Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:33]3[CH:34]=[CH:35][C:30]([CH2:29][O:28][CH3:27])=[CH:31][CH:32]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: COCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 110 °C
Yield: 105.3 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.00 g, 3.26 mmol) in N,N-dimethylacetamide (15 mL). Add potassium carbonate (1.29 g, 9.36 mmol), 4-methoxymethylbenzeneboronic acid (649 mg, 3.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0225 g, 0.034 mmol), then water (5 mL) and degas with nitrogen for 30 min. Heat at 110° C. for 18 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Combine the DCM extracts and pass through an IST Phase Separator Frit® and concentrate. Purify (silica gel chromatography, eluting with 20:80 ethyl acetate:isohexane), to give 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester as a yellow oil (1.32 g, 105%). MS (ES): m/z=385 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]([C:6]1[C:7]([CH3:33])=[N:8][C:9]2[CH2:10][CH2:11][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[O:5].[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:5][CH:4]([C:6]1[C:7]([CH3:33])=[N:8][C:9]2[CH2:10][CH2:11][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:3]([O:2][CH3:1])=[O:34]
Reactant: COC(=O)C(=O)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(O)c1c(C)nc2c(c1-c1ccc(C)cc1)CN(C(=O)OCc1ccccc1)CC2
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A solution of benzyl 3-(2-methoxy-2-oxoacetyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.53 g, 5.52 mmol) (intermediate 10) and 1M (toluene) R-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborlidine (2.21 ml, 2.21 mmol) in toluene (100 ml) was cooled to −35° C. Catecholborane (50 wt % in toluene) (1.65 ml, 7.73 mmol) was added dropwise and the solution stirred at −35° C. for 30 min then at −15° C. for 2 h. The reaction was diluted with EtOAc and stirred vigorously with sat'd Na2CO3 for 1 h. The organic phase was washed with twice with satd Na2CO3, dried (Na2SO4), filtered and concentrated. The resulting oil was purified by flash column chromatography (Biotage; 0%-100% EtOAc/hexane) to provide benzyl 3-(1-hydroxy-2-methoxy-2-oxoethyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (1.29 g, 50% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.20-7.49 (m, 7H), 7.08 (t, J=8.68 Hz, 2H), 5.11 (d, J=15.65 Hz, 3H), 4.22 (br. s., 2H), 3.67-3.89 (m, 5H), 3.14 (d, J=2.45 Hz, 1H), 2.99-3.11 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H). LCMS (M+H) calcd for C27H29N2O5: 461.20. found: 461.0.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:27][S-:28].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][S:28][CH3:27])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and 0.21 g of sodium methanethiolate in 5 ml of dimethylformamide are stirred at room temperature for 16 hours. The reaction mixture is poured into 100 ml of water and the aqueous mixture is extracted with 50 ml of ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (7:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-methylthiomethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.67 ppm (d, 1H), 3.62 ppm (d, 1H), 3.50 ppm (s, 3H), 2.43 ppm (s, 3H), 2.17 ppm (s, 3H), 1.36 ppm (2xd, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4](C2C=CC(C(O)(C#C)C)=CC=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[C:28]2[C:23](=[CH:24]C=CC=2)[C:22](O)=[CH:21][CH:20]=1.[O:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]3=2)[CH:33]=[CH:32][CH2:31]1>C1(C)C=CC=CC=1>[CH3:24][C:23]1([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[CH:28]1[CH:31]1[CH:32]=[CH:33][C:34]2[C:39](=[C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]3=[CH:36][CH:35]=2)[O:30]1
Reactant: Cc1ccc(O)c2ccccc12
Reactant: C1=Cc2ccc3ccccc3c2OC1
Reactant: C#CC(C)(O)c1ccc(N2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: CC1=CC=CC(C)(N2CCOCC2)C1C1C=Cc2ccc3ccccc3c2O1

Procedure:
2-p-Morpholinophenylpropargyl alcohol (3C) (8 g) and 4-methyl-1-naphthol (5 g) were dissolved in hot toluene (300 cm3) and the solution added to dry acidic alumina (200 g) in a flask fitted with a condenser. The mixture was heated (20 minutes) on a water bath, cooled and filtered. The residual alumina was extracted with chloroform (3×100 cm3). The combined organic filtrates and extracts were evaporated and the residual oil was purified by chromatography on acidic alumina (100 g) using a 1:20 mixture of dichloromethane and petroleum as eluant. The heliochromic fraction was separated and the solvent removed, leaving a dark brown oil. Two further chromatographic separations failed to improve the quality of the benzochromene (3D; R=Me). The brown oil darkens in air but its n.m.r. spectrum indicates less than 5% impurities.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2)=[O:4].[OH-].[Na+]>CO.O>[C:5]12([C:3]([OH:4])=[O:2])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2
Reactant: COC(=O)C12CC3CC(CC(C3)O1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C12CC3CC(CC(C3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of Example 81A (2.5 g, 12.6 mmol) in methanol/water (1:1, 100 mL) was added 5 N aqueous NaOH (3.8 mL, 19 mmol). The mixture was stirred at room temperature for 3 hours and then extracted with methylene chloride to remove unreacted starting material. The aqueous layer was acidified (pH˜2) with 6 N aqueous HCl and then extracted with methylene chloride. The combined acidic extracts were dried (Na2SO4), filtered and concentrated to afford 1.92 g of the title compound. MS (ESI+) m/z 183 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:19](=[O:20])[O:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:13]([CH3:14])[CH:12]=1
Reactant: CN=C=O
Reactant: Cc1cc(O)cc(C)c1Sc1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNC(=O)Oc1cc(C)c(Sc2ccccn2)c(C)c1
Reaction time: 6 h

Procedure:
4-(2-Pyridylthio)-3,5-dimethylphenol (161 g.), prepared in part A, and methylisocyanate (48 g.) was dissolved in dry toluene (1500 ml.) containing triethylamine (10 ml.) and the mixture was then stirred under reflux overnight. Further quantities of methyl isocyanate (22 g.) and triethylamine (10 ml.) were then added and refluxing was continued for a further 6 hours.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([N:16]1[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]1)=[O:33])=[CH:26]2
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc2[nH]c(C(=O)N3CCc4cc(C(=O)NOC5CCCCO5)ccc4C3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 152 mg 5-methoxyindol-2-carboxylic acid, 111 mg HOBt, 276 mg EDC, 0.603 ml triethylamine and 7 ml DMF is stirred overnight at ambient temperature. The reaction mixture is evaporated. The residue is then purified by silica gel chromatography. 50 mg of the title compound are obtained as yellowish foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10].[CH:21]1([NH:28][C@H:29]2[CH2:34][CH2:33][C@H:32](C)[CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]C1>CN(C1C=CN=CC=1)C.C1COCC1>[CH:29]1([N:28]([CH:21]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:9]([NH:1][C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[O:10])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Nc1ncc(C=O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](NC2CCCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.3 %

Procedure:
2-Amino-5-formylthiazole (2.56 g, 20.0 mmol), carbonyldiimidazole (3.25 g, 20.0 mmol) and a catalytic amount of DMAP were heated together in 60 mL THF at 50° C. for 3 h. To this solution was added cycloheptyl-(trans-4-methylcyclohexyl)amine (4.18 g, 20.0 mmol) and the reaction mixture was stirred for an additional 6 h at room temperature. The reaction mixture was concentrated and the crude product was purified by flash chromatography (silica, CH2Cl2-EtOAc, 4:1) to obtain 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (2.3 g, 31% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH2:34][CH3:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[N:25]([CH2:34][CH3:35])[C:26]4[C:31]([C:32]=3[CH:33]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.5 %

Procedure:
To a solution of the compound obtained in Step 1 (300 mg, 1.07 mmol), 3-amino-9-ethylcarbazole (270 mg, 1.28 mmol) and DIEA (0.560 mL, 3.21 mmol) in DMF (6 mL) was added HATU (610 mg, 1.60 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (225 mg, 0.476 mmol, 44.5%) as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:11]=2[N:10]([CH3:26])[C:9]1=[O:27])(=[O:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH:16]=[C:17]([Br:35])[C:11]=2[N:10]([CH3:26])[C:9]1=[O:27])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCCn1c(=O)c2c(ccn2Cc2ccc(Cl)cc2)n(C)c1=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2c(c(Br)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H, 4H,5H)-yl)propyl acetate (1.50 g, 3.85 mmol) in DCM (1 mL) was added NBS (0.68 g, 3.85 mmol). The reaction was stirred at RT for 1 h then diluted with DCM (10 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(7-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (1.2 g, 66.5% yield) as a solid. LCMS: MH+ 468 and TR=1.777 min. Used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][C:19]1[O:20][C:16]([CH3:15])=[CH:17][CH:18]=1)[CH:11]=[CH:10]2)=[O:28])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Reactant: CC(C)N=C=O
Product: Cc1ccc(CNc2ccc3cc(NC(=O)NC(C)C)ccc3n2)o1

Procedure:
The title compound, MS: m/e=339.3 (M+H+), was prepared in accordance with the general method of example 14 from 2-chloro-6-nitro-quinoline, 5-methyl-2-furanmethanamine and isopropyl isocyanate.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C-:24]#[N:25].[K+]>C(O)C.O>[C:1]([O:9][CH:10]1[CH2:15][CH2:14][C:13]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([C:24]#[N:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: C1CCNCC1
Reactant: O=C1CCC(OC(=O)c2ccccc2)CC1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CC1(N2CCCCC2)CCC(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
4-Benzoyloxycyclohexanone (13.5 g, 62 mmoles), piperidine hydrochloride (8.1 g, 67 mmoles) and potassium cyanide (4.25 g, 65 mmoles) were dissolved in 60 ml of 95% ethanol and 60 ml of water. The mixture was stirred at room temperature for 16 hours (overnight). The resulting solid material was collected by filtration. The filtrate was diluted with 100 ml of water and the solution was extracted with ether. Concentration of the ethereal solution gave more solid material. The combined solid material was recrystallized from 90% ethanol to give 14.5 g of white crystalline solid (mp: 165°-171° C.) in 75% yield.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[CH:21]([CH3:23])[CH3:22])(=O)OC.O.[NH2:26][NH2:27]>>[CH:21]([C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:27][N:26]=1)([CH3:23])[CH3:22]
Reactant: NN
Reactant: COP(=O)(CC(=O)C(C)C)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: CC(C)c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
off-white crystalline solid. MS (ESI): 231.0 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, (3-methyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCC(C(=O)OCC)n1cnc2cc([N+](=O)[O-])ccc21
Yield: 22.9 %

Procedure:
5-Nitrobenzimidazole (0.109 moles, 17.8 g.) was reacted with sodium hydride (0.122 moles, 4.9 g of 60% in mineral oil) and ethyl 2-bromooctanoate (0.102 moles, 22 ml) as in Example 11 to produce a mixture of the 5 and 6 isomer. The isomers were separated to yield 7.8 g of ethyl 2-(5-nitro-1H-benzimidazol-l-yl)octanoate.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:40])([CH3:39])NC(=O)C1C=CC([N+]([O-])=O)=CC=1.[Br:41]N1C(=O)CCC1=O>ClCCl>[Br:41][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:40])([CH3:39])[CH3:25])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: C[Si](C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 44 %

Procedure:
263.4 mg of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide (0.76 mmoles) were added to a solution of 256 mg (1.08 mmoles) of N-trimethylsilyl-4-nitrobenzamide in 50 ml of dichloromethane and the clear solution that was obtained after refluxing this mixture for one hour was cooled in an ice-bath. Bromination was carried out in half an hour using 194.4 mg (1.09 mmoles) of N-bromosuccinimide as the brominating agent and some precipitate was formed after 20 minutes irradiation to obtain a 44% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[C:17](=O)[C:18]([OH:20])=[O:19])=O)=[CH:3][CH:2]=1.[NH3:28]>C(O)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:28]=[C:17]([C:18]([OH:20])=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[C:13]([F:16])[CH:12]=3)[N:9]=2)=[CH:3][CH:2]=1.[C:18](=[O:20])=[O:19]
Reactant: O=C(O)C(=O)c1cc(F)ccc1NC(=O)c1ccc(-c2ccccc2)cc1
Reactant: N
Solvent: CCO
Product: O=C(O)c1nc(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc12
Product: O=C=O

Procedure:
To 6 g of 2-[(1,1'-biphenyl-4-yl)carbonylamino]-5-fluoro-α-oxobenzeneacetic acid in ethanol (120 ml) was added anhydrous ammonia (27 g). The resulting mixture was heated in a sealed tube under autogenous conditions at 120° for six hours. The reaction mixture was cooled and the solvent and ammonia removed by evaporation in vacuo. The dry residue was suspended in water (200 ml) and the mixture was acidified with acetic acid to pH 3-4. The precipitated solids were collected, washed thoroughly with water and air dried. Recrystallization from ethanol afforded the title compound, m.p. 168°-169° (dec. with evolution of CO2). Mass. Calcd. for C21H13FN2O2 : 344, found 344.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:13](=O)[O:12][C:10](=O)[C:9]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:8]23)=[CH:4][CH:3]=1.CSC1[NH:24][CH2:25][CH2:26][N:27]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:12])[N:24]3[CH2:25][CH2:26][N:27]=[C:13]23)=[CH:19][CH:20]=1
Reactant: CSC1=NCCN1
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(Cc2ccc(F)cc2)C2=NCCN12
Reaction time: 4 h

Procedure:
A solution of 5.4 g. of N-(p-fluorobenzyl)isatoic anhydride, 2.5 g. of 2-methylmercapto-imidazoline and one pellet (about 100 mg.) sodium hydroxide in 75 ml. of dioxane is refluxed with stirring for 4 hours. The resulting mixture is evaporated to dryness, the residue dissolved in methylene chloride, washed with water and extracted twice with 1N hydrochloric acid. The combined aqueous extracts are washed with methylene chloride and then with diethyl ether and made basic with sodium bicarbonate. The resulting precipitate is filtered off, washed thoroughly with water, dried by suction, dissolved in methylene chloride, dried with sodium sulfate, treated with charcoal and the methylene chloride exchanged for methanol to crystallize 10-(4'-fluorobenzyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 192°-195°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:11])[NH:6]2.[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=O.C(NCC)C.C([OH:36])C>>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([C:15]2[C:14]([CH3:13])=[C:4]([C:5]([OH:11])=[O:36])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]=2)=[CH:22][CH:21]=1
Reactant: CCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCO
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Solvent: CCNCC
Product: Cc1c(-c2ccc(-c3ccccc3)cc2)nc2cccc(Cl)c2c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A mixture of 4-chloroisatin (7.28 g, 0.04 mol), [J. Am. Chem. Soc., 1251 (1956)], 4-phenylpropiophenone (8.8 g, 0.04 mol), diethylamine (4 ml, 0.04 mol) and ethanol (200 ml) was stirred for a period of 18 hours at room temperature. The precipitated solids were collected by filtration, washed with ice-cold ethanol and air dried to yield the adduct (9.1 g, 58%) m.p. 209°-214° dec.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[S:24](N)([NH2:27])(=[O:26])=[O:25].O>O1CCOCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Yield: 100.4 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.25 gms, 0.7 mmole), sulfamide (70 mg) and water (10 mL) were added to 30 mL dioxane. The reaction mixture was refluxed for 24 hours, then cooled and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give 280 mg of (R)—N-[6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-aminosulfonamide, MS M+H=399.