Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].[Cl-].[Cl:13][C:14](Cl)=[N+:15]([CH3:17])[CH3:16]>ClCCl>[C:10]([C:3]1[C:4]([CH2:7][CH2:8][CH3:9])=[N:5][S:6][C:2]=1[N:1]=[C:14]([Cl:13])[N:15]([CH3:17])[CH3:16])#[N:11]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CCCc1nsc(N)c1C#N
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1nsc(N=C(Cl)N(C)C)c1C#N
Yield: 50.4 %

Procedure:
In the manner of Example VI, a solution of 8.4 g of 5-amino-4-cyano-3-propylisothiazole in 50 ml of dichloromethane was treated with 9.8 g of N-(dichloromethylene)-N,N-dimethylammonium chloride. After removal of the volatile materials under reduced pressure, the residue was recrystallized from 90:10 hexane:benzene to yield 6.5 g of N'-(4-cyano-3-propyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 108°-109°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH:27][C@H:28]3[CH2:31][C@H:30]([NH2:32])[CH2:29]3)=[N:24][C:23]=2[CH:33]=1.C(N(C(C)C)CC)(C)C.CC(C)([O-])C.[Na+]>ClCCl.O1CCCC1.C(OCC)(=O)C.O>[F:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([NH:27][C@H:28]3[CH2:31][C@H:30]([N:32]4[C:2]5=[N:7][CH:6]=[CH:5][N:4]=[C:3]5[C:8]([CH3:13])([CH3:12])[C:9]4=[O:11])[CH2:29]3)=[N:24][C:23]=2[CH:33]=1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: N[C@H]1C[C@H](Nc2nc3cc(F)ccc3s2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4cc(F)ccc4s3)C2)c2nccnc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(3-Chloropyrazin-2-yl)-2-methylpropanoic acid, INTERMEDIATE 29 (0.250 g, 1.246 mmol) was dissolved in a mixture of thionyl chloride (5 ml, 68.5 mmol) and dichloromethane (5 mL) and heated to reflux. After 20 minutes the solution was evaporated to dryness under reduced pressure. The crude was dissolved in carbon tetrachloride (20 mL) and evaporated to dryness once more. The crude was dried further under high vac then dissolved in dichloromethane (20 mL). The product was then added to an ice cooled solution of trans-N1-(5-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine, in the presence of INTERMEDIATE 73 (0.245 g, 1.032 mmol) and diisopropylethylamine (1.0 ml, 5.75 mmol) in dry tetrahydrofuran (30 mL). The mixture was stirred for 5 minutes then sodium tert-butoxide (0.50 g, 5.20 mmol) was added in one portion and the reaction stirred for an additional 20 minutes. Water (200 mL) and ethyl acetate (300 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired 5-(trans-3-((5-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.135 g, 0.352 mmol, 34.1% yield) m/z: 384.0 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 1.46 (s, 6 H) 2.45-2.55 (m, 2 H) 3.40-3.51 (m, 2 H) 4.53-4.63 (m, 1 H) 5.31 (quin, J=8.46 Hz, 1 H) 6.62 (br. s., 1 H) 6.84 (td, J=8.80, 2.15 Hz, 1 H) 7.27 (dd, J=9.98, 2.15 Hz, 1 H) 7.51 (dd, J=8.70, 5.38 Hz, 1 H) 8.11 (dd, J=13.99, 3.03 Hz, 2 H).
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:24](=[O:33])[C:23]2=[O:34])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.[ClH:37]>[C].[Pd].CO>[ClH:37].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:24](=[O:33])[C:23]2=[O:34])=[CH:35][CH:36]=1)(=[NH:11])[NH2:13]
Reactant: COC(=O)CN1CCN(CCCOc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CN1CCN(CCCOc2ccc(C(=N)N)cc2)C(=O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 1.05 g of methyl [4-[3-(4-benzyloxycarbonylamidinophenoxy) propyl]-2,3-dioxopiperazin-1yl]acetate, 0.35 g of 5% palladium-carbon, 0.39 ml of 6N hydrochloric acid and 15 ml of methanol was subjected to hydrogenation at ordinary temperature and atmospheric pressure for 3 hours. Then, the pallasium-carbon was filtered off and the solvent was distilled off under reduced pressure to obtain 0.8 g of methyl [4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazin-1yl]acetate hydrochloride. The compound obtained was dissolved in 14 ml of 6N hydrochloric acid and the resulting solution was refluxed for 1 hour, after which the solvent was distilled off under reduced pressure to obtain 0.6 g of [4-[3-(4-amidinophenoxy)-propyl]-2,3-dioxopiperazin-1-yl]acetic acid hydro-chloride as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[CH3:11].[N:12](OC)=[O:13]>>[OH:13][N:12]=[C:8]([C:9]#[N:10])[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: CON=O
Reactant: Cc1ccc(CC#N)cc1C
Product: Cc1ccc(C(C#N)=NO)cc1C
Yield: 51.2 %

Procedure:
In a sulfonation flask, 37.6 g (0.26 mol) of 3,4-dimethylacetonitrile are reacted with 0.52 mol of gaseous methyl nitrite, as described under 3.1. After the customary isolation, 23.2 g (50%) of α-hydroxyimino-3,4-dimethylbenzylcyanide are obtained as a brown resin. This crude product is used in the next step without any further purification. The 1H-NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(NCC)C>[CH2:7]([N:8]([CH2:9][CH3:10])[C:19](=[O:21])[CH2:18][CH2:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)[CH3:1]
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)cc2ccccc12
Solvent: CCNCC
Product: CCN(CC)C(=O)CCc1nc(-c2ccccc2)cc2ccccc12
Yield: 42.2 %

Procedure:
The procedure is as in Example 1, starting with ethyl 3-phenyl-1-isoquinolinepropionate (6.1 g) and diethylamine (30 cc). The crude product is purified by means of 4 successive chromatographic separations on silica gel, using a cyclohexane/ethyl acetate (7:3 by volume) mixture as eluant. N,N-Diethyl-3-phenyl-1-isoquinolinepropanamide (1.4 g), m.p. 58° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH:21]=[CH:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1)=[O:10])[C:2]1C=CC=C[CH:3]=1.Cl.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][C@H:12]1[CH2:21][CH2:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1)=[O:10])[CH:2]=[CH2:3]
Reactant: Cn1ccnc1C=C[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1nccn1C
Reaction time: 1 h
Yield: 113.2 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[2-(1-methylimidazol-2-yl)vinyl]pyrrolidine (5.70 g), conc. hydrochloric acid (2.34 ml) and 10% palladium on carbon (50% wet) (3.0 g) in methanol (120 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature for 4 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The resulting residue was dissolved in a mixture of tetrahydrofuran (60 ml) and water (60 ml). To solution was added dropwise a solution of allyloxycarbonyl chloride (1.94 ml) in tetrahydrofuran (5 ml) keeping the pH 8-10 with 4N sodium hydroxide under ice-cooling and then the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 ml) and then the solution was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-2-[2-(1-methylimidazol-2-yl)ethyl]-4-methanesulfonyloxypyrrolidine (5.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH2:18][CH:19]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)C(O)=O)[C:14](O)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>C(OC(=O)C)(=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[CH2:17][CH2:18][C@H:19]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[C:14]2=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(CCC(C(=O)O)c2cc(OC)c(OC)c(OC)c2)C(=O)O)cc(OC)c1OC
Solvent: CC(=O)OC(C)=O
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A mixture of α,α'-bis(3,4,5-trimethoxyphenyl)adipic acid (10 g, 21 mmoles) and acetic anhydride (30 ml) was heated at 150° C. for 30 minutes. Acetic acid and anhydride were removed in vacuo. The flask containing the solid residue was fitted with a distillation head and while under vacuum (~150 mm) was placed in an oil bath heated to 287° C. The solid melted; there was a vigorous evolution of gas and about 5 ml of liquid distilled. After 6.5 minutes the flask was cooled rapidly with a water bath. The yellow-brown syrupy residue was dissolved in 80 ml of hot ethanol, filtered from some insoluble material and seeded. After standing at room temperature overnight, the crystalline solid was filtered, washed with cold ethanol (3 times) and dried to give 5.57 g (64%) of trans-2,5-bis(3,4,5-trimethoxyphenyl)cyclopentanone, m.p. 140°-142.5°. IR 1740 cm-1 (C=O), mass spec m/e 416 (M+).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[N:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC.C(Cl)(=O)C.C(N(CC)CC)C>C(Cl)Cl.C(=O)(O)[O-].[Na+].[Cu](I)I.O1CCOCC1>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:2]2[CH2:3][CH2:4][N:5]3[C:6](=[N:7][C:8]4[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=43)[C:1]2=[O:14])=[CH:22][CH:23]=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: O=C1NCCn2c1nc1c2CCCC1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])O
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1CCn2c(nc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 152c (485 mg, 2.54 mmol), 104g (1.56 g, 5.08 mmol), cesium carbonate (1.66 g, 5.08 mmol), N,N′-dimethylethylene-diamine (447 mg, 5.08 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (484 mg, 2.54 mmol) was added, and the reaction mixture was heated at 100° C. (oil bath temperature) for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a yellow oil, which was dissolved in methylene chloride (5 mL). Acetyl chloride (506 mg, 2.54 mmol) and triethylamine (1.28 g, 12.7 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was diluted with methylene chloride (50 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford a 13% yield (140 mg) of 152d as a yellow oil: 1H NMR (500 MHz, CDCl3) d 7.60 (d, 1H, J=8.0 Hz), 7.27 (t, 1H, J=8.0 Hz), 7.18 (d, 1H, J=8.0 Hz), 5.26 (d, 1H, J=12.0 Hz), 5.14 (d, 1H, J=12.0 Hz), 4.32 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H), 3.87 (m, 1H), 2.75 (m, 2H), 2.56 (m, 2H), 2.07 (s, 3H), 1.83 (m, 4H); MS (APCI+) m/z 418.8 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18](Cl)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:21]([OH:26])[CH2:22][CH2:23][CH2:24][CH3:25].[H-].[Na+]>CN(C)C=O>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]([O:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2nc(Cl)c3ccccc3n2)CC1
Reactant: CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2nc(OCCCCC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-(4-allyl-l-piperazinyl)-4-chloroquinazoline (3.0 g) obtained in Example 2 was suspended in 20 ml of N,N-dimethylformamide, and under ice cooling, 1 g of 1-pentanol and 0.5 g of sodium hydride (oily, 60 %) were added. The mixture was then stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [eluted with chloroform/methanol (30:1, v/v)] to give 2-(4-allyl-l-piperazinyl)-4-pentyloxyquinazoline as a pale yellow oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1(I)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: IC1CCCCCCC1
Product: CCOC(=O)/C(=N\OC1CCCCCCC1)C(C)=O
Yield: 69 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (2.Og) was treated with cyclooctyl iodide as described in Example 4a, Method 1, to give the title compound as a colourless liquid (2.35 g, 69%). νmax (film) 2930, 1740, 1695 cm-1, δH (CDCl3) 1.31 (3H, t), 1.4-2.0 (14H, m), 2.38 (3H, s), 4.33 (2H, q), 4.4 (1H, m). [Mass spectrum, +ve ion, MH+ (270)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.Cl.Cl.[CH3:18][NH:19][CH2:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:23]=2[N:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:19]([CH3:18])[CH2:20][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:23]=4[N:22]=3)=[O:14])[C:6]=2[CH:15]=1
Reactant: O=C(O)Cn1c(=O)oc2ccc(Cl)cc21
Reactant: CNCc1nc2cc(C(F)(F)F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(Cc1nc2cc(C(F)(F)F)ccc2[nH]1)C(=O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (300 mg), N-methyl-1-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]methanamine dihydrochloride (420 mg), and dichloromethane (10 mL) were added TEA (552 μL), HOBt (214 mg), and WSC.HCl (303 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The resulting solid was collected by filtration and washed with EtOAc. To a mixture of the obtained solid (325 mg) and MeOH (5 mL) was added 4 M hydrogen chloride/EtOAc (330 μL), followed by stirring at room temperature for 1 hour. To the reaction mixture was added EtOAc. The resulting solid was collected by filtration and then washed with EtOAc to obtain 2-(5-chloro-2-oxo-1,3-benzoxazol-3 (2H)-yl)-N-methyl-N-{[5-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}acetamide hydrochloride (277 mg).
Reaction SMILES: [BH4-].[Na+].OC(C(F)(F)F)=O.[C:10]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]([C:16]([N:18]2[CH2:23][C:22](=[O:24])[CH2:21][CH2:20][CH:19]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>CO>[C:10]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:11]([C:16]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCC(O)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Temperature: 25 °C

Procedure:
NaBH4 (3.49 mmol, 0.13 g) was added to a solution of N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide TFA salt (0.46 mmol, 0.26 g) in MeOH (10 mL) at 0° C. in three portions. The resulting mixture was stirred at rt and the reaction was tracked by analytical HPLC. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give crude residue which was purified by preparative HPLC to give desired N-((1-(biphenylcarbonyl)-5-hydroxypiperidin-2-yl)methyl)quinoline-8-carboxamide with unidentified stereochemistry (Y: 75%). MS (ESI) 466 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH2:25][CH2:26][OH:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH2:25][CH:26]=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCC1CCCCN1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCC1CCCCN1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (0.55 mL, 6.44 mmol) was added to a stirred solution of DMSO (0.92 mL, 12.87 mmol) in dry DCM (40 mL) at −78° C. and the reaction mixture was stirred for 15 minutes. Compound 22 (1 g, 4.29 mmol) dissolved in DCM (15 mL) was the added drop-wise and the reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was then quenched by adding Et3N (2.9 mL, 21.45 mmol) drop-wise and the solution was stirred at rt for 15 minutes. Water was then added to the solution and the reaction mixture was extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound 23 which was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1N.F[B-](F)(F)F.N#[O+].[C-:18]#[N:19].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:18]#[N:19]
Reactant: Nc1c(F)cc(Cl)cc1Br
Reactant: [C-]#N
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-phenylamine (10 g, 44.5 mmol) in anhydrous CH2Cl2 (100 ml) was added nitrosonium tetrafluoroborate (5.72 g, 49.01 mmol) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then cooled to 0° C. prior to addition of KCN (5.8 g, 89.1 mmol) followed by a dropwise addition of an aqueous solution (50 ml) of cupric sulfate hexahydrate (22.24 g, 89.1 mmol). After stirring for 40 minutes at 0° C., the reaction mixture was allowed to warm to 25° C. and stirring was continued for 1 h. The reaction mixture was diluted with CH2Cl2 (100 ml) and slowly quenched by the addition of aqueous saturated solution of NaHCO3 until gas evolution was no longer observed. The resulting heterogeneous mixture was then filtered through a pad of celite and the organic layer was separated, washed twice with brine, dried with Na2SO4 and evaporated. The crude residue thus obtained was purified by chromatography (silica gel; hexane/EtOAc 90:10) to obtain the title compound (4 g, 38%) as reddish solid.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([CH2:8][SH:9])[C:5]([OH:7])=[O:6].CS(=O)([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.C(N(CC)CC)C>CO.O1CCCC1>[NH2:3][C@H:4]([CH2:8][S:9][S:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([OH:7])=[O:6]
Reactant: N[C@H](CS)C(=O)O
Reactant: CC(C)(C)SS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)SSC[C@@H](N)C(=O)O
Temperature: 0 °C
Yield: 52 %

Procedure:
A solution of (S)-2-amino-3-mercaptopropanoic acid hydrochloride hydrate (1.00 g, 5.69 mmol) in methanol (5.1 mL) was mixed with a solution of the prepared S-tert-butyl methanesulfonothioate (Compound SP684, 1.05 g, 6.26 mmol) in tetrahydrofuran (2.0 mL) and triethylamine (2.38 mL, 17.1 mmol) with stirring at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-amino-3-(tert-butyldisulfanyl)propanoic acid (H-D-Cys(StBu)-OH) (Compound SP641) (620 mg, 2.96 mmol, 52%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[F:11].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][C@@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:21]1
Reactant: COc1cccc(F)c1CBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(F)c1CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Bromomethyl)-1-fluoro-3-methoxybenzene (3.19 g, 14.57 mmol), (R)-3-(tert-butoxycarbonylamino)piperidine (3.0 g, 12.67 mmol), and K2CO3 (2.63 g, 19.01 mmol) were taken up in DMF (25 mL) in a 50 mL flask. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL, ×2), dried over MgSO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash chromatography (6-50% EtOAc/hexanes) to give (R)-tert-butyl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-ylcarbamate. MS ESI calc'd. For C18H22FN2O3 [M+1]+ 339. found 339.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.CCCCCC>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:4]2[CH2:5][CH2:6][C:7]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:3]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C)CCNCC1C
Solvent: CCCCCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of ethyl 3,4-dimethylpiperidine-4-carboxylate (0.2 g, 1.08 mmol) in EtOH (7 mL) was added DIPEA (0.6 mL, 3.24 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.21 g, 1.08 mmol) then heated up to 70° C. for 1 h. After reaction completion (by TLC), solvent was evaporated and the crude residue was purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the desired product as a yellow solid (0.33 g, 95% yield). MS: 341.03 [M+H]+.