Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Br)(Br)[Br:2].N[C:6]1[C:10]([CH:11]2[CH2:13][C:12]2([Br:15])[Br:14])=[CH:9][N:8]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:7]=1.N(OC(C)(C)C)=O>C(#N)C>[Br:2][C:6]1[C:10]([CH:11]2[CH2:13][C:12]2([Br:15])[Br:14])=[CH:9][N:8]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:7]=1
Reactant: Nc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1(Br)Br
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)c1cc(Cl)c(-n2cc(C3CC3(Br)Br)c(Br)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromoform (2 ml) was added to a stirred solution of the title compound of Example 8 (0.25 g) in acetonitrile (2 ml) and the mixture cooled to about 0° C. t-Butyl nitrite was added dropwise, then the reaction mixture allowed to warm to room temperature, stirred for 1 hour at room temperature and then for 1 hour under reflux, allowed to cool and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using mixtures of hexane:ether (19:1 then 9:1) as eluants, to provide the title compound as a colourless gum. δ (CDCl3): 1.85 (t,1H), 2.25 (dd,1H), 2.70 (dd,1H), 7.25 (s,1H 7.70 (s,2H). MS (thermospray): M/Z [M+H] 554.5; C13H6Br3Cl2F3N2 +H requires 554.75.
Reaction SMILES: I[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[N-:17]=[N+:18]=[N-:19].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[N:17]([CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(I)CCCCCCCCCCC(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66751.6 %

Procedure:
A mixture of 6 (0.15 g, 0.44 mmol) sodium azide (0.09 g, 1.4 mmol) and 18-crown-6 (0.015 g, 0.057 mmol) in dimethylformamide (3 ml) was stirred at room temperature for 16 h. DMF was distilled under vacuum, cold 2N HCl (2 ml) was added and the mixture was extracted with ethylacetate (10 ml). The organic phase was washed with water (2×10 ml), dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow solid which was purified by flash chromatography (silica gel) using 20% ethylacetate in hexane to afford the title compound 7 (0,075 g, 67%) as a white solid. 1H NMR (CDCl3) δ: 3.26 (t, 2H, J=6.9 Hz); 2.35 (t, 2H, J=7.5 Hz); 1.62 (m, 4H); 1.35 (m, 14H), FABMS: (m/z), 256 (M+H); 230 and 210. HRMS C13H25N3O2Li calc.: 262.2107, found: 262.2164 (M+Li).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([S:8]([N:11](C2C=CC=CC=2)[C:12](=[O:14])[O-])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([S:8]([NH:11][C:12]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=2)=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])N(c1ccccc1)S(=O)(=O)c1ccc(Cl)nn1
Reactant: COc1nc(C)nc(N)n1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccc(Cl)nn2)n1
Yield: 43.3 %

Procedure:
A mixture of 14.2 g of N-(3-chloropyridazine-6-sulfonyl)phenylcarbamate and 6.3 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are refluxed for 1 hour in 120 ml of absolute dioxan. When the reaction is complete, the mixture is concentrated in vacuo and the residue is taken up in a saturated aqueous solution of sodium bicarbonate and the insoluble constituents are extracted with methylene chloride. The aqueous phase is acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and concentrated, affording 7 g of the compound of the above formula with a melting point of 135° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=O)[CH2:10]2)[CH:8]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].Cl.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:10]2)[CH:8]=1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Cl)ccc1F)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1cc(Cl)ccc1F)C2
Temperature: 110 °C
Reaction time: 2 h
Yield: 170.7 %

Procedure:
To a solution of 7-(5-chloro-2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (0.6 g) and aminoguanidine hydrochloride (0.233 g) in ethanol (10 ml) was added concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 110° C. (bath temperature) for 2 hours. The reaction solution was cooled to room temperature, and the crystals were filtered and dried to give 7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 171) (0.6 g) as colorless crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[I:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.CO>N1C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[N:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(I)cn1
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Temperature: 25 °C

Procedure:
p-Toluenesulfonyl chloride (2.00 g, 10.4 mmol) was added to a solution of 5-iodo-2-aminopyridine (2.50 g, 11.4 mmol) in 6 mL of pyridine, and the resultant solution was warmed at 90° C. for 18 h. After cooling to room temperature, the solution was added portionwise to 75 mL of ice-water with stirring. The resultant precipitate was collected, washed with water, and dried in vacuo to afford a pale yellow powder, which was stirred with 20 mL of methanol for several minutes. The solid product was then collected, washed with methanol, and dried in vacuo to provide the title compound as an off-white powder. LC/MS 374.8 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:17]O>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:10]([O:12][CH3:17])=[O:11]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
10 g of concentrated sulfuric acid was added to a methanol (120 g) solution of 50 g of 3,5-dichlorobenzoic acid, and the mixture was refluxed by heating for 5 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was dissolved into 200 g of ethyl acetate, washed with water (200 g×2), then washed with a saturated aqueous solution of sodium bicarbonate, and further washed with water. After drying the organic phase over anhydrous magnesium sulfate, 48.6 g of the target product was obtained as a white solid by removing the solvent by distilling under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=O)[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2].Cl.[NH2:26][OH:27]>C(N(CC)CC)C.C(O)C>[CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]=2[C:6](=[O:16])[C:5]2[C:17](=[N:26][OH:27])[C:18]3[C:23]([C:4]1=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:2]
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=NO)c1ccccc1-2

Procedure:
5-Ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (300 mg, 0.95 mmol) was dissolved in a solution of hydroxylamine hydrochloride (525 mg, 7.6 mmol) and triethylamine (0.5 mL) in 20 mL of ethanol. The solution was refluxed overnight and then concentrated dryness. The residue was diluted with water and extracted with chloroform twice. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate followed by evaporation to remove the solvent. The title compound was obtained by subjecting the resulting residue to silica gel-chromatography (chloroform:actone=20: 1) and then to crystallization from diethyl ether. 1H-NMR(CDCl3)δ 1.32(6H,d,CH(CH3)2, 1.73(3H,t,NCH2CH3), 3.03(1H,septet,CH), 4.79(2H,q,NCH2), 7.41-8.00(6H,m,Ar-H), 8.25(1H,s,H-9), 15.31(1H,s,N═OH)
Reaction SMILES: [CH3:1][CH:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH2:3][OH:4].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][CH:2]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:29][C:30]([O:32][CH3:33])=[O:31])[CH2:15][C@@H:16]2[O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH2:3][O:4][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Solvent: c1ccncc1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
In 1 ml of pyridine was dissolved 81 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-dien-21 -ol and, then, under ice-cooling, 70 mg of p-toluenesulfonyl chloride was added. The mixture was stirred at that temperature for 3 hours. The reaction mixture was then poured into ice water and extracted with diethyl ether. The extract was serially washed with aqueous copper sulfate solution, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 79 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-p-toluenesulfonyloxypregna-5,7-diene.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])[CH:15]=3)[N:10]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[O:20])[CH:15]=3)[N:10]([C:22]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:30])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(/C=C/C(=O)O)cc12
Reactant: C1CNC1
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(/C=C/C(=O)N3CCC3)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 85, with the exceptions that (E)-3-(1′-acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)acrylic acid was used instead of 2-(5-chloro-1′-(methoxycarbonyl)spiro[indoline-3,3′-pyrrolidin]-1-ylcarboxamido)thiazole-4-carboxylic acid, and that azetidine hydrochloride was used instead of dimethylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH2:16]Cl)=[CH:14][N:15]=1>CN(C=O)C>[Cl:10][C:11]1[S:12][C:13]([CH2:16][N:3]2[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]2)=[CH:14][N:15]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n(Cc2cnc(Cl)s2)n1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A solution of 3,5-dimethyl-1H-pyrazole (Aldrich, 114 mg, 1.190 mmol) in DMF (5 ml) was added over NaH (Aldrich, 34.3 mg, 1.42 mmol) at 0° C. under N2 atmosphere. The mixture was stirred during 5 min and 2-chloro-5-(chloromethyl)-1,3-thiazole (AK scientific, 200 mg, 1.19 mmol) in DMF (2 ml) was added. The mixture was allowed to stir overnight. Finally, it was heated to 50° C. for 1 h. DMF was eliminated by washing with 14 ml of a mixture EtOAc/NH4Cl 1N (1:1). The organic layer was dried over Na2SO4 and the solution concentrated to dryness under vacuum, to afford a crude product which was chromatographed (silica gel cartridge, Hex/EtOAc) yielding the title compound. 1H NMR (300 MHz, CDCl3) δ ppm: 7.37 (s, 1H); 5.82 (s, 1H), 5.26 (s, 2H); 2.24 (s, 3H); 2.22 (s, 3H). [ES+MS] m/z: 228.1 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:26])[C:22]#[C:23][CH2:24][CH3:25]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:21](=[O:26])[CH:22]=[C:23]([CH2:24][CH3:25])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC#CC(=O)OCC
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Product: CCc1cc(=O)nc2n1CC(COc1ccc(C3CCCCC3)cc1)O2
Temperature: 170 °C
Yield: 39.4 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (300 mg, 1.095 mmol) in ethanol (6 mL) was added ethyl 2-pentynoate (276 mg, 2.19 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 70 min. The solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 1-12% EtOH/CH2Cl2) to afford 153 mg of 2-(4-cyclohexyl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a slightly yellow solid.
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH2:11]>C(Cl)(Cl)(Cl)Cl>[C:1]([S:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:11])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(S)c1ccccc1
Reactant: C=Cc1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(C)SC(=S)c2ccccc2)cc1
Temperature: 70 °C
Yield: 53 %

Procedure:
A mixture of dithiobenzoic acid (3.6 g), 4-vinylanisole (2.9 g) and carbon tetrachloride (20 mL) were heated at 70° C. overnight. The solvent was evaporated and the residue subjected to column chromatography (aluminium oxide (activity 111) column, 2% diethyl ether in n-hexane eluent) which gave the title compound (53% yield). 1H-nmr (CDCl3) d (ppm): 1.80 (d, 3H, SCHCH3); 3.80 (s, 3H, OCH3); 5.22 (q, 1H, SCHCH3) and 6.88-7.97 (m, 9H, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:23])[CH3:22])[CH:15]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1.ClCCl.C(N(CC)C(C)C)(C)C.[O:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](Cl)=[O:55]>>[CH3:22][N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:54]([C:50]3[O:49][CH:53]=[CH:52][CH:51]=3)=[O:55])=[C:3]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])[CH2:28][CH2:29]3)[CH:4]=2)[C:9]1=[O:12])[CH3:23]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2ccco2)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 7-amino-2-(3-dimethylaminomethyl-benzyl)-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 11b (73.70 mg, 0.15 mmol) was taken up in clean, dry, reagent-grade dichloromethane (3.00 ml, 46.52 mmol) and the mixture was stirred at room temperature under nitrogen atmosphere until the solids were all in solution. To this stirred solution was then added the N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) followed by the furan-2-carbonyl chloride (0.02 ml, 0.20 mmol) and the reaction was allowed to stir overnight. The reaction was quenched with 3 ml of 2N HCl. The product solution was diluted with 10 ml of water and 10 ml of dichloromethane. The layers were separated and the product was extracted using dichloromethane (3×10 ml). The organic phases were combined and washed with brine (1×25 ml) and the product solution was then dried over MgSO4. The solution was then filtered under vacuum and the collected solution was concentrated under reduced pressure. The resultant yellow oil was then purified using silica gel column chromatography, eluting 100% dichloromethane to 7.5% MeOH in dichloromethane. The product needed further purification and was subjected to reverse-phase HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. Furan-2-carboxylic acid [2-(3-dimethylaminomethyl-benzyl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide 11c (11.30 mg, 0.02 mmol) was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1C(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[CH2:12]([O:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]2)=[C:2]([NH2:1])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Yield: 77.9 %

Procedure:
Phenylmethyl 2-{3-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperidinecarboxylate (1.16 g, 2.336 mmol) in ethanol (130 ml) was hydrogenated over 10% palladium on carbon (0.497 g, 0.467 mmol) at ambient temperature overnight. The mixture was filtered through a Celite cartridge under N2, washed with EtOH and evaporated in vacuo to give the title compound as a cream solid (0.66 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.[Br:15]Br>C(O)(=O)C>[Br:15][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]([CH2:11][CH2:12][OH:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: BrBr
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Solvent: CC(=O)O
Product: COc1cc(CCO)c(OC)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
(2,5-Dirnethoxy-phenyl)-acetic acid (3.00 g, 15.29 mmol) was dissolved in 30 ml of acetic acid and cooled to 0° C. To this solution was added bromine (2.44 g, 15.33 mmol), the reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure, the solid residue was washed with cold hexane and dried overnight. The residue was dissolved in THF and cooled to 0° C. LAH (20 ml of 1.0 M in THF) was added slowly and then the reaction mixture was stirred at 0° C. for 2 h. Excess LAH was destroyed by careful addition of ethyl acetate and an aqueous solution of 0.10 M hydrogen chloride. The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure to give an oil (3.1 g), which solidifies slowly. MS (m/z) 278 (M+NH4)+. 1HNMR(CDCl3): δ ppm 2.86 (m, 2H), 378-3.84 (2s+m, 8H), 6.77 (s, 1H), 7.04 (s, 1H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[N:18]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)[CH2:17][CH2:16]2
Reactant: CNC(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: C1CN2CCC(CC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCN3CCC2CC3)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 81.8 %

Procedure:
To a solution of 4-fluoro-N-methyl-2-nitrobenzamide (Intermediate 3L) (0.65 g, 3.3 mmol) in dimethylsulfoxide (50 mL) was added 1,4-diazabicyclo[3.2.2]nonane (0.62 g, 4.9 mmol) and potassium carbonate (1.36 g, 9.8 mmol). The resulting suspension was heated at 90° C. for 4 days. The mixture was filtered and the filtrate purified using a 20 g SCX cartridge to afford 4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-2-nitrobenzamide (0.8 g, 2.7 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1.O([CH:25]([CH3:27])[CH3:26])S(C(F)(F)F)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH:25]([CH3:27])[CH3:26])=[CH:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1
Reactant: CC(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C(Cn1cnnn1)c1ccc(Cl)cc1Cl
Product: CC(C)OC(=Cn1cnnn1)c1ccc(Cl)cc1Cl

Procedure:
Analogously to Example 7a,b, after reacting 1-(2,4-dichlorophenyl)-2-tetrazol-1-yl-ethanone with isopropyl triflate there was obtained 1-[2-(2,4-dichloro-phenyl)-2-isopropoxy-vinyl]-1H-tetrazole as a white powder with m.p. 82° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[NH:34][CH2:33][CH2:32][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: NCCN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: c1ccc(C[C@@H]2CN3C(NCCN4CCCCC4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Compound 67a (100 mg, 0.240 mmol) obtained in Example 67 was dissolved in tetrahydrofuran (2 mL), and to the solution were added 2-piperidinoethylamine (61 μL, 0.480 mmol, 2.0 equivalents) and N,N-diisopropylethylamine (344 μL, 0.960 mmol, 4.0 equivalents) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform:methanol=90:10, chloroform: a 7 mol/L ammonia/methanol solution=90:10). To the product was added diisopropyl ether, and the deposited crystals were collected by filtration and dried to obtain the title compound (110 mg, 94%) as white crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:24]([C:23]1[N:22]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:27])[NH:20][C:19]=1[CH2:17][CH3:18])[CH3:25]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1nc(C(=O)O)[nH]c1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1nc(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)[nH]c1CC

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (120 mg, 0.52 mmol), 4,5-diethyl-1H-imidazole-2-carboxylic acid obtained in Example (43c) (36.7 mg, 0.22 mmol), WSC hydrochloride (145 mg, 0.76 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 55.0 mg of the title compound as a white foamy substance (66%).