Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[C:29]1([CH2:39][O:40][NH2:41])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[C:29]1([CH2:39][O:40][NH:41][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: NOCc1cccc2ccccc12
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Solvent: CN(C)C=O
Product: O=C(NOCc1cccc2ccccc12)c1ccccc1NCc1ccncc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C, 150 mg) and O-naphthalen-1-ylmethyl-hydroxylamine (preparation 53, 1.05 eq.) was dissolved in DMF and the stirred mixture was heated to 50° C. The reaction mixture was stirred at this temperature for 15 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) and gave the title compound. 13C-NMR (DMSO-d6) δ 167.3, 149.5, 149.1, 148.4, 133.2, 132.5, 131.9, 131.4, 129.3, 128.4, 128.2, 126.3, 126.1, 125.9, 125.2, 124.8, 121.9, 114.8, 113.4, 111.5, 75.3, 44.8.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Clc1cc(Cc2ccccc2Br)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccccc2Br)ncn1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.06 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2-bromobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(2-bromobenzyl)pyrimidine (the present compound (103)).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)ccc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-fluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 9-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzdiazepine is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[NH:36][N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([F:46])[CH:40]=3)[C:31]=12>CN(C=O)C>[NH2:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([F:46])[CH:40]=3)[C:31]=12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Reactant: Nc1ncnc2[nH]nc(-c3ccc(O)c(F)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(O)c(F)c1)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of compound (8) (200 mg, 0.502 mmol) and potassium carbonate (83 mg, 0.60 mmol) in DMF (2.0 mL) was added a solution of 4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenol (see Table 1, below) (148 mg, 0.602 mmol) in DMF (2.0 mL) and the reaction mixture stirred at RT for 18 hr. The solvent was removed in vacuo and the crude material was purified by flash column chromatography, eluting with 5% methanol in DCM, to afford the title compound, Intermediate D (81 mg, 27%) as a off-white solid: m/z 606/608 (M+H)+ (ES+) (Method B).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].[N:22]1([C:27]2[CH:28]=[CH:29][C:30](O)=[N:31][CH:32]=2)[CH:26]=[N:25][CH:24]=[N:23]1>CN(C=O)C>[N:22]1([C:27]2[CH:28]=[CH:29][C:30]([O:1][CH2:2][CH2:3][C@@H:4]3[CH2:6][C@@H:5]3[CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]4([CH3:19])[CH2:18][CH2:17]4)=[O:14])[CH2:9][CH2:8]3)=[N:31][CH:32]=2)[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCO)CC2)CC1
Reactant: Oc1ccc(-n2cncn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4cncn4)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (100 mg, 0.37 mmol) in DMF (5 mL) was added NaH (22 mg, 0.56 mmol) in small portions. After total addition, the grey solution was stirred at RT for 10 minutes and then cooled to −26° C. via dry ice/methanol bath. A solution of 5-(1H-1,2,4-triazole-1-yl)pyridin-2-ol (120 mg, 0.74 mmol) in DMF (0.5+0.5 mL) was added via syringe drop-wise and the resulting mixture was stirred for 30 minutes. The reaction was quenched with a cold solution of NH4Cl (10 mL) via syringe. Water (10 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organics were combined, dried by MgSO4, filtered, and concentrated under reduced pressure. The residue was purified via flash column chromatography (80 g silica gel, ISCO, eluant 5% methanol in DCM) to afford the product after being concentrated to dryness under reduced pressure. LC/MS (m/z): 412 (M+H)±. LC/MS (m/z): 424 (M+H)+. GPR119 Human EC50: 0.88 nM
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3CCC[C:18]=3[CH:19]=2)[N:14]=1)=[O:10]>C(Cl)Cl>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3[CH2:18][CH2:3][C:1](=[O:5])[C:2]=3[CH:19]=2)[N:14]=1)=[O:10]
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Reactant: CC(C)(C)OO
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
To a stirred solution of (Ph3SiO)2CrO2 (L. M. Baker and W. L. Carrick, J. Org. Chem. 1970, 35, 774) (10.6 mg, 0.017 mmol) in CH2Cl2 (5 ml) was added sequentially aqueous 70% tert-butyl hydroperoxide (0.18 ml, 1.3 mmol) and 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (0.1 g, 0.33 mmol). The mixture was stirred at room temperature with protection from the light for 24 h. The solvents were removed in vacuo and the residue purified by column chromatography (20 g of silica gel) eluting with a gradient of 10-30% EtOAc in CHCl3 to yield 2-(2,2-dimethylpropionyloxyrnethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione as a white solid (47 mg, 45%); m.p. 185-190° C.; 1H-NMR (DMSO-d6) δ 1.23 (s, 9H, CMe3), 2.72 (m, 2H, 7-H), 3.25 (m, 2H, 8-H), 5.00 (s, 2H, 2-CH2), 7.70 (s, 1H, 9-H), 8.29 (s, 1H, 5-H), 12.20 (br, 1H, NH); MS (FAB, m/z). Found 315 [(M+H)+, 100%], 337 [(M+Na)+, 75%]; HRMS: measured 315.1360; calculated for C17H19N2O4 (M+H)+: 315.1345. Found C, 64.18; H, 5.72; N, 8.81. C17H18N2O4.0.2H2O requires C, 64.23; H, 5.79; N, 8.82%.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1C(C1C=CC(Cl)=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1>O1CCOCC1.[Cu]I>[Cl:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:2]2[CH:24]=[N:23][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:9](=[O:10])[C:4]=3[CH:3]=2)=[CH:50][CH:49]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3ccc(Cl)cc3)cnc21
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To a mixture of 6-(4-chlorophenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4400 mg, 1 mmol), CuI (24.7 mg, 0.13 mmol), Cs2CO3 (650 mg, 2 mmol), 2-(dimethylamino)acetic acid (51.5 mg, 0.5 mmol) in dioxane (6 mL) was added 4-chlorophenol (192 mg, 1.5 mmol). The reaction was heated at 140° C. (MW) for 1.5 h, cooled to RT and filtered. The filtrate was diluted with EA (5 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 give 6-(4-chlorophenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (250 mg, 56.2% yield) as an oil. LCMS: MH+ 446 and TR=3.000 min.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[CH2:10]([C:4]1[N:3]=[CH:2][NH:7][C:6](=[O:8])[C:5]=1[F:9])[CH3:11]
Reactant: CCc1nc(Cl)[nH]c(=O)c1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1nc[nH]c(=O)c1F
Reaction time: 8 h

Procedure:
To the product of part (iv) (6 ) g in ethanol (60 ml) was added sodium acetate (5.5 g) and 5% palladium-on-carbon (0.6 g). The mixture was hydrogenated at 3 atmospheres pressure for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated to a volume of 10 ml then mixed with water (2 ml) and dichloromethane (80 ml). Toluene (32 ml) was added and the solution was concentrated to a volume to 5-6 ml and then mixed with further toluene (8 ml). The crystals of the title compound that separated were isolated by filtration and characterised by 1H-NMR and mass spectrometry (Yield=3.9 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O.CN([CH:20]=[O:21])C>>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CCOC(C)=O)c1ccccc1
Reactant: CN(C)C=O
Solvent: O
Product: CCN(CCOC(C)=O)c1ccc(C=O)cc1
Temperature: 5 °C

Procedure:
To 60 ml of dry DMF in a 250 ml-flask, equipped with a CaCl2-tube, cooled in an ice bath, 29.1 (310 mmol) of OPCl3 is dropwise added and the mixture is stirred for two h at 5° C. Then, 58.5 g (288 mmol) of 16, dissolved in 30 ml of dry DMF, is added and the reaction mixture is stirred for 3 h at 90° C. After cooling down, the mixture is poured into iced water, stirred for 30 min and extracted with dichloromethane. The organic layer is washed with a saturated NaHCO3-solution, with brine and dried over MgSO4. After evaporation of the solvent, the compound is purified with column chromatography (silicagel; eluent:dichloromethane/acetonitrile (90:10 v/v)) and collected as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=[CH2:7].[K]>[Fe]>[CH3:7][C:6]1[CH:5]=[CH:4][C:3]([CH:2]([CH3:10])[CH3:1])=[CH:9][CH:8]=1
Reactant: C=C1CCC2CC1C2(C)C
Agent: [Fe]
Agent: [K]
Product: Cc1ccc(C(C)C)cc1
Yield: 90 %

Procedure:
High density fuel candidates have been synthesized in up to 90% yield from β-pinene, a renewable strained bicyclic compound derived from wood and plant sources. These novel synthesis are based on heterogeneous acidic catalysts (also referred to as heteropolyacidic catalysts) including Montmorillonite-K10 and Nafion® NR-50 which promote selective isomerization and dimerization of pinenes under moderate conditions (100° C., atmospheric pressure). Montmorillonite clays have been used as catalysts for number of organic reactions and offer several advantages over classical acids. For example, the strong acidity, non-corrosive properties, mild reaction conditions, high yields, selectivity, low cost, and the ease of setting and working-up. The mesoporous Montmorillonite clays, which are dioctahedral phyllosilicates, are composed of hydrated sodium calcium aluminium magnesium silicate hydroxide (Na,Ca)0.33(Al,Mg)2(Si4O10)(OH)2.nH2O, with an octahedral layer (AlO6 units) sandwiched between two tetrahedral layers (SiO4 units). Potassium, iron, and other cations are common substitutes. These clays typically have a surface area of 220-270 m2/g. Montmorillonite-K10 is a strong Bronsted and Lewis acidic catalyst shown to be a highly active catalyst for dimerization but is also active in the ring opening of β-pinene followed by dehydrogenation to produce p-cymene. This limited the yield of dimer to about 75%. Nafion catalysis was capable of producing dimers in up to 90% yield but was less active than the acidic clay. Amberlyst-15, a common industrial catalyst had very poor activity and conversion even at 150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19]O)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH2:19][Br:28])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CO)c(C(F)(F)F)c2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CBr)c(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylbenzyl alcohol (0.63 g, 1.7 mmol) from Step 3 above in ether (10 mL) at 0° C. was added CBr4 (0.85 g, 2.6 mmol) and triphenylphosphine (0.68 g, 2.6 mmol). The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 14 h. The ether solution was decanted away from the gummy precipitate of triphenylphosphine oxide that had formed and the solvent was removed unde reduced pressure. The residue was purified by pressurized silica gel column chromatography using 5% EtOAc:hexanes as eluant to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylbenzyl bromide as a colorless gum (HPLC retention time=12.6 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:18][C:19]#[N:20])[CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH2:18][CH2:19][NH2:20])[CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[O:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#CC[C@@]1(c2ccc(F)cc2)CCOC2(CCCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC[C@@]1(c2ccc(F)cc2)CCOC2(CCCC2)C1
Temperature: 25 °C

Procedure:
To a solution of 2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (500 mg, 1.8 mmol) in anhydrous ether (30 ml) at 0° C. was added dropwise LAH (1.0 M in Et2O, 3.7 ml, 3.7 mmol). The reaction was then warmed up to room temperature. After 2 h the reaction was quenched with 1 ml H2O, 0.2 ml 15% NaOH and then 1 ml H2O. The reaction mixture was extracted with Et2O (3×30 ml), dried over NA2SO4 and concentrated to give 2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine as an yellow oil, which used without further purification (500 mg, 100%, m/z 277.2 [M+H]+ observed).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Cl.[CH:18](OC(C)C)(C)C>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([O:9][CH3:18])=[O:8]
Reactant: O=C(O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(C)OC(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)C=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
2.25 g of 3,4-dihydroxy-5-nitrocinnamic acid are dissolved in 50 ml of methanol and hydrochloric acid gas is introduced into this solution for 10 minutes. After 1 hour 50 ml of isopropyl ether are added thereto, and the separated precipitate is filtered under suction and washed with isopropyl ether. After recrystallization from methanol/ether there is obtained methyl 3,4-dihydroxy-5-nitrocinnamate in the form of yellow crystals of m.p. 186°-187°.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C[Si](C#N)(C)C>C(#N)C>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[O:24])=[CH:21][CH:20]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)CC(=O)C(C(=O)c2ccc(Cl)cc2)C(=O)C1
Temperature: 25 °C

Procedure:
5,5-dimethylcyclohexane-1,3-dione (7.01 g, 0.05 mole), acetonitrile (80 ml), and triethylamine (21 ml, 0.15 mole) were combined in a flask, and placed under a nitrogen atmosphere. A solution of 4-chlorobenzoyl chloride (6.4 ml, 0.05 mole) in acetonitrile (20 ml) was added over 15 inutes while stirring and cooling with an ambient temperature water bath. Trimethylsilyl cyanide (0.33 ml, 2.55 mmole) was added, and the reaction was heated and stirred at 40° C. for 3 hours whereupon the reaction was complete.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:9]1(O)[CH:14]=[CH:13][CH:12]=[CH:11]C=1>>[C:1]([O:7][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1)(=[O:6])[C:2]([O:4][C:5]1[CH:9]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: COC(=O)C(=O)OC
Reactant: Oc1ccccc1
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
Diphenyl oxalate was prepared from dimethyl oxalate and phenol by using the apparatus shown in FIG. 3 including first and second distillation reactors and a refining distillation column.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)(=[O:3])[CH3:2]>CCO.[Ni]>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[NH2:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)NCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To a solution of compound 15 (1.13 g, 3 mmol) in EtOH (30 mL) was added Ra—Ni (0.20 g, 10% wet basis) and the mixture was subjected to hydrogenation in Parr apparatus at 20 psi for 6 hours. After filtering over the pad of celite, the solution was concentrated and purified over silica column, eluting with CH2Cl2:MeOH (95:5) and then changing to (92:8) afforded compound 16 as a light yellow thick oil (0.85 g, 82%). IR (KBr) νmax. cm−1: 3441, 3421 (NH), 3042 (Ar—H), 2960 (Alph-H), 1699, 1696 (C═O), 1607, 1577 (C═C), 1240 (C—N), 1165 (C—O). 1H NMR (500 MHz, CDCl3) δ=1.48 (s, 9H, (C(CH3)3), 2.16 (s, 3H, CH3), 3.38 (br. s, 4H, 2CH2), 3.52 (br. s, 4H, 2CH2), 5.28 (br. s, 2H, NH2), 5.49 (s, 2H, CH2), 6.78 (dd, 1H, J=2.3, 9.3 Hz, H-6), 6.80 (br. s, 1H, H-2), 6.87 (d, 1H, J=9.2 Hz, H-5). 13C NMR (125.7 MHz, CDCl3) δ=20.97 (CH3), 28.35 (C(CH3)3), 42.53 (CH2), 46.26 (CH2), 62.54 (CH2), 79.85 (C(CH3)3), 112.10 (aromatic-C), 112.38 (aromatic-C), 117.09 (aromatic-C), 130.22 (aromatic-C), 135.03 (aromatic-C), 143.02 (aromatic-C), 154.58 (CO), 170.51 (CO). Calculated (%) for C18H28N4O3 (348.22); C, 62.05; H, 8.10; N, 16.08. found (%); C, 62.00; H, 8.15; N, 16.00.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=[O:5].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:12]([O:5][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CC(C)CCCCCCCCCCO
Product: CC(C)CCCCCCCCCCOC(=O)CC(C)CC(C)(C)C

Procedure:
Preparation according to Example 3 from 3,5,5-trimethyl-hexanoic acid and isotridecyl alcohol (mixture of methyl branched primary tridecanols from Hoechst); colorless liquid of medium viscosity;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:32][CH2:31][CH2:30][CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN1CCN(CCCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12

Procedure:
A stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methyl ester (440 mg, 1.30 mmol) in 1,4-dioxane (10 mL) is treated with 3-(4-methyl-piperazin-1-yl)- propylamine (610 mg, 3.90 mmol) and diisopropylethylamine (500 mg, 3.90 mmol), the resultant mixture is heated at 90° C. under nitrogen for 16 hours. After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 1-10%, the title compound is isolated as a solid (310 mg, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:33][CH:32]([O:35][CH3:36])[O:31][CH3:30])[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(CBr)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21)OC
Temperature: 50 °C
Yield: 136.2 %

Procedure:
To a solution of (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (135 mg, 1 mmol) in DMF (1 mL) was added KHMDS (0.5 M in THF, 1.1 mL) was dropwise at room temperature. The mixture was stirred for half an hour before adding bromoacetaldehyde dimethyl acetal (95 mg, 0.55 mmol). The mixture was warmed to 50° C. and stirred at that temperature for 2 hours. The mixture was poured into water, extracted with ethyl acetate (3×15 mL), dried and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) gave the desire product as colorless oil (268 mg, 75%). LC/MS m/e calcd. for C20H20ClNO3: 3570, observed (M+H)+: 358.7.