Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cu]C#N.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)CCC.[F-].[K+]>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOP(=O)(OCC)c1csc(I)c1P(=O)(OCC)OCC
Agent: N#C[Cu]
Agent: [Pd]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1csc(-c2cccs2)c1P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 9.25 h

Procedure:
3,4-bis(diethoxyphosphoryl)-2-iodothiophene, different types of palladium catalysts (0.05 equivalents, commercially available products) indicated in the following Table 5 and commercially available copper(I) cyanide (0.20 equivalents) were dissolved in toluene, to which 2-tributylstannylthiophene (1.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 70° C. and stirred for 8.5 to 10 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. The resulting solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substances.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([C:3](=[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)=[O:5])#[N:2]
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)CC#N)cc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)C(C#N)=C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 19.3 g of methyl 4-(3-{4-[(cyanoacetyl)amino]phenyl}propyl)benzoate, 18 mL of cyclohexanone, and 100 mL of toluene was added dropwise 5.0 mL of morpholine at room temperature. In a reaction device in which a Dean-Stark type dehydration tube was installed, the reaction mixture was stirred for 8 hours under heating and refluxing. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-chloroform and ethyl acetate-chloroform) to obtain methyl 4-[3-(4-{[cyano(cyclohexylidene)acetyl]amino}phenyl)propyl]benzoate in the form of a reddish brown amorphous substance as a crude product. ESI+: 417
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11](=[O:36])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:34][CH3:35])[C:21](=[O:33])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[F:10]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:36])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:34][CH3:35])[C:21](=[O:33])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=3)[CH2:16][CH2:15]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C1CCN(CCC(=O)c2ccc(F)c(F)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)C1CCN(CCC(O)c2ccc(F)c(F)c2)CC1
Temperature: 25 °C

Procedure:
A solution of sodium borohydride (7.7 mg) in ethanol (1 ml) was added to a solution of N-[1-(3-[3,4-difluorophenyl]-3-ketopropyl)-piperidin-4-yl]-N-ethyl-4-methanesulphonylphenylacetamide (0.25 g) in ethanol (3.2 ml) at 0° C. under argon and the reaction allowed to warm to room temperature over 20 hours. The reaction was quenched with brine, extracted three times with ether and the combined extracts dried. The filtrate was then concentrated to a clear oil, yield 0.21 g. MS (MH+) 495.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.[OH-].[K+].Cl>CCO>[OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])/[CH:12]=[CH:18]/[C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:15]([F:14])([F:24])[F:25]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1ccccc1C(F)(F)F)c1cccc([N+](=O)[O-])c1O
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A solution of 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (788 mg, 4.4 mmol), 2-(trifluoromethyl)benzaldehyde 8 (1.1 g, 6.5 mmol) and 25% aq KOH (90 mL) in EtOH (90 mL) was stirred for 12 h at room temperature. The reaction mixture was poured into ice-water and the pH was adjusted to 2 using conc. HCl. The resulting precipitate was collected by filtration, rinsed with H2O and dried under vacuum to give 9 as a yellow solid (1.4 g, 95% yield).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:22])/[CH:17]=[CH:18]/[C:19](Cl)=[O:20]>C(Cl)Cl>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16](=[O:22])/[CH:17]=[CH:18]/[C:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: ClCCl
Product: O=C(/C=C/C(=O)N(Cc1ccccc1)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
To a cooled (−5° C.) solution of N,N-dibenzylamine (19.3 mL, 100 mmol) in DCM (200 mL) is added TEA (13.8 mL, 100 mmol). To this solution is added, drop wise over 5 minutes, fumaroyl chloride (4.2 mL, 40 mmol). On complete addition, the cold bath is removed and stirring continued for 1 hr. This solution is diluted with DCM, washed with HCl (approx. 100 mL of 1M aq.) then water (2×), dried over MgSO4 and concentrated. The solid residue is crystallized from hot (109° C.) toluene to give the title compound (17.9 g) as a white solid. ESI-MS (m/z) 475 (MH)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([O:21]CC)=[O:20])[N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[CH2:3]([C:13]1[N:14]=[N:15][N:16]([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:19]([OH:21])=[O:20])[N:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCc1nnn(C(C(=O)O)c2ccccc2)n1
Reaction time: 1 h
Yield: 92 %

Procedure:
Solid NaOH (0.33 g, 0.0084 mol) was added to a solution of ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate in 50 mL ethanol (90%). The resulting solution was stirred for 1 hour and concentrated in vacuo. The residue was partitioned between diethyl ether and water and the aqueous layer was acidified with 1N HCl. The acidified aqueous layer was extracted with diethyl ether and this ether layer was dried over MgSO4, filtered, and evaporated to give the title compound (1.78 g, 92%), mp 62°-64° C.
Reaction SMILES: [BrH:1].[N+:2]([C:5]1[N:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][N:9]=1)([O-:4])=[O:3].[N+]([C:16]1N(C[C@H]2CO2)[CH:18]=[CH:19][N:20]=1)([O-])=O.O1CCNC1=O.C[Si](C)(C)[O-].[K+]>>[BrH:1].[Br:1][CH2:18][CH2:19][NH:20][CH2:16][C@H:11]([OH:12])[CH2:10][N:6]1[CH:7]=[CH:8][N:9]=[C:5]1[N+:2]([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1nccn1C[C@H]1CO1
Reactant: O=[N+]([O-])c1nccn1CCO
Agent: Br
Agent: C[Si](C)(C)[O-]
Agent: O=C1NCCO1
Product: O=[N+]([O-])c1nccn1C[C@@H](O)CNCCBr

Procedure:
A process for preparing (R)-(+)-α-[[2-bromoethyl)-amino]methyl]-2-nitro-1H-imidazole-1-ethanol, monohydrobromide which comprises reacting (S)-2-nitro-1-(2-oxiranylmethyl)-1H-imidazole with a 2-oxazolidinone of the formula ##STR15## in the presence of potassium trimethylsilanolate to give the (S)- enantiomer of a compound of the formula ##STR16## which is treated with hydrobromic acid in the presence of acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([O:33]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:5][CH:4]=1)#[N:2].[CH3:43][NH:44][CH3:45]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([N:44]([CH3:45])[CH3:43])=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Product: CN(C)C(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 51 mg, 8 μmol) and dimethylamine (2.0 M in tetrahydrofuran, 220 μL, 440 μmol) in acetonitrile (1.5 mL) is stirred at room temperature for 30 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 14 mg; ESI mass spectrum [M+H]+=483; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1)(=[O:21])=[O:22]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (200 mg, 0.77 mmol) and 3-methylsulphonylaniline hydrochloride (80 mg, 0.39 mmol, Acros) afforded a crude reaction product mixture, which was partitioned between EtOAc (100 mL) and 1 N NaOH (50 mL). The organic layer was washed with 1 N NaOH (50 mL), water (50 mL), satd NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (9:1 CH2Cl2/EtOAc) provided the title product as a white solid. MS (ESI, pos. ion) m/z: 394 (M+1). MP: 204-205° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=C)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].C[OH:25]>>[OH:25][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C=CC(NC(=O)OC(C)(C)C)C1CCC2(CC1)OCCO2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(CO)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 250 mL round bottom flask was charged with tert-butyl (1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)carbamate (5.3 g, 17.8 mmol), prepared in the previous step, and methanol (198 mL). The mixture was cooled to −78° C. and ozone was bubbled through the solution at a rate of 3 L/min for 1 hour. The mixture turned pale blue in color after 30 minutes. After 1 hour air was bubbled through the solution for 30 minutes until the blue color disappeared. Sodium borohydride (2.7 g, 71.3 mmol) was added to the mixture in 4 portions. The mixture was gradually warmed to room temperature. After 6 h at room temperature the mixture quenched with saturated aqueous ammonium chloride. After dilution with water and extraction with ethyl acetate, the organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the product as a clear oil.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[C:12]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl.Cl[CH2:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][N:34]=1.[OH-].[Na+]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH:2]([C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:26]=[N:27][N:28]([CH2:32][C:33]3[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][N:34]=3)[CH:29]=2)[C:12]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: Cc1ccnc(CCl)c1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3ccccc32)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4ccccc43)c3ccc(C(C)C)nc3)cn2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.99 g) in methylene chloride (10 mL) were added tetra-n-butylammonium hydrogensulfate (0.82 g), 2-chloromethyl-4-methylpyridine hydrochloride (0.86 gland 1 mol/L-aqueous sodium hydroxide solution (24.0 mL). The mixture was stirred at room temperature for one day. The reaction mixture was partitioned between water and chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide. This compound was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane (2.4 mL) was added. The precipitated solid was collected by filtration to give N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.61 g).
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13](Br)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>CN1CCCC1=O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([C:2]#[N:3])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)c(C(C)C)cc1OC
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)c(C(C)C)cc1OC
Temperature: 0 °C
Yield: 74.8 %

Procedure:
Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4-iso-propylbenzoate (861 mg) in N-methyl-2-pyrrolidinone (30 ml). The mixture was stirred under argon and boiled under reflux for 4 h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO4). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (1:4). The product was obtained as a white solid (523 mg).
Reaction SMILES: CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[Cl:22][C:23]1[C:28]([C:29]#[CH:30])=[C:27](/[N:31]=[N:32]/[N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[C:25]([C:45](=[O:47])[CH3:46])[CH:24]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl>[Cl:22][C:23]1[C:28]([C:29]#[CH:30])=[C:27](/[N:31]=[N:32]/[N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[C:26]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)=[C:25]([C@H:45]([OH:47])[CH3:46])[CH:24]=1
Reactant: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1c(Cl)cc([C@@H](C)O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 126.4 %

Procedure:
A solution of (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (280 g, 1.0 mol) in tetrahydrofuran (2.8 L) at room temperature under an atmosphere of nitrogen was treated with 1.0 M borane-THF complex in THF (1.2 L, 1.2 mol) in small portions, stirred for 15 minutes, and then cooled to −20° C. The reaction mixture was treated with a solution of 1-{4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-yl}ethanone (380 g, 1.0 mol) in anhydrous tetrahydrofuran (3.0 L) dropwise over 60 min with the internal temperature rising from −20 to −12° C. The flask that contained the ketone was rinsed with tetrahydrofuran (500 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at −12 to −10° C. for 30 minutes. The reaction mixture was quenched with water (440 mL, 24 mol) at −10° C. over 10 minutes (temperature rose to 0° C.), warmed to room temperature, treated with 10% potassium carbonate in water (3.0 L, 2.1 mol), and stirred for 20 minutes. The organic layer was separated, diluted with ethyl acetate (2 L) and hexanes (0.5 L) and washed with 0.5 M citric acid in water (3.0 L, 1.5 mol), 1.0 M hydrogen chloride in water (3.0 L, 3.0 mol), and 0.5 M citric acid in water (3.0 L, 1.5 mol). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (470 g, theoretical 380 g). The main impurities were the alcohol with triazene moiety removed and the hydrolyzed ligand. The product had ˜91 ee %. This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(c1ccccc1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (N I+): m/z=423.1, tR (minutes, Method D)=0.81
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=O)[NH:17]2.[CH3:24][CH2:25][O:26]CC>>[C:25]([N:17]1[C:18]2[C:13](=[C:12]([CH3:11])[CH:21]=[C:20]([CH3:22])[CH:19]=2)[CH2:14][CH2:15][CH2:16]1)(=[O:26])[CH3:24]
Reactant: CCOCC
Reactant: Cc1cc(C)c2ccc(=O)[nH]c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CC(=O)N1CCCc2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (687 mg) was suspended in ether (16 ml), and aluminum chloride (4.2 g) was added. A solution of 5,7-dimethylquinolone (1.6 g) in ether (16 ml) was dropwise added and the mixture was refluxed for 0.5 hr. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 5,7-dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in chloroform (30 ml), and acetic anhydride (929 mg) was added, which was followed by stirring at room temperature for 1 hr. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous solution of sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5-1/1) to give 1.5 g of oily 1-acetyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([O:10]CC)=[O:9].Cl>[OH-].[Na+]>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CCC(=O)C21
Temperature: 27.5 °C
Reaction time: 2.5 h

Procedure:
A mixture of 60 g of ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate and 300 ml of 1N sodium hydroxide was stirred at 25-30° C. After 2.5 hours, concentrated hydrochloric acid was added to adjust the pH to 0.8-1.2. The resulting solution was extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated to give 49.1 g (98%) of the crude material. Recrystallization from 100 ml of ethyl acetate gave the title compound, mp 123.5-128° C.
Reaction SMILES: Cl.[N:2]1[C:7]2[CH:8]=[CH:9][C:10](B(O)O)=[CH:11][C:6]=2[N:5]=[CH:4][CH:3]=1.C1(P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[CH2:59]([O:58][C:56](=[O:57])[CH2:55][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[N:2]=[CH:3][CH:4]=[N:5]2)[CH3:60]
Reactant: CCOC(=O)CBr
Reactant: OB(O)c1ccc2nccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1ccc2nccnc2c1
Yield: 18.7 %

Procedure:
A vial under nitrogen atmosphere was charged with benzopyrazine-6-boronic acid hydrochloride (500 mg, 2.38 mmol), palladium (II) acetate (16 mg, 0.071 mmol), tri-1-naphthylphosphine (88 mg, 0.214 mmol), potassium phosphate tribasic (2.52 g, 11.9 mmol), and tetrahydrofuran (10 mL). Ethyl 2-bromoacetate (0.315 mL, 2.85 mmol) was then added and the reaction mixture was stirred at reflux for 6 h. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were adsorbed on silica gel. Purification on silica gel with 0-100% gradient of ethyl acetate in hexane provided 96 mg of product as a dark yellow oil. 1H NMR 500 MHz (DMSO) δ 1.20 (t, 3H), 3.99 (s, 2H), 4.11 (q, 2H), 7.79 (dd, 1H), 8.01 (d, 1H), 8.06 (d, 1H), 8.94 (d, 2H); MS (m/z) 217 [M+H+]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](OC)=[O:34])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:33]2=[O:34])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCCCCCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCCCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 9-(pyridin-4-yl)nonanoate (1.5 eq., prepared in Synthetic Example 16) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[7-(pyridin-4-yl)heptyl]-1,8-naphthyridin-2(1H)-one, mp 189 to 192° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.