Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]>ClCCl.[O-2].[Mn+4].[O-2]>[CH2:1]([N:4]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCN(CCC)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
The compound (443 mg) obtained in Example 80-2 was dissolved in dichloromethane (9.0 ml) and added with manganese (IV) oxide (chemically treated product, manufactured by Wako Pure Chemical Industries, Ltd.) (873 mg), followed by stirring at room temperature for 5 hours. After completion of the reaction, the solution was filtrated through Celite and the filtrate was then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (397 mg) as a brown solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].B.C1COCC1.Cl.C(O)(=O)C(O)=O>O1CCCC1.CO.C(OCC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13]
Reactant: N#CCc1ccc2ccccc2c1
Agent: B
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1ccc2ccccc2c1
Yield: 85 %

Procedure:
Arylethylamines that were not commercially available were made by the following procedure. 2-Naphthylacetonitrile Compound 3-2 (16.7 g, 0.10 mol) in anhydrous tetrahydrofuran (50 mL) was added to 1M solution of BH3-THF (250 mL, 0.25 mol) over 10 min at room temperature. The reaction proceeds with an induction period of 2-4 min. Following the addition, the mixture was heated under reflux and under argon for one hour (TLC of a quenched aliquot showed no starting material). The reaction was cooled in an ice bath and 10% aqueous HCl (150 mL) was added with caution over a 30 min period (vigorous reaction with the first few drops). Following the addition concentrated hydrochloric acid (100 mL) was added and the mixture brought up to reflux for 30 min. The reaction was cooled in an ice bath and extracted once with ethyl ether. The aqueous layer was carefully brought to pH 12 with 40% sodium hydroxide solution (use of concentrated base allows for smaller volumes of the aqueous layer and simplifies the extraction of the amine) and extracted with diethyl ether (4×250 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and evaporated at reduced pressure below 40° C. The solvent was not completely removed to avoid loss of product. TLC (85:15 CHCl3/MeOH, Rf=0.1) shows that the amine is essentially pure. Oxalic acid (9.0 g, 0.10 mole) was dissolved in methanol (10 mL) and added to the crude amine diluted with diethyl ether to a 300 mL volume. The white precipitate was collected by filtration, washed with ether, and dried in vacuo to provide Compound 3-3 (22.3 g, 85%) as the oxalate salt (mp=191-193° C.). Anal Calcd. for C12H13N-0.85 C2O4H2: C, 66.42; H, 5.98. Found: C, 66.67; H, 6.05. Compound 3-3 freebase: 1H NMR (300 MHz, CDCl3) δ 7.83-7.77 (m, 3H), 7.65 (s, 1H), 7.49-7.40 (m, 2H), 7.34 (d of d, J=8.5 and 1.6 Hz, 1H), 3.06 (t, J=7 Hz, 2H), 2.92 (t, J=7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:21]([C:28]([F:31])([F:30])[F:29])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:21]([C:28]([F:31])([F:30])[F:29])=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)nc2C(F)(F)F)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C(F)(F)F)n(CCCO)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A mixture of methyl 4-chloro-2-[(3-hydroxypropyl)amino]-3-({[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]carbamothioyl}amino)benzoate (1.85 g, 3.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.79 g, 4.12 mmol) and triethylamine (0.57 mL, 4.16 mmol) in tetrahydrofuran (20 mL) was stirred at 50° C. for 3 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture to give the title compound (1.50 g, 3.27 mmol, 87%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:16]>O>[NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[C:8]([NH2:9])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(N)oc2ccccc2c1=O
Solvent: O
Product: NC(=O)c1c(N)oc2ccccc2c1=O

Procedure:
-- A mixture of 1.5 g of 2-amino-4-oxo-4H-1-benzopyran-3-carbonitrile and 7 ml of 80% sulfuric acid is heated for 1 hour on the steam bath. The mixture is cooled, poured into water, and the solid filtered and recrystallized from ethanol, mp 264°-6°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:29]([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30])[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1)C(=O)OCC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CN1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Compound 123 (6.5 g) and imidazole (3.4 g, 50 mmol) was dissolved in DCM (100 ml), TBDMSCl (3.9 g, 26 mmol) was added and the reaction mixture was left stirring at room temperature overnight. The reaction mixture was washed with aqueous citric acid and brine, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica (EtOAc/n-Heptane 50/50-100/0) to give the title compound (4.26 g, 56%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:50]1([S:56](Cl)(=[O:58])=[O:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][S:56]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)(=[O:58])=[O:57])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:39][CH2:40]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](NS(=O)(=O)c4ccccc4)CC3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (20.00 mg, 0.037 mmol) in CH2Cl2 (1 mL) was added DIEA (0.00617 mL, 0.035 mmol) and benzenesulfonyl chloride (1.5 mg, 8.49 μmol). The reaction solution was stirred at room temperature for 30 min, concentrated and then treated with TFA (1.132 mL, 14.69 mmol) at 70° C. for 1 hr. The reaction mixture was concentrated and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-N-(2-fluoropyridin-4-yl)-6-((trans)-4-(phenylsulfonamido)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.6 mg, 12.54% yield) as a white solid (13.0 mg, 44.4%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.910 minutes. [M+H]=565.25. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.36-11.55 (1H, m), 8.13-8.33 (1H, m), 7.89-8.01 (1H, m), 7.76-7.91 (3H, m), 7.47-7.70 (5H, m), 7.20-7.38 (1H, m), 6.78-6.96 (1H, m), 5.83-6.02 (1H, m), 3.48-3.72 (1H, m), 2.92-3.13 (1H, m), 1.83-2.12 (2H, m), 1.53-1.80 (2H, m), 0.99-1.41 (5H, m), 0.66-0.85 (2 H, m), 0.41-0.67 (2H, m), 1.80-2.05 (2H, m), 1.39-1.70 (2H, m), 1.14-1.41 (2H, m), 0.77 (2H, d, J=4.77 Hz), 0.63 (2H, d, J=3.01 Hz).
Reaction SMILES: Cl.Br[CH:3]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-]=[N+]=[N-].[Na+].[OH2:19]>CN(C)C=O>[OH2:5].[N:12]1[CH:13]=[CH:14][C:9]([C:3](=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(Br)c1ccncc1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=O)c1ccncc1
Reaction time: 0.5 h

Procedure:
Ethyl bromo(pyridin-4-yl)acetate hydrochloride (2.05 g) was dissolved in N,N-dimethylformamide (10 ml) at room temperature, followed by the addition of sodium azide (1.43 g). The resulting mixture was stirred for 30 minutes. After the addition of water and stirring, the insoluble matter was filtered off and the filtrate was concentrated. The residue was extracted with diethyl ether and saturated aqueous NaCl solution. The organic layer thus obtained was dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was crystallized from methylene chloride, whereby the title compound (yellow powder, 300 mg) was obtained.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]1([CH2:54][NH:55][C:56]([C:58]2[NH:59][C:60]3[C:65]([CH:66]=2)=[CH:64][CH:63]=[CH:62][C:61]=3[N:67]([CH3:76])[S:68]([C:71]2[S:72][CH:73]=[CH:74][CH:75]=2)(=[O:70])=[O:69])=O)[CH2:53][CH2:52][C:47]2([O:51][CH2:50][CH2:49][O:48]2)[CH2:46][CH2:45]1)C1C=CC=CC=1.CSC.C(=O)([O-])O.[Na+]>C(#N)C>[S:43]1[C:44]2([CH2:53][CH2:52][C:47]3([O:51][CH2:50][CH2:49][O:48]3)[CH2:46][CH2:45]2)[CH2:54][N:55]=[C:56]1[C:58]1[NH:59][C:60]2[C:65]([CH:66]=1)=[CH:64][CH:63]=[CH:62][C:61]=2[N:67]([CH3:76])[S:68]([C:71]1[S:72][CH:73]=[CH:74][CH:75]=1)(=[O:70])=[O:69]
Reactant: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC4(CC3)OCCO4)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CSC
Product: CN(c1cccc2cc(C3=NCC4(CCC5(CC4)OCCO5)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
To a solution of triphenylphosphine oxide (1.98 g) in acetonitrile (30 mL) was slowly added trifluoromethanesulfonic anhydride (0.60 mL) at 0° C., and the mixture was stirred for 10 min. N-{[8-(Benzylthio)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.45 g) and dimethylsulfide (0.52 mL) were added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the precipitated solid was collected by filtration, and washed with water. The obtained solid was washed with ethyl acetate, and dried to give the title compound (0.75 g, yield 63%) as colorless crystals. melting point 224-225° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(C)nc2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (123 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a colorless oil (yield 88 mg, 91%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (27 mg) in ethanol (2 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 78 mg, 77%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28](OC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13]
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)N1C(=O)NC(COC)=C(C(=O)OC)[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
β-Alanine ethyl ester hydrochloride (87 mg, 0.57 mmol), (+)-5-methyoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6(S)-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine (as described in Section I.A.(c)) (227 mg, 0.48 mmol), and triethylamine (209 mL, 1.50 mmol) were combined in 5 mL of dichloromethane. The yellow mixture was stirred at ambient temperature for 1 hour, then evaporated to dryness. The resulting oil was purified by “flash” chromatography (5.02, 98:2:0.2 of dichloromethane:methanol:ammonium hydroxide). The product fractions were evaporated to dryness to give the title compound as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:18])=[N-]>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: C=[N+]=[N-]
Reactant: CCC(C)(C)c1ccc(O)c(C(=O)O)c1
Product: CCC(C)(C)c1ccc(O)c(C(=O)OC)c1

Procedure:
Following the procedure of Schmitt et al., Synthesis, 1984, 758-760; and treating the resulting 2-hydroxy-5-(1,1-dimethylpropyl)benzoic acid with diazomethane gave the title compound. 1H NMR (250 MHz, CDCl3) δ10.61 (s, 1H), 7.75 (d, 1H), 7.44 (dd, 1H), 6.92 (d, 1H), 3.95 (s, 3H), 1.61 (q, 2H), 1.26 (s, 6H), 0.67 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH3:21][CH:20]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1)[CH3:22]
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1ccc2c(c1)C(=O)CCC2
Temperature: 80 °C

Procedure:
A suspension of 2.0 g of 7-hydroxy-3,4-dihydronaphthalen-1(2H)-one, 4.04 g of caesium carbonate and 3.15 ml of 2-iodopropane in 23 ml of acetonitrile is heated for 1 hour at 80° C. The reaction medium is brought back to ambient temperature and then evaporated to dryness. The residue is taken up with 100 ml of water and 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure, so as to obtain 2.24 g of 7-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in the form of an orangey-coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1
Temperature: -50 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
1-(4-Bromophenyl)ethanone (9.25 g, 46.5 mmol) was dissolved in tetrahydrofuran (200 mL). The solution was cooled in a −50° C. bath. Methylmagnesium bromide (3M in ether, 46.5 mL, 139 mmol) was added over a 15 min period. The reaction was allowed to warm to room temperature and then stirred for 20 h. The reaction was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an oil. The oil was purified on a silica gel column (0-20% ethyl acetate in hexanes) to give the product a colorless oil (9.1 g, 46.2 mmol, 91% yield). MS (ESI) m/z 197.1 [M]+, 199.1 [M+2]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:14]=[C:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][N:21]=2)[N:16]1[CH2:25][C:26](O)=[O:27]>>[Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([NH:7][C:26](=[O:27])[CH2:25][N:16]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][CH:18]=3)[CH2:23][CH2:24][C:15]2=[O:14])[S:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Cc1n[nH]c(-c2c(Cl)csc2N)n1
Product: Cc1n[nH]c(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The title compound was prepared from 4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (69 mg, 321 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (82 mg, 397 umol) using protocol A. The residue was purified by HPLC. Method [8] Retention time 3.40 min by HPLC (M+=403 and 405) and (M+Na=425 and 427). 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=5.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4 and 5.4 Hz, 1H), 6.86 (s, 1H), 5.46 (broad s, 2H), 4.95 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.50 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1COCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Yield: 87 %

Procedure:
Morpholine (1.2 g, 14.12 mmol) was added to a stirring solution of 3,4,5-trifluoronitro benzene (1 g, 5.65 mmol) in acetonitrile (15 mL) and the reaction mixture was refluxed for 5 h. A viscous liquid was obtained upon concentration, which was then poured into crushed ice. The solid thus obtained was filtered off and dried under reduced pressure to obtain the title compound (1.2 g, 88%).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[O:25])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1>O1CCCC1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:25])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCCC1
Temperature: -25 °C

Procedure:
A solution of cyclohexyl magnesium bromide in ether (2.0 M, 3.10 mL, 6.25 mmol) (Aldrich) was added dropwise to a suspension of 6-chloroisatin (0.45 g, 2.5 mmol) (Crescent) in tetrahydrofuran (12.5 mL) with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 2 hours, 15% aqueous ammonium chloride solution (12.5 mL) was added and mixture was extracted with ethyl acetate. Ethyl acetate layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 30 minutes and filtered to give crude rac-6-chloro-3-cyclohexyl-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. (Yield 0.28 g, 43%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]#[N:22])[O:3]1.Cl.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].O>C1(C)C=CC=CC=1>[C:15]1([C:14]#[C:13][C:9]2[CH:8]=[C:7]([C@@H:5]3[C@@H:4]([C:21]4[NH:33][N:32]=[N:31][N:22]=4)[O:3][C:2](=[O:1])[NH:6]3)[CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#C[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](c2nnn[nH]2)O1
Reaction time: 48 h
Yield: 74.4 %

Procedure:
To a solution of (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonitrile (35 mg, 0.121 mmol) in Toluene (2 mL) was added triethylamine hydrochloride (50.6 mg, 0.364 mmol) and sodium azide (23.68 mg, 0.364 mmol) and the reaction was heated to reflux. After 2 days, the reaction was poured into water (1 ml) and extracted with ethylacetate (10 mL×2). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to an off white solid that was purified by Preparative HPLC method 4 providing (4R,5S)-4-(3-(phenylethynyl)phenyl)-5-(1H-tetrazol-5-yl)oxazolidin-2-one (30 mg, 0.090 mmol, 73.8% yield) 1H NMR (500 MHz, DMSO-d6) δ ppm 5.21-5.55 (m, 2H) 7.10 (br. s., 3H) 7.34 (d, J=7.93 Hz, 1H) 7.39-7.49 (m, 4H) 7.51 (d, J=7.32 Hz, 1H) 7.57 (dd, J=6.41, 3.05 Hz, 2H) 8.27 (s, 1H). Mass spec.: 331.99 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].[CH3:20][C:21]1([CH3:29])[O:25][C@H:24]([C@H:26]([OH:28])[CH3:27])[CH2:23][O:22]1>O1CCCC1.CC1CCCO1>[Cl:8][C:6]1[CH:7]=[C:2]([O:28][C@@H:26]([C@@H:24]2[CH2:23][O:22][C:21]([CH3:29])([CH3:20])[O:25]2)[CH3:27])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:5]=1
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Reactant: Fc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2ccc(F)cc2)n1)[C@@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The sub-title product of step (ii) (85.7 g) and 60% sodium hydride (14.2 g) were suspended in tetrahydrofuran (1000 mL) and cooled in ice/water for 30 minutes. A solution of (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (Intermediate A) in 2-methyltetrahydrofuran (53% w/v) (104 mL) was added dropwise over 20 minutes and the reaction was stirred at 0° C. to room temperature for 20 hours. The reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The aqueous was re-extracted with ethyl acetate (2×500 mL) and the combined organics were dried and evaporated in vacuo. The crude material was purified by flash silica chromatography with gradient elution 0-30% ethyl acetate in isohexane using Isolera LS. Pure fractions were evaporated to dryness to afford to afford the sub-title product (94 g) as a yellow oil.