Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.075 g, 0.34 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.095 g, 1.7 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.102 g, 0.85 mmol) was added and stirred for further at 80 deg C. 3 h. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×5.0 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC to get the desired compound as yellow oil (0.020 g, 13% yield). 8-Chloro-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.06 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.008 g, 0.06 mmol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 32% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:31][CH:32]([CH3:36])[CH2:33][CH:34]=O.COCCOC.[BH4-].[Na+]>ClCCl.O>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:34][CH2:33][CH:32]([CH3:36])[CH3:31])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)CC=O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CNCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 3-methylbutanal (8.6 mg, 0.10 mmol) and Ti(OPr)4 (82 μL, 0.30 mmol) were dissolved in dichloromethane (1.0 mL) and mono-glyme (1.0 mL) and allowed to stir at 25° C. for 16 hours. NaBH4 (5.7 mg, 0.15 mmol) was added and the reaction was stirred for an additional 1 h. The reaction was diluted to 5 mL with dichloromethane before water (5 mL) was added. The reaction was filtered through celite to remove the titanium salts and the layers separated. The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-((isopentylamino)methyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (5.7 mg, 10%). ESI-MS m/z calc. 470.3, found 471.5 (M+1)+; retention time 2.76 minutes.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:30]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(N2CCCCC2)n1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(N2CCCCC2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 6-(piperidin-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 396.00 g/mol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[O:15][CH3:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)P(=O)(N(C)C)N(C)C.[Cu]>[CH3:16][O:15][C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[O:1][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)c(OC)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
6.67 g of ethyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate and 5.69 g of 3-bromopyridine were dissolved in 13.3 ml of hexamethyl phosphoric triamide. To the solution were added 4.15 g of potassium carbonate and 0.57 g of a copper powder. The mixture was stirred for 3 hours at 160° C. in a nitrogen atmosphere. The reaction mixture was mixed with 100 ml of ice water and 100 ml of ethyl acetate. The resulting insolubles were removed by filtration. An organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: benzene/ethyl acetate=10/1) to obtain 1.93 g of light yellow oily ethyl (E)-3-[3-methoxy-4-(3-pyridyloxy)phenyl]acrylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1

Procedure:
2-Chloro-5-nitropyridine (10.0 g, 63.08 mmol) and 4-benzyloxyphenol (12.6 g, 63.08 mmol) were reacted in analogy to example 30b. Yield: 19.5 g (96%), M+H+: 323.11.
Reaction SMILES: [OH-].[Na+].CS(C)=O.[CH3:7][C:8]1([CH3:23])[O:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]2[CH2:19][CH2:20][CH2:21][CH2:22][C:9]1=2.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>O>[CH3:7][C:8]1([CH3:23])[O:13][C:12]2[CH:14]=[C:15]([O:18][CH2:24][CH:26]3[CH2:27][O:28]3)[CH:16]=[CH:17][C:11]=2[C:10]2[CH2:19][CH2:20][CH2:21][CH2:22][C:9]1=2
Reactant: CC1(C)Oc2cc(O)ccc2C2=C1CCCC2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2cc(OCC3CO3)ccc2C2=C1CCCC2

Procedure:
To a stirred solution of NaOH (4.0 g, 0.1 m) DMSO (250 ml) and water (250 ml) was added 7,8,9,10-tetrahydro-6,6-dimethyl-3-hydroxy-6H-dibenzo[b,d]pyran (21.3 g, 0.0926 m) and then epichlorohydrin (60 g, 0.648 m) and the mixture stirred for 5 hours, treated with water (1 L) and extracted with ether (3×500 ml). The combined extracts were dried over MgSO4 and evaporated to give 7,8,9,10-tetrahydro-6,6-dimethyl-3-(oxiranylmethoxy)-6H-dibenzo[b,d]pyran as a pale yellow oil, 23.2 g. This material was of sufficient purity to use as is for further chemical processing.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:30][OH:31])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: NO
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C=NO)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.88 g), hydroxylamine hydrochloride (0.7644 g) and sodium acetate (1.0664 g) in acetic acid (20 ml) was stirred at room temperature for an hour to form isopropyl 2-methyl-4(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4dihydropyridine-3-carboxylate. To the reaction mixture was added acetic anhydride (3.37 g) and the mixture was heated at 95° to 100° C. for 6 hours. After removal of the acetic acid, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual oil (3.69 g) was chromatographed on a column of silica-gel (100 g), and eluted with a mixture of benzene and ethyl acetate (5:1, v/v) to give an oil of isopropyl 2-methyl-4(2-nitrophenyl)-5-methoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (2.0 g), which was left in a refrigerator for several days to crystallize. Recrystallization from methanol gave pure crystals, m.p. 175.5°-176.5° C.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1ccc(F)c(C(=O)O)c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(F)ccc(C)c1F
Temperature: 25 °C
Yield: 86 %

Procedure:
To a 0° C. solution of 2,6-difluoro-3-methylbenzoic acid (10.0 g, 58.1 mmol, 1.0 equiv) in dry methanol (100 mL) was added dropwise thionyl chloride (4.64 mL, 63.9 mmol, 1.1 equiv). The resulting solution was refluxed overnight. After the reaction mixture was allowed to cool to room temperature, the solvent was removed in vacuo. The product was dissolved in ethyl acetate and washed with aq. satd. NaHCO3. The EtOAc layer was dried over sodium sulfate, filtered and concentrated in vacuo to provide the desired ester (9.35 g, 86%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:16]>>[ClH:16].[Cl:16][CH2:12][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1-c1ccccc1
Product: Cl
Product: ClCc1nccn1-c1ccccc1
Temperature: 0 °C
Yield: 74 %

Procedure:
27 g (0.179 mol) of (1-phenyl-1H-imidazol-2-yl)methanol were added to 25 ml of SOCl2 under stirring at 0° C. The solution obtained was refluxed for 30 min and then the excess SOCl2 removed under vacuum. The thus obtained residue was recrystallized from 50 ml of a mixture of toluene:EtOH=5:1 to give 16.6 g (74%) of 2-(chloromethyl)-1-phenyl-1H-imidazole hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([NH2:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.[NH:30]1[CH2:33][CH:32]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:38]([O:37][C:36](=[O:42])[NH:35][CH2:34][CH:32]1[CH2:33][N:30]([C:19](=[O:21])[NH:17][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[N+:14]([O-:16])=[O:15])[CH2:31]1)([CH3:39])([CH3:41])[CH3:40]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2ccc(F)cc2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of 4′-fluoro-4-nitro-[1,1′-biphenyl]-3-amine (1.5 g, 6.46 mmol) in DCM (50 mL) were added triphosgene (1.917 g, 6.46 mmol) and TEA (8.5 g, 84 mmol) at 0° C. The reaction mixture was stirred at room temperature for two hours. tert-butyl azetidin-3-ylmethylcarbamate (1.203 g, 6.46 mmol) was then added at 0° C. and the reaction mixture was stirred at room temperature for four hours. The reaction crude was diluted with saturated citric acid solution and extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated to yield crude residue which was purified by column chromatography eluting with 30% EtOAc in Hexane to afford tert-butyl((1-((4′-fluoro-4-nitro-[1,1′-biphenyl]-3-yl)carbamoyl)azetidin-3-yl)methyl)carbamate (2 g, 69.7% yield).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[S:21]1[C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[C:22]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=Cc1ccncc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccncc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a 50-mL round-bottom flask was added 3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) and N,N-dimethylformamide (14 mL) and the solution was cooled to 0° C. To this solution was added potassium carbonate (1.22 g, 8.828 mmol) and methyl 2-mercaptoacetate (0.754 mL, 8.427 mmol). The solution turned to a clear yellow solution after stirring for 10 min. After 30 min at 0° C., the reaction was warmed to room temperature and stirred over the weekend by which time a solid precipitate was formed. Water was added provide a homogeneous solution, which was cooled to 0° C., the solid was collected via vacuum filtration, and washed with cold water until clear and colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate (1.55 g, 82%) as a white solid. LCMS: (FA) ES+ 194; 1H NMR (d6-DMSO, 300 MHz) δ9.37 (s, 1 H), 8.56 (d, J=5.4 Hz, 1 H), 8.26 (d, J=0.6 Hz, 1 H), 7.97 (dd, J=5.4 Hz, 1.2 Hz, 1 H), 3.92 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)[CH:3]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)[CH:3]=2)=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: N#CC1(c2cc(Br)ccn2)CC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CC2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 40.3, but using 1-(4-bromo-pyridin-2-yl)-cyclopropanecarbonitrile (Step 49.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 49.4). The reaction mixture is stirred for 2 h at 100° C., quenched by dilution with EtOAc/H2O, and extracted with EtOAc. The crude product is purified by silica gel column chromatography (Hex/EtOAc, 1:1) to afford 122 mg of the title compound as a white solid: ESI-MS: 357.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.29 (Hex/EtOAc, 1:1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(O)cc3)CC2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OC(C)=O)cc3)CC2)CC1

Procedure:
8 g of acetyl chloride is added to a solution of 30 g of trans-1-p-hydroxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane and 20 ml of pyridine in 300 ml of toluene and the mixture is warmed to 80° for 1 hour. After cooling and customary working up, trans-1-p-acetoxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[BrH:17]>O>[Br:17][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14]
Reactant: Br
Reactant: Cc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Solvent: O
Product: Cc1ccc(C2(Br)C(=O)NC(=O)NC2=O)cc1
Reaction time: 3 h

Procedure:
To a suspension of 5-(4-methylphenyl)barbituric acid (218 mg) in 2 ml of water, kept at 10° C. under stirring, 136 μl of 48% hydrobromic acid are added, then 56 μl of brominr are dropped and the stirring is continued for 3 hours. The precipitate which formed is recovered by filtration and washed with water. then it is dried under vacuum to give 270 mg of the product, m.p. 210-213° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[NH2:21])[CH:16]=O.Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[NH2:21]
Reactant: O=C1COc2cc(O)ccc21
Reactant: Nc1ccc(C=O)cc1Cl
Agent: Cl
Solvent: CO
Product: Nc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1Cl
Temperature: 25 °C
Yield: 91.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-chloro-4-aminobenzaldehyde 1.24 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 1.75 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:4]([NH2:17])[N:3]=1.C1(C)C=C(C)C=C(C)C=1S([NH:29]O)(=O)=O.[Br:32][C:33]1[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=1.[OH-].[K+]>O1CCOCC1.CO>[NH2:17][C:4]1[N:3]2[N:29]=[C:38]([C:36]3[O:37][C:33]([Br:32])=[CH:34][CH:35]=3)[N:1]=[C:2]2[CH:7]=[C:6]([CH2:8][NH:9][C:10]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:11])[CH:5]=1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: Nc1cc(CNC(=O)C2CCCC2)cc(N)n1
Reactant: O=Cc1ccc(Br)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(CNC(=O)C2CCCC2)cc2nc(-c3ccc(Br)o3)nn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
To a solution of 39 mg (0.17 mmol) cyclopentanecarboxylic acid (2,6-diamino-pyridin-4-ylmethyl)-amide in 1.4 ml dioxane was added 40.2 mg (0.187 mmol, 1.1 eq.) o-mesitylenesulfonylhydroxylamine and after 2h 38.6 mg (0.221 mmol, 1.3 eq.) 5-bromo-2-furaldehyde. The mixture was heated to 100° C. for 2.5 h and afterwards 0.17 ml 1N KOH in MeOH was added. Opening of the reaction vessel and stirring of the mixture at room temperature for 16 h preceded the evaporation to dryness. The residue was taken up in 4.5 ml water and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried with MgSO4 and evaporated. Purification of the residue with column chromatography on silica eluting with yielded the 12 mg (21%) of the title compound.
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: CC1CN(Cc2ccccc2)CC2Cc3ccccc3C(=O)N12
Reactant: [H][H]
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: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=S)=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:18][NH2:19])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Fc1ccccc1C(=S)Nc1ccc(Br)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: NN=C(Nc1ccc(Br)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N1-(4-bromophenyl)-2-fluoro-1-benzenecarbothioamide (1.50 g, 0.00485 mol) and a 1M solution of hydrazine in tetrahydrofuran (6.3 mL, 0.0063 mol) were heated in absolute ethanol (25 mL) at reflux under nitrogen atmosphere for 14 hours. Additional 3 mL of a 1M solution of hydrazine in tetrahydrofuran was added and the stirring at reflux was continued for another 6 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated to yield N1-(4-bromophenyl)-2-fluoro-1-benzenecarbohydrazonamide (1.54 g, 0.0050 mol) as a tan solid. TLC (ethyl acetate/heptane 1:3) Rf 0.10
Reaction SMILES: C(Cl)CCl.C1C=C[C:8]2[N:13](O)N=[N:11][C:9]=2C=1.C(Cl)Cl.[C:18]([O:22][C:23](=O)[C:24]1[CH:29]=[CH:28][C:27](N)=[CH:26][CH:25]=1)(C)(C)C.CN(C=[O:36])C>[Cu](Cl)Cl>[NH2:11][CH2:9][CH2:8][NH:13][C:18](=[O:36])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: On1nnc2ccccc21
Agent: Cl[Cu]Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 92 %

Procedure:
1.5 grams (3.77 mMol) of Fmoc-citruline were dissolved in 3 mL of DMF in a round bottom flask to which was added 0.87 grams (4.5 mMol) of EDC, 0.61 grams (4.5 mMol) of HOBt. 6 mL of DCM were then added followed by the addition 0.88 grams (4.5 mMol) of t-butyl-4-aminobenzoate and a catalytic amount of copper chloride. The reaction mixture was allowed to stir overnight The solvents were evaporated and the crude product purified over silica gel with 5 to 10% MeOH in DCM to give 2 grams of 1 in 92% yield. M+1=574