Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[CH:12]=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:17][O:18]C(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[OH:15][C:14]1[C:2]([CH3:1])=[C:3]2[C:11](=[C:12]([CH:17]=[O:18])[C:13]=1[CH3:16])[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2
Reactant: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1c(O)c(C)c2c(c1C=O)OC1(CCC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (1 g) in DCM (20 mL) was added TiCl4 (0.53 mL) which turned the solution a red color. To the solution was added dichloromethyl methyl ether (0.42 mL) and stirred at 0° C. for 30 min and then at room temperature for 30 min. The solution was poured into water and the DCM was separated, dried and evaporated. The residue was purified by silica gel column eluting with 20% ethylacetate in hexane to give 700 mg of 6-hydroxy-5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-8-carbaldehyde as a yellow solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:12])[CH:22]=2)[CH:18]=[N:19]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc2cn[nH]c2c1
Product: O=C1Nc2ccccc2C1=C=Nc1ccc2cn[nH]c2c1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 3-hydroxymethylene-1,3-dihydro-indol-2-one and 6-aminoindazole according to Procedure J: 1H NMR (DMSO-d6): δ 13.02 (s, 1H), 10.86 (d, 1H), 10.51 (s, 1H), 8.7 (d, 1H), 8.0 (s, 1H), 7.74 (d, 1H), 7.63 (d, 1H), 7.51 (s, 1H), 7.15 (dd, 1H), 7.02 (m, 1H), 6.94 (m, 1H), 6.85 (d, 1H); ESI-MS m/z 275 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[F:28])=[C:10]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:11]=[CH:12][CH:13]=[O:14].[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32]>O1CCCC1>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[C:10]([C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)[CH:11]=[CH:12][CH:13]([OH:14])[CH2:33][C:31](=[O:32])[CH2:30][C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: Cc1ccc(C(=C(C=CC=O)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)c2nnnn2C)c2ccc(C)cc2F)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of 5,5-bis(2-fluoro-4-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (1.3 g, 3.4 mmoles) in tetrahydrofuran (15 mL) at -50° C. was added the dianion of t-butyl acetoacetate (3.4 mL of a 1M solution, 3.4 mmoles). After stirring for 2 hours, another 0.7 mL of dianion solution was added and the solution stirred for an additional hour. The reaction was quenched with 1N hydrochloric acid and the mixture extracted with methylene chloride. The extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 1.3 g of the title compound; m.p.=55°-63° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[C@@:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:14])[C@@:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[N:11]=[C:10]2[C:30]2[CH:31]=[N:32][C:33]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:34][C:35]=2[O:36][CH2:37][CH3:38])=[O:8])[CH2:3]1.[C:43](O)(=[O:47])[C:44]([NH2:46])=[O:45]>>[C:39]([C:33]1[N:32]=[CH:31][C:30]([C:10]2[N:9]([C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:43](=[O:47])[C:44]([NH2:46])=[O:45])[CH2:3]3)=[O:8])[C@@:13]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([CH3:14])[C@@:12]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)([CH3:22])[N:11]=2)=[C:35]([O:36][CH2:37][CH3:38])[CH:34]=1)([CH3:41])([CH3:40])[CH3:42]
Reactant: NC(=O)C(=O)O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)C(N)=O)C1

Procedure:
In a manner analogous to the method described in examples 99, (3-amino-pyrrolidin-1-yl )-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone was coupled with oxalamic acid (Aldrich) to give the title product. HR-MS (ES, m/z) calculated for C35H41Cl2N6O4 [(M+H)+] 679.2561, observed 679.2561.
Reaction SMILES: [I:1]Cl.ClCCl.[Cl:6][C:7]1[N:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[N:8]=[C:9]2[C:15]([I:1])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: Clc1cnc2[nH]ccc2n1
Reactant: ClI
Solvent: ClCCl
Solvent: c1ccncc1
Product: Clc1cnc2[nH]cc(I)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A 1 M solution of iodine monochloride in dichloromethane (9.84 mL, 9.84 mmol) was added dropwise to an ice-cold solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (6.75 g, 11.07 mmol) in anhydrous pyridine (12 mL). The reaction mixture was stirred at 0° C. for 60 minutes, then concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The crude product was stirred with 15 mL of dichloromethane. The yellow solid material was collected by filtration, washed with dichloromethane and dried to give 2.86 g of the title product. Yield: 66%. MS (DCI+) m/z 280 (M+H)+.
Reaction SMILES: NC1C=C(C=CC=1NC)OC1C=CN=C(C(NC)=O)C=1.N([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=C=S.IC>CO>[C:28]([OH:30])(=[O:29])[C:27]1[CH:31]=[CH:32][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(N=C=S)cc1
Agent: CNC(=O)c1cc(Oc2ccc(NC)c(N)c2)ccn1
Solvent: CO
Solvent: CI
Product: O=C(O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To {4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 4-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) and heated to 60° C. for 3 h. and concentrated the solvent and purified on silica gel to yield 4-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoic acid. MS: MH+=417.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8].C(O)C.[NH2:20][NH2:21]>O>[F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([NH:20][NH2:21])=[O:8]
Reactant: NN
Reactant: COC(=O)c1ccccc1OCC(F)(F)F
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccccc1OCC(F)(F)F

Procedure:
Methyl 2-(2,2,2-trifluoroethoxy)benzoate (1.22 g. 5.2 mmole), ethanol (15 ml.) and 5 ml. of 95 per cent hydrazine (4.75 g., 158 mmole) are refluxed for two hours, cooled, diluted with water (100 ml.) and cooled. The white solid product, 2-(2,2,2-trifluoroethoxy)benzoic acid hydrazide is recrystallized from ethanol, m.p. 102°-104°.
Reaction SMILES: Cl[C:2](Cl)([C:12]([CH3:14])=[O:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[H][H]>O.C1(C)C=CC=CC=1.[H][H]>[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[CH2:2][C:12]([CH3:14])=[O:13]
Reactant: CC(=O)C(Cl)(Cl)C(=O)Nc1ccccc1
Reactant: [H][H]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccccc1

Procedure:
2.46 g (0.01 mole) of α,α-dichloroacetoacetanilide was dissolved in 20 ml of water and 30 ml of toluene, and dehalogenated with hydrogen using 5% Pd/C as catalyst. Hydrogen was allowed to react until no more would be absorbed. The first equivalent (251 ml at 739 mm pressure and 25° C.) was absorbed in 50 minutes (a rate of about 5 ml/min) whereas the 274 ml (second equivalent) was absorbed at the much slower rate of about 0.9 ml/min. On the basis of the hydrogen absorbed, it was concluded that the dehalogenation had proceeded to remove both chlorines and hence to give acetoacetanilide. This was confirmed by filtering off the catalyst, separating off the water phase and finally isolating the product from the toluene. Obtained were 1.57 g or 89% of acetoacetanilide, mp 79°-84° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:19][N:8]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:23][C:20]2[CH:14]=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: CN(c1cccc(C(F)(F)F)c1)c1cc(Cl)ncn1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc(C(F)(F)F)c1)c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Temperature: 60 °C
Yield: 77.4 %

Procedure:
4-Chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (0.30 g, 0.001 mol.) and sodium carbonate (0.28 g, 0.003 mol.) in DMF are stirred for 10 minutes. m-Trifluoro-methylphenol (0.16 g, 0.001 mol) is added and the mixture is heated to 60° C. for 12 hours. The mixture is then cooled and poured into water. The product is extracted into ethyl acetate, washed with 10% sodium hydroxide, 10% hydrochloric acid, and 5% potassium carbonate, dried over Na2SO4, filtered, and is concentrated under reduced pressure. 6-(N-methyl-3-trifluoromethylanilino)-4-(3-trifluoromethyl-phenoxy)pyrimidine (0.16 g) obtained by chromatography as a white solid. M.p. 118-119° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:31][C@@H:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[O:19])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]([Mg]Cl)([CH3:43])[CH3:42].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:31][CH:30]2[C@:25]([CH3:39])([CH2:26][CH2:27][C@H:28]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:29]2)[C@@H:24]2[C@@H:10]1[C@H:11]1[C@:21]([CH3:40])([CH2:22][CH2:23]2)[C@@H:14]([C@H:15]([CH3:20])[CH2:16][CH2:17][CH:18]([OH:19])[CH:41]([CH3:43])[CH3:42])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Mg]Cl
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)CC4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 77.2 %

Procedure:
A solution of compound 2009 (0.374 g, 0.679 mmol) in anhydrous THF (10 ml) under argon was treated with isopropylmagnesium chloride (2 ml, 2M in THF, 5.43 mmol) at room temperature. The reaction was stirred until no starting material remained by TLC. Aqueous NH4Cl solution (10%, 15 ml) was added to quench the reaction and the THF was removed in vacuo. Distilled H2O (5 ml) was added and the solution extracted 3× with 15 ml CH2Cl2. The combined organic layers were washed with aqueous saturated NaCl solution (15 ml), dried over anhydrous MgSO4, filtered and the solvent removed in vacuo. Flash chromatography (SiO2, 12:1 hexanes:EtOAc) gave compound 2010 (0.3117 g, 77%) as a white foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar—H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.9 Hz, 1H, benzyl-CH2), 4.31 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.295 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.94-3.91 (m, 1H, THP, OCH2), 3.62-3.58 (m, 1H, THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, C-7 H), 3.32-3.31 (m, 1H, C-24 H), 0.81 (s, 3H, C-19 H), 0.63 (d J=2.4 Hz, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3605, 2900 cm−1; MS (CI/isobutane) m/z 595 (M+1, 10%), 401 (M+1-THP-Bn-H2O, 25%), 385 (M+1-THP-HOBn, H2O, 100%); m.p. 55-59° C.; Anal. calcd. for C39H62O4: C=78.74; H=10.50. Found: C=78.65; H=10.54.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1ccc(Cl)c(N=Cc2cccc(Br)c2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-4-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C@H:4]([O:11][C:12]1[C:17]([NH:18]C(=O)C)=[CH:16][C:15](C2C=CC=CC=2C([O-])=O)=[C:14]([N+:31]([O-:33])=[O:32])[CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O.Cl>C(O)C>[CH3:3][C@H:4]([O:11][C:12]1[C:17]([NH2:18])=[CH:16][C:15]([OH:1])=[C:14]([N+:31]([O-:33])=[O:32])[CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(-c2ccccc2C(=O)[O-])cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCC[C@H](C)Oc1cc([N+](=O)[O-])c(O)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Sodium hydroxide (687 mg, 17.2 mmol) was carefully added to a stirred solution of 50a (294 mg, 0.69 mmol), water (8 ml), and ethanol (25 ml). The reaction mixture was stirred overnight at 25° C. and then was neutralized with concentrated HCl. The resulting solution was extracted twice with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was concentrated and purified via flash chromatography over silica gel with gradual elutions from 90/10 to 80/20 (v/v, Hex/EtOAc). Evaporation of the solvent yielded 164 mg (84%) of an orange oil which eventually solidified.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:19]([O-])=O)=[C:16]([CH3:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCC[CH2:23]1>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[NH:19][CH:23]=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(COCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Yield: 22 %

Procedure:
5(2-Benzyloxy-ethoxy)-2-nitro-toluene (12.4 g, 43.0 mmol), N-N-dimethylfomamide dimethyl acetal (6.55 g, 51.6 mmol) and pyrrolidine (3.68 g, 51.6 mmol) were dissolved in N-N-dimethylfomamide (25 mL). The mixture was heated to 120° C. for 16 h. The solvent was evaporated under vacuum and the crude reaction was dissolved in 70% ethyl acetate/methanol (250 mL). The reaction was placed in a Parr Hydrogenator under a hydrogen atmosphere for 16 h with 10% palladium on carbon [10% w/w] (3.00 g) at 50 psi. The reaction was filtrated over celite and the crude mixture was purified via column chromatography with silica gel eluting with hexane/ethyl acetate to give the title compound (22% yield). 1H NMR (CDCl3) δ 7.27–7.41 (m, 6H), 7.19 (t, 1H, J=2.5 Hz), 7.13 (d, 1H, J=2.3 Hz), 6.91 (dd, 1H, J=2.5, 8.8 Hz), 6.48 (m, 1H), 4.67 (s, 2H), 4.21 (m, 2H), 3.87 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:23]([OH:25])=O)=[CH:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[CH3:26][N:27]([CH3:28])[C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:14][CH:15]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(C(=O)O)c3ccccc32)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 48.4 %

Procedure:
A solution of the above crude carboxylic acid (300 mg, ca. 0.87 mmol), dimethylamine (2.0M in THF, 0.88 ml, 1.76 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 338 mg, 1.76 mmol), hydroxybenzotriazole hydrate (178 mg, 1.31 mmol) in DMF (10 ml) was stirred at room temperature for 24 h, poured into water, extracted with EtOAc (three times). The extracts were dried (Na2SO4), concentrated and purified by flash chromatography (hexane/EtOAc 1:0 to 0:1) to give tert-butyl 4-(dimethylcarbamoyl)-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B2) (156 mg). LC-MS: m/e=371.1 (M+H), 315.0 (M+H−C(CH3)3). Rt=3.16 min. 1H-NMR (500 MHz, CDCl3): 7.32-7.27 (m, 2H), 7.13 (t, 1H), 6.97 (d, 1H), 6.00 (t, 1 H), 3.91 (br. d, 2H), 3.04 (br. s, 3H), 2.97 (t, 2H), 2.85 (br. s, 3H), 2.44 (br. s, 2H), 1.85 (m, 2H), 1.70 (d, 2H), 1.40 (s, 9H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]([C:14]1[N:23]=[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=2)[N:15]=1)OC)=[O:7])C.Cl.[CH2:38](O)C>>[C:6]([CH2:8][CH2:9][CH2:10][N:11]([C:14]1[N:23]=[C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]#[N:36])[CH:20]=2)[N:15]=1)[CH3:38])([OH:5])=[O:7]
Reactant: CCOC(=O)CCCN(OC)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(CCCC(=O)O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
20 ml of ethanol and 2.61 ml of a 1N aqueous solution of sodium hydroxide were added to 389 mg of 2-[N-(3-ethoxycarbonylpropyl)-N-methoxyamino]-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 4 hours and at 50° C. for 10 minutes and neutralized with 1N hydrochloric acid. The crystals precipitated were recovered by filtration, purified by silica gel column chromatography (chloroform/methanol) and recrystallized from ethanol/acetone/water to give 305 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=1>O1CCCC1>[CH3:14][C:12]1[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCOCC2)nc1-c1ccc(C)cc1
Yield: 80.7 %

Procedure:
Methyl 2-(4-methyl-2-morpholino-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from morpholine (0.107 mL; 1.20 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.100 g; 0.239 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-25%) in heptane furnished 74 mg (81%) of the title compound as an oil. ESI/APCI(+): 384 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:28])/[C:18](/[C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)=[N:19]\[O:20][CH3:21])[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+]=[N-].CO.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>[Ni].CO>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH2:1][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:28])/[C:18](/[C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)=[N:19]\[O:20][CH3:21])[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Agent: [Ni]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1
Yield: 45 %

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A: 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1(B(O)O)C=CC=CC=1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO>O>[C:17]1([CH:23]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1](=[O:7])[CH2:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CCCC1
Reactant: Cc1ccccc1
Agent: OB(O)c1ccccc1
Solvent: O
Solvent: CO
Product: O=C1CCCCC(c2ccccc2)C1
Temperature: 50 °C
Yield: 83 %

Procedure:
Next, the scope of boronic acids that can be utilized was briefly examined. More specifically, the general experimental procedure for the 1,4-addition of arylboronic acids to enones will be described using 2-cyclohexen-1-one and phenylboronic acid. A mixture of 2-cyclohexen-1-one (96 mg, 1 mmol) and phenylboronic acid (158 mg, 1.3 mmol) was taken in a round bottom flask. A toluene solution (3 ml) containing Rh(acac)(CO)2 (5 mg, 0.02 mmol) and JanaPhos (70 mg, 0.03 mmol, Rh/P=1/3) was added to it in an inert atmosphere. A solution of methanol and water (1:1, 0.5 ml) was added to it via syringe. The reaction mixture was heated at 50° C. for 15 hours until the starting material was consumed as indicated by TLC. Then 25 ml methanol was added to it mixture and the catalyst was precipitated out as a white solid. It was filtered out by a Schlenk filter and underwent for the consecutive runs. The filtrate was evaporated under reduced pressure to obtain the crude product which was further purified by column chromatography (10% ethyl acetate in hexane) to obtain the pure product (144 mg, 83% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCCOCCOC>[N:12]1([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1cc2ccccc2cn1
Solvent: COCCOCCOC
Product: c1ccc2cc(N3CCNCC3)ncc2c1
Yield: 92.1 %

Procedure:
2.0 g of 3-chloroisoquinoline are boiled under reflux for 120 hours with 20 g of piperazine in 100 ml of diethylene glycol dimethyl ether. Working up as in Example 1 gives 2.4 g of 3-(piperazin-1-yl)-isoquinoline, melting point 95°-96°; its hydrochloride decomposes at 266°-268° C.