Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19].CCOC(C)=O.CO>CN(C=O)C.C1COCC1>[OH:1][CH2:2][C:3]1[N:4]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: OCc1nc2ccccc2[nH]1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCCn1c(CO)nc2ccccc21
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 2-hydroxymethylbenzimidazole (29.63 g, 200 mmol) in a mixture of DMF/THF (150 mL, 1:1) was added sodium hydride (60% in mineral oil, 8.4 g, 210 mmol) in several portions at room temperature. After stirring for 1 hour, 4-bromobutyronitrile (29.6 g, 200 mmol) was added and the resulting solution was stirred at 80° C. for 16 hours. The solvent was evaporated and the residue diluted with water and extracted with EtOAc. The combined extracts were dried over MgSO4 and evaporated. The residue was purified by flash chromatography (gradient, EtOAc/hexane, 1:1 to 2:1, then EtOAc/MeOH, 10:1) to give 22.11 g (51% yield) 4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyronitrile, 68 as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C(c1ccccc1)c1ccccc1
Yield: 56.9 %

Procedure:
Diphenylacetic acid (0.75 g) and (S)-3-amino-1-(2-phenylethyl)pyrrolidine (0.67 g) were dissolved in DMF (10 ml), and triethylamine (1.4 ml) was added thereto, which was followed by addition of diethyl cyanophosphate (0.67 ml) under ice-cooling. After completion of the reaction, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed successively with an aqueous potassium carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)diphenylacetamide (0.77 g). The obtained compound was dissolved in acetone (3 ml), and a solution of oxalic acid (0.18 g) in acetone (3 ml) was added thereto. The precipitated crystals were collected by filtration and washed with acetone to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)diphenylacetamide oxalate, melting point 191-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(C)=O>[CH2:34]([O:27][C:23]1[CH:22]=[C:21]([CH2:20][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:26]=[CH:25][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
171 (580 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (238 mg, 1.1 equivalent) and benzylbromide (1.1 equivalent, 206 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 172 as white solid (513 mg, 71%). 1H NMR (CDCl3): δ 1.46 (s, 9H), 2.64 (s, 1H), 3.05 (m, 1H), 3.18 (m, 1H), 4.39 (m, 1H), 5.20 (s, 1H), 5.25 (s, 4H), 6.95 (d, 1H, J=7.1 Hz), 7.00 (d, 1H, J=7.9 Hz), 7.07 (s, 1H), 7.20 (m, 2H), 7.27 (d, 2H, J=7.4 Hz), 7.32 (t, 1H, J=7.9 Hz), 7.50 (m, 6H).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[CH2:7][CH3:8].[B:16](OC)([O:19]C)[O:17]C.Cl>O1CCCC1.O>[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:16]([OH:19])[OH:17])[CH2:7][CH3:8]
Reactant: COB(OC)OC
Reactant: CCCc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
15.5 mL of butyl lithium (1.6 mol/L solution in hexane) was placed in a reaction vessel, which was chilled in a dry ice-acetone bath. To this was added a solution of 4.412 g of 2-propylbromobenzene in 45 mL of tetrahydrofuran at −70° C. dropwise over 85 minutes under a nitrogen atmosphere. The mixture was stirred at −70° C. for 30 minutes, to which 3.75 mL of trimethyl borate was then added at −70° C. dropwise over 15 minutes. The mixture was stirred at −70° C. for one hour and then at room temperature for 18 hours. To the reaction mixture was added 33 mL of 2N hydrochloric acid dropwise over 10 minutes and then the mixture was stirred at room temperature for 4 hours. To the mixture was added 20 mL of water, which was extracted with 70 mL of ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to a silica gel column chromatography (as eluent, ethyl acetate:hexane=1:2, and then 2:1) to yield 1.641 g of the title compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:24]2[CH2:25][CH2:26][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=358.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]([OH:13])=O)([O-:7])=[O:6].[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[S:36][C:35]=2[CH:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N+:5]([C:8]1[CH:9]=[C:10]([C:11]([C:38]2[C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:42][C:35]=3[S:36][C:37]=2[N:39]([CH3:41])[CH3:40])=[O:13])[CH:14]=[CH:15][C:16]=1[CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:7])=[O:6]
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: O=C(O)c1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield by essentially following the procedures outlined in Example 39, Part B (except using thionyl chloride instead of oxalyl chloride) from 3-nitro-4-[(1-pyrrolidinyl)methyl]benzoic acid (Part C, above) and 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene (Example 81, Part B).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][CH:15]([C:18]([OH:20])=O)[CH2:16][Cl:17])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl.[CH3:22][O:23][C:24](=[O:28])[CH:25]([CH3:27])[NH2:26].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)Cl>[CH3:22][O:23][C:24](=[O:28])[CH:25]([CH3:27])[NH:26][C:18](=[O:20])[CH:15]([CH2:16][Cl:17])[NH:14][C:12](=[O:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)N
Reactant: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)NC(C)C(=O)OC)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(DL)-alanine (0.622 g) was dissolved in dry tetrahydrofuran (10 ml). To the solution was added (DL)-alanine methyl ester hydrochloride (0.3 g) in dry methylene chloride (3.0 ml) containing dry triethylamine (0.3 ml). DCC (0.413 g) was added and the reaction mixture was stirred at room temperature. After being stirred overnight, the reaction mixture was worked up. DCU was filtered off. The volatile material was evaporated at reduced pressure. The semi-solid residue was dissolved in chloroform (20 ml). The chloroform solution was washed with aqueous hydrochloric acid (0.5M, 2×20 ml), saturated aqueous sodium bicarbonate solution (2×20 ml) and finally with water (2×20 ml). The extract was dried (anhydrous sodium sulphate). The solvent was evaporated at reduced pressure to leave a small volume of material. Light petroleum (b.p. 60°-80° C.) was added to obtain a solid product (400 mg) of m.p. 100°-105° C. After recrystallisation from chloroform/light petroleum (b.p. 60°-80° C.) the above-named product, (200 mg), m.p. 105°-107° C., was obtained.
Reaction SMILES: [CH3:1][N:2]([CH:25]([CH3:27])[CH3:26])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]#[N:14])=[CH:8][CH:7]=2.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[CH:25]([N:2]([CH3:1])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)=[N:5][C:6]2[C:11](=[CH:10][C:9]([C:13]3[NH:30][N:29]=[N:28][N:14]=3)=[CH:8][CH:7]=2)[N:12]=1)([CH3:27])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2cc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)ccc2[nH]1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2cc(-c3nc4ccc(-c5nnn[nH]5)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 130 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carbonitrile (200 mg, 0.56 mmol) in DMSO (20 ml) was added NaN3 (110 mg, 1.69 mmol) in water (2 ml), and ZnBr2 (64 mg, 0.28 mmol). The resulting solution was stirred overnight at 130° C. and then quenched with water (200 ml). The pH was adjusted to 3 with HCl (2N). Then the solution was extracted with ethyl acetate (4×50 ml) and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (10%-15% dichloromethane in methanol) to afford N-isopropyl-N-methyl-3-(2-methyl-1H-indol-5-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as an orange solid (47.4 mg, 21%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[N:7]=2)=[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.149 g, 0.276 mmol) and 2-aminoethyl-methyl-sulfone (0.3 g, 2.4 mmol), the title compound was obtained as a white solid (75 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.65-7.79 (m, 1H), 7.36-7.53 (m, 3H), 7.22-7.34 (m, 3H), 6.28 (br. s., 1H), 3.60-3.75 (m, 2H), 3.35-3.40 (m, 2H), 3.02 (s, 3H), 1.42 (s, 9H). MS (ESI): 626.2 [M+H]+.
Reaction SMILES: [Cl:1]C1C=C(OC)C(C(O)=O)=NC=1.[CH3:13][O:14][C:15]1[CH:24]=[N:23][C:22]2[C:21](=O)[N:20]=[CH:19][NH:18][C:17]=2[CH:16]=1>>[Cl:1][C:21]1[C:22]2[N:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1cc(Cl)cnc1C(=O)O
Reactant: COc1cnc2c(=O)nc[nH]c2c1
Product: COc1cnc2c(Cl)ncnc2c1

Procedure:
Using an analogous reaction to that described for Intermediate 14, step 3, 7-methoxypyrido[3,2-d]pyrimidin-4(1H)-one was converted to the title compound. LC/MS (ESI+) m/z=196 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.Cl.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=2[C:42]([F:45])([F:44])[F:43])[CH2:28][CH2:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:38])=[CH:35][C:34]=2[C:42]([F:45])([F:43])[F:44])[CH2:30][CH2:31]1)[CH3:25]
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cncnc2)ccn1
Reactant: CCN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4cc(-c5cncnc5)ccn4)c3)cc2C(F)(F)F)CC1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline (Reference Example 22) and 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 5) were used, and that the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=O)[C:7]1([CH3:12])[CH3:11])=[O:5])[CH3:2].P(OCC)(OCC)OCC.[Cl:23][C:24](Cl)([Cl:28])C([O-])=O.[Na+].O>COCCOCCOC>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:24]([Cl:28])[Cl:23])[C:7]1([CH3:12])[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: CCOP(OCC)OCC
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 150 °C
Yield: 73 %

Procedure:
A mixture of 17.0 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester, 16.6 g (0.1 mole) of triethyl phosphite and 18.5 g (0.1 mole) of sodium trichloroacetate in 100 ml of diglyme was heated to 150° C. under argon for 6 hours. The reaction mixture was then poured into water. Extraction with 2 portions of 100 ml each of methylene chloride followed. The combined methylene chloride extracts were dried over sodium sulphate. 3-(2,2-Dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained as a crude product in a yield of 73% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[NH:4][CH:3]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.I[C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[CH:30][CH:29]=[CH:28]3)=[O:21])=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[CH3:1][C:2]1([CH3:14])[O:6][C:5](=[O:7])[N:4]([C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:32]=3[N:31]=[CH:30][CH:29]=[CH:28]4)=[O:21])=[CH:18][CH:17]=2)[CH:3]1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Reactant: CC1(C)OC(=O)NC1c1cccnc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Nc3cccc4cccnc34)cc2)C1c1cccnc1
Temperature: 140 °C
Yield: 55.9 %

Procedure:
A microwave vial was charged with 5,5-dimethyl-4-(pyridin-3-yl)oxazolidin-2-one (0.072 g, 0.376 mmol), 4-iodo-N-(quinolin-8-yl)benzamide (0.155 g, 0.414 mmol), tribasic potassium phosphate (0.399 g, 1.880 mmol) and dioxane (3.50 mL). The mixture was purged with argon and then copper (I) iodide (0.072 g, 0.376 mmol) and N,N′-dimethylethylenediamine (0.081 mL, 0.752 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 140° C. for 1 hour in a microwave. The reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford an orange brown solid. This residual material was purified by column chromatography on silica gel (RediSep 40 g column, gradient elution with 50-100% EtOAc-hexane) to afford (+/−)-(R/S)-4-(5,5-dimethyl-2-oxo-4-(pyridin-3-yl)oxazolidin-3-yl)-N-(quinolin-8-yl)benzamide (0.092 g, 0.210 mmol, 56% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (s, 3H), 1.69 (s, 3H), 5.69 (s, 1H), 7.40 (dd, J=8.02, 4.79 Hz, 1H), 7.57-7.79 (m, 6H), 7.90-8.04 (m, 2H), 8.45 (dd, J=8.31, 1.66 Hz, 1H), 8.54 (dd, J=4.74, 1.61 Hz, 1H), 8.60 (br. s., 1H), 8.67 (dd, J=7.63, 1.27 Hz, 1H), 8.95 (dd, J=4.25, 1.71 Hz, 1H), 10.56 (s, 1H). m/z (ESI) 439 (M+H)+.
Reaction SMILES: Br[C:2]([CH:16]([CH3:18])[CH3:17])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:30]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:30]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:16]([CH3:18])[CH3:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CC(C)C(Br)=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Into a reactor were introduced 1.20 g (4.00 mmol) of the 2-bromo-1,1-diphenyl-3-methylbutene and 12 mL of THF under a nitrogen atmosphere. The contents were cooled to −70° C., and 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium was gradually added dropwise thereto. The resultant mixture was stirred at that temperature for 30 minutes. Thereafter, 1.1 mL (4.8 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred at that temperature for 3 hours and then heated to room temperature over 13 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and toluene to obtain 0.72 g (43%) of the target compound as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:12].[OH-].[Na+]>O1C=COC=C1.[Pd]>[CH3:14][O:13][C:5]1[CH:4]=[CH:3][CH:2]=[C:11]2[C:6]=1[C:7](=[O:12])[CH:8]=[CH:9][NH:10]2
Reactant: COc1ccc(Br)c2[nH]ccc(=O)c12
Agent: [Pd]
Agent: C1=COC=CO1
Agent: [Na+]
Product: COc1cccc2[nH]ccc(=O)c12
Yield: 68 %

Procedure:
Quinolone (b) (5.4 g, 21 mmol) was dissolved in a mixture of dioxin (300 ml) and 2M aqueous sodium hydroxide solution (21 ml, 42 mmol) then hydrogenated over 10% palladium on charcoal (2.3 g) for 18 hours. The mixture was filtered, neutralised (5M hydrochloric acid) and concentrated when crystallisation commenced. Filtration, washing with water and drying in vacuo afforded a solid (2.5 g, 70%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][O:6][CH2:7][CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:7]([O:6][CH2:5][CH2:4][C:3]([CH:2]=[P:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:8]
Reactant: CCOCCC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 53.3 %

Procedure:
A solution of 1-chloro-4-ethoxybutan-2-one (7.5 g.) and triphenylphosphine (13.5 g.) in chloroform (20 ml.) was saturated with nitrogen and heated at reflux under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in dichloromethane (35 ml.). Dry diethyl ether (300 ml.) was added to precipitate 4-ethoxy-2-oxobutyltriphenylphosphonium chloride (19 g.). This compound was added portionwise to a solution of sodium carbonate (10g.) in water (1000 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 60°-80° C.) to give 3-ethoxypropionylmethylenetriphenylphosphorane (10.0 g.), m.p. 63°-65° C. Elemental analysis: found C, 76.6; H, 6.5; P, 8.2%; C24H25O2P requires: C, 76.6; H, 6.7;P 8.3%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1.O>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
Benzoyl chloride (0.92 ml, 7.93 mmol) was added dropwise to a stirred solution of 2-amino-5-nitropyrimidine (1.00 g, 7.14 mmol) in pyridine (20 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature, poured into water (200 ml) and allowed to stand for 16 hours. The solid was collected by suction filtration, washed with water (3×20 ml) and dried in vacuo. An oil residue on the surface of the aqueous phase was dissolved in dichloromethane (50 ml) and then purified by flash chromatography on silica gel, eluting with 1–3% methanol in dichloromethane. The two materials were identical and yielded 2-(N-benzoyl)amino-5-nitropyrimidine (826 mg, 47% yield) as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].Cl>O1CCCC1.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:16][CH2:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNC(=O)CCc1ccc(O)cc1

Procedure:
3-(4-Hydroxyphenyl)propionic acid (12.0 g, 72.0 mmol) was dissolved in tetrahydrofuran (20 mL). n-Propylamine (5.1 g, 86.4 mmol) was added dropwise at room temperature. Subsequently, under ice-cooling, solution (20 mL) of WSCI-hydrochloric acid salt (16.5 g, 86.4 mmol) in methylene chloride was slowly added thereto, and the resultant mixture was stirred overnight. Diluted hydrochloric acid was added dropwise under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (9.7 g, 65%).