogen carbonate (27.0 mg), and methanol (2.00 mL) was added benzaldehyde (0.022 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was cooled in an ice bath, sodium borohydride (12.2 mg) was added and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was diluted with dehydrated THF (4.00 mL), and cooled in an ice bath, and sodium borohydride (8.12 mg) was added. The ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methanol (2.00 mL) and dehydrated THF (2.00 mL), and cooled in an ice bath, sodium borohydride (8.12 mg) was added, and the mixture was stirred at 0° C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the fractions containing the object product were combined and concentrated. The residue was dissolved in methanol (5.00 mL), 10% hydrochloric acid methanol solution (1.00 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (82.3 mg).