Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.Br[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:22]4[CH:27]=[N:26][CH:25]=[CH:24][N:23]=4)[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Reactant: Brc1cnccn1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1OC[C@H](c2cccc(Oc3cnccn3)c2)N1c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Reference: Org Lett 2003, 5(21), 3799. A small reaction tube fitted with a screw cap containing a septum is charged with (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-oxazolidin-2-one (0.06 mmol), 2-bromopyrazine (0.076 mmol), CuI (0.04 mmol), N,N-dimethylglycine (0.04 mmol), Cs2CO3 (0.13 mmol) and 1,4-dioxane (1 mL) is stirred at 120° C. for 18 h. The reaction mixture is then cooled to room temperature and filtered through a Whatman 0.42 μM filter and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). 1H NMR (CDCl3, 400 MHz) δ 8.41 (d, J=1.2 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.04 (dd, J=2.8, 1.2 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.12-7.19 (m, 2H), 7.10 (s, 1H), 5.37 (dd, J=8.8, 6.0 Hz, 1H), 4.80 (t, J=8.8 Hz, 1H), 4.26 (dd, J=8.8, 6.0 Hz, 1H); HPLC-MS calculated for C19H14ClN3O3 (M+H+) 368.1, found 368.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C:35]1=O.C([BH3-])#N.[Na+].Cl>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]3[CH3:33])[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Reactant: CC1CCCCC1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCC1N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)C1
Yield: 157.5 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), 2-methylcyclohexanone (0.12 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded, after treatment with HCl, 82 mg (80%) of the title compound as the hydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH2:27])[CH3:20].O>C(O)COCCO>[CH2:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][NH:27][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[CH3:20]
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Reactant: CCN1CCCC1CN
Solvent: O
Solvent: OCCOCCO
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 10 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 7.0 g of 1-ethyl-2-aminomethylpyrrolidine in 50 ml of diethylene glycol is heated at 120°-130° C. and stirred for 18 hours. The reactant solution is cooled to room temperature and added slowly with stirring to 300-400 ml of water. Under ice-cooling crystals are thoroughly deposited. The crude crystals are collected by suction filtration and washed with cold water. The crude crystals obtained are dried and recrystallized from about 220-230 ml of ethyl acetate by the use of decolorizing charcoal to give crystals of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 167°-169° C.
Reaction SMILES: [F:1][C:2](I)([F:19])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[H][H]>[Ni]>[CH:2]([F:19])([F:1])[C:3]([F:17])([F:18])[C:4]([F:15])([F:16])[C:5]([F:13])([F:14])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8]
Reactant: [H][H]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Ni]
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -80 °C
Yield: 81.1 %

Procedure:
A 225-mL Hastelloy™ nickel alloy tube was charged with 134.0 g (0.30 mol) of perfluorohexyl iodide, cooled to −80° C. and evacuated, then warmed to 22° C. and pressured to 380 psi (2.72 mPa) with hydrogen (0.17 mol). Heating to 300° C. was accompanied by at least three temperature spikes, the first beginning at 240° C. The pressure at 300° C. began at 990 psi (6.93 mPa) and dropped to 860 psi (6.03 mPa) within 2 hours. When cooled to 25° C., the reactor showed zero pressure on the gauge. Distillation of the liquid product afforded 77.9 g (81%) of pure 1H-perfluorohexane (Boiling Point 70.6-71.2° C.), confirmed by GC and NMR.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]2=[N:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].[Cu](C#N)C#N.C(Br)C=C>C1COCC1.[Cl-].[Na+].O>[Cl:11][C:10]1[C:5]2[N:6]([C:2]([CH2:18][CH:16]=[CH2:17])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)c1nc2c(Cl)nccn2c1Br
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: O
Product: C=CCc1c(C(=O)OC)nc2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
To a suspension of methyl 3-bromo-8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (250 mg, 0.861 mmol) in THF (8.6 mL) cooled to −40 C was added isopropylmagnesium chloride (0.99 mL, 1.29 mmol) dropwise. After 1 h stirring, copper cyanide (7.7 mg, 0.09 mmol) and allyl bromide (0.15 mL, 1.7 mmol) were added and the mixture was warmed to r.t. After 1 h, the reaction was poured into brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified on silica (gradient elution, 0-80% EtOAc/hexanes) to yield the title product (48 mg). HRMS (ESI) calc (M+H)+=252.0534. found 252.0539.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5]([C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])#[N:2]
Reactant: Cc1ccccc1C(=O)NCC#N
Reactant: ClSC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(CC#N)SC(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred mixture of 5.0 g (0.029 mole) N-cyanomethyl-o-toluamide (the product of Example 10) and 5.8 g (0.031 mole) trichloromethylsulfenyl chloride in 125 ml methylene chloride, 3.6 g (0.036 mole) triethylamine in 25 ml methylene chloride were added dropwise over 40 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed three times with 75 ml water, dried over magnesium sulfate and stripped to give a brown oil. The oil did not crystallize when rubbed with hexane. The oil was column chromatographed through 125 g of silica gel, eluting with chloroform to give 5.6 g of a glass-like product which crystallized partly upon cooling to room temperature.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[N:13]3)=[O:9])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[N:21](S(CCC)(=O)=O)[S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23].[OH-].[Na+]>CO>[F:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[N:13]3)=[O:9])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-N-(propylsulfonyl)propane-1-sulfonamide (30 mg, 0.06 mmol, 1 eq.) in MeOH (5 mL) was added NaOH solution (1 N, 0.12 mL, 0.12 mmol, 2 eq.). The resulting mixture was stirred at rt for 1 h, then concentrated. The residue was purified via flash column (PE/EA=1/1, v/v) to afford N-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (20 mg, 84.7%). LRMS (M−H+) m/z calculated 390.1. found 389.8. 1H NMR (CDCl3, 400 MHz) δ 8.93-8.98 (dd, 2H), 8.45 (s, 1H), 8.38-8.41 (m, 1H), 8.25-8.28 (m, 1H), 7.79-7.82 (m, 1H), 7.07-7.11 (t, 1H), 6.71 (s, 1H), 3.10-3.14 (m, 2H), 1.87-1.92 (m, 2H), 1.04-1.08 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[N:11]3[N:10]=2)=[N:5][C:4]([CH2:28]O)=[N:3]1.S(Cl)([Cl:32])=O>ClCCl>[Cl:32][CH2:28][C:4]1[N:5]=[C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[N:11]3[N:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc(CO)nn4C)nn23)no1
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc(CCl)nn4C)nn23)no1
Yield: 78 %

Procedure:
A suspension of [1-methyl-5-({[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl]-1H-[1,2,4]triazol-3-yl}methanol (350 mg, 0.9 mmol) in dichloromethane (15 ml) was treated portionwise with thionyl chloride (5 ml) at room temperature for 1 h. The mixture was evaporated in vacuo and the residue partitioned between 5% MeOH/DCM and water. The aqueous layer was basified with saturated K2CO3 solution. The organic layer was separated, dried (MgSO4), and concentrated to give the title compound as a white solid (0.28 g, 78%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[CH3:22].Cl>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH2:21][CH3:22])=[CH:24][CH:25]=4)=[O:31])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: CCc1ccc(N=C=O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: CCc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
TEA (0.3 ml, 2.2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.32 g, 0.85 mmol) and 1-ethyl-4-isocyanato-benzene (0.14 ml, 1 mmol) in acetonitrile (20 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-ethyl-phenyl)-urea as a white solid (230 mg, 64%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.53 min (98%); mp. 263-265° C. 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H, CHH), 2.38 (qd, J=4.2, 13.1 Hz, 1H, CHH), 2.60 (d, J=17.0 Hz, 1H, CHH), 2.84-3.00 (m, 1H, CHH), 4.26-4.50 (m, 4H, CH2+CH2), 5.03 (s, 2H, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHN), 6.64 (t, J=5.9 Hz, 1H, Ar), 6.90 (d, J=8.9 Hz, 2H, Ar), 7.26-7.48 (m, 8H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.43 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.79, 47.10, 51.56, 69.38, 114.92, 119.44, 121.85, 122.91, 126.88, 127.59, 127.68, 128.35, 130.25, 133.73, 137.26, 142.36, 145.00, 153.02, 155.41, 167.95, 170.99, 172.86; LCMS MH=421. Anal Calcd for: C23H24N4O4+0.15 CH3CN: C, 65.60; H, 5.78; N, 13.62. found: C, 65.42; H, 5.69; N, 13.24.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([CH:10]=1)[O:4][CH2:3][CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24]
Reactant: COc1ccc(F)cc1OCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Yield: 84.4 %

Procedure:
A suspension of 8.00 g of 2-(2-chloroethoxy)-4-fluoroanisole, 5.75 g of phthalimide and 3.24 g of potassium carbonate in 15 ml of N,N-dimethylformamide was heated for 2 hours at 120°-130° C. After cooling, the reaction mixture was poured into water. The precipitate was filtered to give 10.4 g of N-[2-(5-fluoro-2-methoxyphenoxy)ethyl]phthalimide as colorless crystals, which were recrystallized from ethanol as colorless needles, m.p. 134.5°-136° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[CH2:14]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[S:17][S:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[S:16]1[CH2:15][CH2:14][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[O:24])[S:17]1
Reactant: COC(=O)/C=C/C(=O)NCCN
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)/C=C/C(=O)NCCNC(=O)CCCC[C@@H]1CCSS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
The HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate (0.515 mmol) was taken up in 10 mL of CH3CN along with R-lipoic acid (TCI, 106 mg, 0.515 mmol), HATU (215 mg, 0.567 mmol) and DIEA (270 μL, 1.55 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) afforded 120 mg of (R,E)-methyl 4-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethylamino)-4-oxobut-2-enoate. MS (EI) calcd for C15H24N2O4S: 360.12. found 361 (M+1).
Reaction SMILES: [BH4-].[Na+].CC1C2C(C)(C)C(C2)CC=1.B(F)(F)F.[C:17]1([CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:24]2[CH2:28][CH:27]=[CH:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH:35]O.[OH-].[Na+]>O1CCCC1>[C:17]1([CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:24]2[CH2:28][CH2:27][C@H:26]([OH:35])[CH2:25]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1=CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: OO
Agent: CC1=CCC2CC1C2(C)C
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 79 %

Procedure:
Sodium borohydride (0.235 mg) was suspended in tetrahydrofuran (2.0 mL) in an argon flow, and the suspension was cooled with ice. Optically active α-pinene (0.63 mL) and boron trifluoride.ether complex (0.25 mL) were added dropwise to the suspension, and the mixture was stirred for 12 hours. 1-Diphenylmethyl-3-pyrroline (0.24 g) was added to the reaction mixture, and the resultant mixture was allowed to react for 9 hours. Thereafter, 30% aqueous hydrogen peroxide (2 mL) and 6 mol/L aqueous sodium hydroxide (2 mL) were added dropwise to the reaction mixture. After 3 h, the reaction mixture was extracted with methylene chloride, and the formed organic layer was dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (0.200 g, yield 79%). HPLC analysis (through use of a Daicel Chiral Pack AD-RH) of the thus-obtained compound indicates that the compound has an optical purity of 72% ee.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][C:13]=3[F:24])[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:25].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:33]=[C:34]1[CH2:39][S:38][C:37]2[CH:40]=[CH:41][C:42]([CH:44]=O)=[N:43][C:36]=2[NH:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[N:9]1[CH2:10][CH2:11][C:5]3([CH2:6][C@H:2]([NH:1][CH2:44][C:42]4[CH:41]=[CH:40][C:37]5[S:38][CH2:39][C:34](=[O:33])[NH:35][C:36]=5[N:43]=4)[C@H:3]([OH:25])[CH2:4]3)[CH2:7][CH2:8]1)=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (0.26 mg, 75.1 μmol) in DCM-EtOH (1 mL, 1:1) were added Na2SO4 (16 mg, 0.112 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (15 mg, 75.1 μmol). After 12 h at 25° C., the imine was quenched by addition of NaBH(OAc)3 (32 mg, 0.150 mmol) in one portion. After an additional 1 h, the solution was partitioned between NaHCO3-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (33 mg, 84%) as a light yellow oil: LCMS (ES) m/e 525 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.5 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.46 (s, 2H), 3.00-3.21 (m, 1H), 1.94-1.96 (m, 1H), 1.79-1.91 (m, 1H), 1.65-1.71 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:28]#[N:29])([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:28]#[N:29])([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1Cl
Yield: 87.6 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 56c (0.6 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.9 g, 7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-4-(2,4-dichloro-phenyl)-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[OH:13])[CH3:2].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1.CC(C)([O-])C.[K+].O>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1)[CH3:2]
Reactant: CC(=O)Nc1cc(Cl)ccn1
Reactant: CCOc1cc2[nH]ccc2cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc2[nH]ccc2cc1Oc1ccnc(NC(C)=O)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
6-Ethoxy-1H-indol-5-ol described in Production Example 15-4 (7.0 g, 39.5 mmol) was dissolved in dimethylsulfoxide (40 mL) under nitrogen atmosphere, then N-(4-chloropyridin-2-yl)acetamide described in Production Example 1-5 (8.09 g, 47.4 mmol) and potassium tert-butoxide (4.88 g, 43.5 mmol) were added at room temperature, and the mixture was heated and stirred at 160° C. for 4 hours. The reaction liquid was cooled to room temperature and water and ethyl acetate were added for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water twice and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-3:2-1:3-1:4-0:1), and then the target fraction was concentrated under vacuum to obtain the title compound (7.16 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:38]4[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (160 mg), acetic acid (0.036 mL) and sodium acetate (51.0 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate hydrochloride (182 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (165 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylate (D90) (200 mg) as a brown oil. The crude product was used for next step without further purification. MS (ES): C27H31ClN2O3S requires 498. found 499.2 (M+H+).