Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C@H:6]([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][C:4](=[O:25])[C:3]=1[O:26]/C=C/C.CO>C(O)(=O)C>[OH:26][C:3]1[C:4](=[O:25])[O:5][C@@H:6]([CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:2]=1[OH:1]
Reactant: C/C=C/OC1=C(O)[C@H](CC/C=C\CCCCCCCCCCCCCC)OC1=O
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCC/C=C\CC[C@@H]1OC(=O)C(O)=C1O

Procedure:
To a 100 mL round bottom flask was added, under nitrogen, 0.2 g (0.49 mmol) (S)-4-hydroxy-5-[(Z)-3-octadecenyl]-3-[(E)-propenyloxy]-2(5H)-furanone was dissolved in 60 mL of 50% aqueous acetic acid. The solution was heated at reflux (oil bath) for 15 minutes, cooled, and the aqueous acetic acid removed in vacuo. The residue was purified over silica gel using 12% methanol in chloroform as eluant to give 0.17 g (95%) of white waxy solid: mp 64°-66°C; [α]D25 -9.9° (C=0.5, CH3OH); IR (neat, cm-1) 3421(br), 2917, 2850, 1754, 1668, 719; 1H NMR (D3COCD3) δ5.49-5.28 (m, 2H), 4.67 (dd, J=3.4, 7.8 Hz, 1H), 2.32-1.88 (m, 4H), 1.69-1.51 (m, 2H), 1.44-1.25 (m,. 24H), 0.87 (t, J=6.7 Hz, 3H); HRMS calculated for C25H38O4 (M+) 366.2770, found 366.2780; analysis calculated for C22H38O4 +0.33 H2O: C, 70.93; H, 10.46; Found: C, 70.73; H, 10.31.
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19]CC)=[O:18].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:3]3[C:17]([OH:19])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
To a solution of ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Cl:6][Si:7](Cl)([Cl:9])[Cl:8]>>[CH2:1]([O:5][Si:7]([Cl:9])([Cl:8])[Cl:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: Cl[Si](Cl)(Cl)Cl
Product: CCCCO[Si](Cl)(Cl)Cl

Procedure:
On the other hand, 14.8 g (0.2 moles) of n-butanol was used in place of methanol as used in Example 3(b) and was reacted with 34.0 g of tetrachlorosilane in the same manner as in Example 3(b). There was thus obtained a solution of n-butoxytrichlorosilane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O.CO>[OH:28][CH2:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:19]2[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C(=O)O)cc23)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CO)cc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinoline-6-carboxylic acid (4.48 g, 10 mmol) in tetrahydrofuran (50 ml) were added dropwise ethyl chlorocarbonate (1.6 ml, 15-mmol) and N-methylmorpholine (1.6 ml, 15 mmol) at 0° C., and after the completion of the dropwise addition, the mixture was stirred at 0° C. for 10 min. Sodium tetrahydroborate (1.32 g, 35 mmol) and methanol (10 ml) were added to the reaction mixture and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl [6-(hydroxymethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (2.42 g, yield 55%) as white crystals.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:14][C:13]([OH:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:22])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:15][C:13]1[CH2:14][N:10]([C:2]([CH3:1])([CH3:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11](=[O:22])[C:12]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(c1ccccc1)N1CC(O)=C(c2ccccc2)C1=O
Solvent: c1ccncc1
Product: CC(=O)OC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
5 g (17 mmol) of 1-(α,α-dimethylbenzyl)-4-hydroxy-2-oxo-3-phenyl-3-pyrroline prepared by the method of Reference Example 13, was dissolved in a solution of 10 ml of acetic anhydride and 20 ml of pyridine, and the solution was stirred at room temperature for one day and night. Ice water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was thoroughly washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from isopropyl ether to obtain 4.2 g (yield: 81%) of the desired compound.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH2:19][CH2:20][CH3:21]>O1CCCC1>[C:1]1([C:7]2[N:8]([CH2:19][CH2:20][CH3:21])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(-c2ccccc2)nc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 3.0 g 2-phenylbenzimidazole and 60 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.41 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes, then cooled to 10 C. 3.1 g 1-iodopropane were added and the mixture was heated to 55 C for 16 hours. Another 0.8 g 1-iodopropane were added and the temperature was held at 55 C for two hours. The mixture was cooled to 22 C, quenched slowly with 40 ml water, extracted with ethyl acetate and washed with water. Following solvent removal, the product was purified by silica gel chromatography using straight 67% ethyl acetate, 24% hexane and 9% methanol. An oil was obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:3]([NH:2][S:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)(=[O:29])=[O:28])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NC(CC(=O)O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
1.1 g of 3-amino-3-(2-hydroxyphenyl)propionic acid hydrochloride, prepared according to J. Agric. Food Chem., 1977, 25, 965, are dissolved in 25 ml of dioxane and 10 ml of 1N NaOH are added; 1.12 g of 2-naphthalenesulphonyl chloride are gradually added while maintaining the pH at 11.5-12 by addition of 1N NaOH. After stirring for 2 hours at RT, the reaction medium is diluted in water, washed with EtOAc (twice) and then acidified to pH=1.5-2 by addition of 6N HCl. The white precipitate formed is drained, washed with water and dried in order to obtain 0.82 g of the expected product, m.p.=190-200° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[O:6][CH2:5]1.Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:14][C:12]1[CH:11]=[CH:10][C:8]2[O:9][CH:4]([CH2:3][N:2]([CH3:1])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=4[CH:29]=3)[CH2:5][O:6][C:7]=2[CH:13]=1
Reactant: CNCC1COc2cc(O)ccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2cc(O)ccc2O1
Temperature: 96 °C
Yield: 24.9 %

Procedure:
N-Methyl-2,3-dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (3.68 g, 17.3 mmole), 7-(3-chloropropoxy)coumarin (4.15 g, 17.4 mmole), diisopropylethylamine (4.4 ml, 25.3 mmole) and sodium iodide (2.59 g, 17.3 mmole) were combined in 75 ml of DMF and heated at 96° C. for 26 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was column chromatographed on silica gel using first 1% methanol/dichloromethane, then 2% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue crystallized from isopropanol with addition of 4N HCl/isopropanol and diethyl ether to give 1.71 g of white solid, monohydrochloride, quarter hydrate, m.p. 186°-193° C.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1COCC1.C([Si](C(C)C)(C(C)C)[S-])(C)C.[Li+].I[C:40]1[CH:41]=[CH:42][C:43]2[CH:52]3[CH:48]([N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50][CH2:51]3)[CH2:47][O:46][C:44]=2[CH:45]=1>O1CCOCC1.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>[CH3:10][CH:9]([Si:4]([S:5][C:40]1[CH:41]=[CH:42][C:43]2[CH:52]3[CH:48]([N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:50][CH2:51]3)[CH2:47][O:46][C:44]=2[CH:45]=1)([CH:1]([CH3:3])[CH3:2])[CH:6]([CH3:8])[CH3:7])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OCC21
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Si]([S-])(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc2c(c1)OCC1C2CCN1C(=O)OC(C)(C)C)(C(C)C)C(C)C
Reaction time: 2.5 h

Procedure:
Anhydrous dioxane was sparged with argon gas for 1 h before being used. Triisopropylsilanethiol (0.95 mL, 4.4 mmol) was dissolved into anhydrous 1,4-dioxane (3 mL) and to this 1.0 M lithium hexamethyldisilazide in THF (4.2 mL, 4.2 mmol) was added slowly. The reaction was stirred for 2.5 h. A portion of the lithium triisopropylsilanethiolate solution (2.64, 1.32 mmol) was added to a suspension of tert-butyl 7-iodo-1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole-3(2H)-carboxylate P02 (480 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.12 mmol) in 1,4-dioxane (2 mL) under argon. The reaction mixture was stirred at 60° C. for 16 h and the solvent was evaporated. The residue was triturated with anhydrous hexane, filtered through a plug of celite, and the filtrate concentrated to yield the crude product which was used in the next step without further purification. MS m/z 408 [M−tBu+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][C@H:15]([CH3:18])[CH2:14][NH:13]1>CN1C(=O)CCC1>[CH3:11][C@H:12]1[CH2:17][NH:16][C@H:15]([CH3:18])[CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1

Procedure:
An NMP solution of fluoro-4-nitrobenzene and (±)-trans-2,5-dimethylpiperazine was stirred at an oil bath temperature of 120° C. for 3 hours to obtain (±)-trans-2,5-dimethyl-1-(4-nitrophenyl)piperazine, which was further treated in a similar manner to Example 4 to obtain an objective compound.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1OC)=O.Cl.COC=O.C([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=O.[OH-].[K+]>CO>[CH2:21]1[CH2:20][CH:19]2[CH:7]3[CH:1]([N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]4[N:18]2[CH2:23][CH2:22]1)[NH:3][CH2:4][CH2:5][CH2:6]3
Reactant: O=CN1CCCCC1
Reactant: COC1CCCCN1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COC=O
Product: C1CNC2C(C1)C1CCCCN1C1CCCCN21

Procedure:
28.6 g (0.2 mol) of 1-formyl-2-methoxypiperidine and 0.3 mol of methanolic HCl were refluxed for 4 hours. At atmospheric pressure in a boiling range of from 30° to 50° C. a mixture of formic acid methyl ester and methanol, which could be re-used for the preparation of 1-formyl-piperidine, was distilled off. The distillation residue was added dropwise to a solution of 21.7 g of KOH (85% strength, 0.33 mol) in methanol and the whole was refluxed for 4 hours. Working up as described in Example 4 yielded 13.3 g (80.1% of the theory) of isotripiperidein melting at 87°-91° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1)[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:11]1([F:15])[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[C:4]([CH2:16][O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:3]=[C:2]([NH:28][C:27]3[CH:29]=[CH:30][C:31]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:25]([O:24][CH3:23])[CH:26]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: FC(F)(F)COCc1cc(N2CCC(F)(F)CC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(N3CCC(F)(F)CC3)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-chloro-4-(4,4-difluoropiperidin-1-yl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (97 mg, 0.28 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (57 mg, 0.28 mmol), cesium carbonate (183 mg, 0.56 mmol), palladium acetate (9 mg, 0.04 mmol) and 2-(dicyclohexylphosphino)biphenyl (15 mg, 0.04 mmol) was stirred under argon at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica gel plug which was washed with 10% solution of methanol in ethyl acetate (75 mL). The eluate was concentrated in vacuum and the residue was purified by preparative HPLC to give the title compound as a gum, 103 mg (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:29]1[C:30]([CH3:35])([CH3:34])[C:31](=[O:32])[N:33]=[C:21]1[C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCCCNC(C)(C)C(N)=O
Product: CCCCN1C(c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)=NC(=O)C1(C)C

Procedure:
Compound 9 was synthesized from 4a (252 mg, 0.66 mmol) and 5d (161 mg, 1.01 mmol) as a white solid (141 mg, 42%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.44 (d, 1H), 7.29-7.24 (m, 3H), 7.13 (d, 1H), 7.05 (d, 2H), 3.80-3.78 (m, 2H), 2.39 (s, 3H), 1.69-1.64 (m, 2H), 1.40 (s, 6H), 1.26-1.22 (m, 2H), 0.81 (t, 3H); ESMS m/z: 503.1 (M+1).
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=[C:12]([F:20])[CH:11]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:17]1[S:18][C:14]2[CH:13]=[C:12]([F:20])[CH:11]=[C:10]([F:9])[C:15]=2[N:16]=1
Reactant: Cl
Reactant: Nc1nc2c(F)cc(F)cc2s1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Fc1cc(F)c2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution containing copper chloride (II) (0.87 g, 6.45 mmol) and tri(ethylene glycol) dimethyl ether (3 mL) in acetonitrile (50 mL) was added isoamyl nitrite (0.94 g, 8.06 mmol), and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 4,6-difluoro-1,3-benzothiazol-2-amine (1.0 g, 5.37 mmol) in tri(ethylene glycol) dimethyl ether (5 mL). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (200 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered and concentrated down to afford 2-chloro-4,6-difluoro-1,3-benzothiazole (1.1 g, 99%). 1H NMR (400 MHz, DMSO-d6) 7.05 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:5]2=O.[C:20](=[N:26][Si](C)(C)C)=[N:21][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[O:8][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:5]2=[N:26][C:20]#[N:21]
Reactant: O=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 6-bromo-7-fluoro-2-phenylchroman-4-one (400 mg, 1.25 mmol) in DCM (10 mL) was added TiCl4 (2.5 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.62 mL, 2.75 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude N-(6-bromo-7-fluoro-2-phenylchroman-4-ylidene)cyanamide (327 mg, 78%). 1H-NMR (CDCl3): 3.19 (m, 1H), 3.49 (m, 1H), 5.34 (m, 1H), 6.81 (d, 1H), 7.41 (m, 5H), 8.27 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH:4]([C:10]([O:12]CC)=[O:11])[C:5]([O:7]CC)=[O:6].CO.[OH-].[K+].C1(C)C=CC=CC=1>O>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH:4]([C:5]([OH:7])=[O:6])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(CC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C(=O)O)C(=O)O

Procedure:
To a solution of the above-obtained diethyl (2,2-dimethylpropyl)malonate on 500 cm3 of methanol a solution of 125 g of KOH in 1000 cm3 of water was added. The obtained mixture was refluxed for 5 h, and then methanol and ethanol were distilled off at atmospheric pressure. To the residue ca. 3000 cm3 of water was added, the obtained solution was acidified by saturated HCl to pH 1. The formed product was extracted with 3×500 ml of ether. To the combined extract 200 ml of toluene was added, and the obtained solution was evaporated in vacuum to give a ca. 3 to 1 mixture of the title product and toluene (on the evidence of NMR spectroscopy). This mixture was further used without an additional purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][CH:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:1][N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(C)C[C@H]2Cc3ccccc3C(=O)N21
Temperature: 40 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
1,2,3,4,11,11a-hexahydro-2-benzyl-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (from Isomer B, 12 mg, 0.04 mmol) and 10% palladium on carbon (5 mg) in MeOH (1 ml) was stirred under a balloon of hydrogen. The catalyst was filtered off and then fresh catalyst added. After stirring an additional 4 h at 40° C. under a balloon of hydrogen, the reaction was filtered through Celite® rinsing with methanol to afford 8 mg of crude product. Column purification (Chiralcel OD, 10% 1/1 MeOH/EtOH in hexanes) afforded pure (4R,11aR)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one (1.5 mg, 17% yield) MS (ESI) 231 (M+H). Further elution afforded (4S,11aS)-1,2,3,4,11,11a-hexahydro-2,4-dimethyl-pyrazino[1,2-b]isoquinolin-6-one (1.6 mg, 18% yield) MS (ESI) 231 (M+H). Further elution also provided (4R,11aR)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (2.4 mg, 29% yield) and (4S,11aS)-1,2,3,4,11,11a-hexahydro-4-methyl-pyrazino[1,2-b]isoquinolin-6-one (2.2 mg, 27% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)(C)C>[CH3:9][O:8][C:6]([CH:5]1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CC(C)O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
One mole of methyl 4-hydroxybenzoate was reacted with two moles of hydrogen in the presence of 5% palladiun-carbon catalyst. This reaction was carried out in isoproyl alcohol at a temperature of 170°-180° C. and a hydrogen pressure of 20-40 kg/cm2. After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to obtain cyclohexanone-4-carboxylic acid methyl ester as the distillate at 140° C./20 mmHg.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][O:3]1.[CH3:5][NH:6][CH2:7][CH:8]=[CH2:9].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>O1CCOCC1>[CH2:7]([N:6]([CH3:5])[CH2:4][C@H:2]([OH:3])[CH3:1])[CH:8]=[CH2:9]
Reactant: C[C@@H]1CO1
Reactant: C=CCNC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1COCCO1
Product: C=CCN(C)C[C@@H](C)O
Temperature: 140 °C
Yield: 29 %

Procedure:
(2R)-2-methyloxirane (13.76 g) was added to a suspension of N-methylprop-2-en-1-amine (25 ml) and ytterbium(III) trifluoromethanesulfonate (100 mg) in dioxane (100 ml) and heated to 140° C. for 1 hour under microwave irradiation. The solution was concentrated in vacuo and the residue partitioned between water (100 ml) and ethyl acetate (200 ml). The organic extract was dried and solvent removed in vacuo yielding (2R)-1-[allyl(methyl)amino]propan-2-ol as a yellow oil (8.8 g, 29%); NMR spectrum (CDCl3) 1.20 (d, 3H), 2.33 (s, 3H), 2.27-2.46 (m, 2H), 3.05 (m, 1H), 3.23 (m, 1H), 3.88 (m, 1H), 5.19-5.29 (m, 2H), 5.90 (m, 1H); Mass spectrum M+ 129.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Product: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.