Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(C3OC(C#N)=CC=3)=O)=[C:29]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:28]=2)[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:20][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:17]([C:6]3[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=3)=[O:19])=[C:29]([N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:28]=2)[CH2:25][CH2:26]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C#N)o3)c(N3CCCCC3)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(N3CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
A flask was charged with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (0.043 g, 0.14 mmol) (as prepared in Example 3, step (d)), 4-(4-methyl-piperazin-1-yl)-2-piperidin-1-yl-phenylamine (0.028 g, 0.10 mmol) (as prepared in Example 5, step (b)), EDCI (0.030 g, 0.16 mmol), DMAP (0.012 g, 0.010 mmol), and DMF (0.5 mL) and was stirred for 12 h at RT and then 1 h at 60° C. The reaction mixture was loaded on a 10-g SPE cartridge (silica) and eluted with 10% MeOH/DCM to give 0.030 g (57%) of title compound. Mass spectrum (ESI, m/z): Calcd. for C27H41N7O2Si, 524.3 (M+H), found 524.1.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:21][CH2:20][C:12]3([S:16][CH2:15][C@@H:14]([C:17]([OH:19])=[O:18])[NH:13]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>C(Cl)Cl>[C:31]([N:13]1[C:12]2([CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:23][CH:22]=3)[CH2:21][CH2:20]2)[S:16][CH2:15][C@H:14]1[C:17]([OH:19])=[O:18])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
In 50 ml of methylene chloride were dissolved 2.40 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid and 2.23 ml of triethylamine. To the solution thus obtained was dropwise added 1.41 g of benzoyl chloride at 0-5° C., and the resulting mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was poured into ice water, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl ether was added to the residue thus obtained, and the deposited crystal was collected by filtration. Thus, 2.10 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid was obtained as a colorless crystalline product.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6]>CO>[CH3:9][CH:4]([CH2:3][NH:2][CH3:1])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(C)C(=O)OC
Reactant: CN
Solvent: CO
Product: CNCC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution of 12.4 g of methylamine in 45 ml of methanol was added with stirring and ice-water cooling a solution of 60.2 g of methyl 2-methylacrylate in 40 ml of methanol over a period of 1 hour. The mixture was allowed to stand at room temperature for 3 days, was evaporated and the residue was distilled at aspirator pressure to give the methyl 2-methyl-3-methylaminopropionate, bp. 57°-59° C./15 mm Hg.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])=[N+:2]=[N-:3].[C:12]1([CH2:18][C:19]#[CH:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:18]([C:19]1[N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=2[Cl:11])[N:2]=[N:3][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCc1ccccc1
Reactant: [N-]=[N+]=Nc1cccc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(-n2nncc2Cc2ccccc2)c1Cl
Temperature: 100 °C

Procedure:
1-Azido-2,3-dichlorobenzene (200 mg, 1.06 mmol) (Cambie J. Organomet. Chem. 1996, 507, 1) and 3-phenyl-1-propyne (150 μL, 1.1 equiv) were combined in toluene (0.2 mL) and heated at 100° C. for 18 hours, allowed to cool to room temperature, and then concentrated under reduced pressure to give a mixture of regioisomers. The residue was purified by flash chromatography eluting with hexanes:ethyl acetate (3:1) to provide the title compound. MS (DCI/NH3) m/z 304 (M+H)+; 1H NMR (CDCl3) δ 3.87 (br s, 2H), 6.98 (m, 2H), 7.13 (dd, 1H), 7.22 (m, 3H), 7.29 (t, 1H), 7.56 (s, 1H), 7.64 (dd, 1H).
Reaction SMILES: [C:1]1([C:7](=[O:14])[C:8](=[N:12]O)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][O:17][C:18]([CH2:20][C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O)=[O:19].C([O-])(=O)C.[Na+]>[Zn].O.C(O)(=O)C>[C:7]([C:8]1[NH:12][C:21]([CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=1[CH3:10])(=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1[nH]c(C(=O)c2ccccc2)c(C)c1C(=O)OCC
Temperature: 100 °C

Procedure:
A solution of 71 g. (0.37 mole) of 1-phenyl-1,2,3-butanetrione-2-oxime in 350 ml. glacial acetic acid and 50 ml. of water is added to 75.5 g. diethyl acetonedicarboxylate in 350 ml. of glacial acetic acid at 70° C. Concurrently, a mixture of 73 g. (1.12 mole) of zinc dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added in portions at such a rate that the temperature is maintained near 100° C. After the additions are complete (about 45 minutes), the mixture is refluxed for one hour and poured into iced water. The resulting crude semisolid is collected by filtration and recrystallized twice from methanol to give ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, m.p. 152-154° C. Analysis: Calcd. for C19H21NO5 : C, 66.46; H, 6.16; N, 4.08%. Found: C, 66.50; H, 6.20; N, 4.17%.
Reaction SMILES: [CH2:1]([N:3]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[C:4]1[CH:5]=[C:6]([C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH2:37][CH2:36][CH:35]([NH:38]C(=O)OC(C)(C)C)[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:7]=[C:8]([C:11](=[O:25])[NH:12][CH2:13][C:14]2[C:15](=[O:24])[NH:16][C:17]([CH3:23])=[CH:18][C:19]=2[CH2:20][CH2:21][CH3:22])[C:9]=1[CH3:10])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:38][CH:35]1[CH2:34][CH2:33][N:32]([C:29]2[N:30]=[CH:31][C:26]([C:6]3[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)[C:9]([CH3:10])=[C:8]([CH:7]=3)[C:11]([NH:12][CH2:13][C:14]3[C:15](=[O:24])[NH:16][C:17]([CH3:23])=[CH:18][C:19]=3[CH2:20][CH2:21][CH3:22])=[O:25])=[CH:27][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCC(N)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a stirred solution of tert-butyl (1-(5-(3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-5-(((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)pyridine-2-yl)piperidin-4-yl)carbamate (0.4 g, 0.00051 mol) in DCM (10 mL) at 0° C., TFA (10 mL) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with aqueous sat. bicarbonate solution (80 mL) till pH 8 and aqueous layer extracted with 20% methanol in DCM (60 mL×4). Combined organic phase was dried over Na2SO4 and solvent removed under reduced pressure to afford the title compound (0.315 g, 92.1%) which was used as such for next reaction.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][CH2:23]Cl)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:23][O:22][CH2:20][CH3:21])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O

Procedure:
20 g (0.078 mol) of 7-benzyl-3-methylxanthine were stirred at 80° C. for 6 hours with 8.8 g (0.094 mol) of ethoxymethyl chloride and 13 g of potassium carbonate in 500 ml of absolute dimethylformamide, the mixture was filtered and concentrated, and the residue which remained was chromatographed (eluent: dichloromethane/methanol 20:1).
Reaction SMILES: [Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH2:24]Br)[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:26][C:27]([F:38])([F:37])[C:28]([NH:30][CH2:31][CH2:32][O:33][CH2:34][C:35]#[CH:36])=[O:29]>>[Si:1]([O:8][O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH2:24][C:36]#[C:35][CH2:34][O:33][CH2:32][CH2:31][NH:30][C:28](=[O:29])[C:27]([F:26])([F:37])[F:38])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#CCOCCNC(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CBr)c(=O)[nH]c2=O)O1
Product: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CC#CCOCCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O1

Procedure:
Next, 5′-O-tert-butyldimethylsilyloxy-5-bromomethyl-2′,3′-dideoxyuridine (3) can be coupled with an alkyne, in this case 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, to form the 5′-O-tert-butyldimethylsilyloxy-(5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl))-2′,3′-dideoxyuridine (4). It will be readily appreciated by one of skill in the art that the coupling of an alkyl halide with an alkyne can be carried out by a number of methods known in the art. Without being limiting in any way, one example of such a method known in the art is the so-called Castro-Stephens coupling, see for example, White, J. D., et. al. J. Am. Chem. Soc., 123(23), 5407-5413 (2001) and Stephens, R. D., et. al. J. Org. Chem., 28, 3313 (1963). For example, as shown in Scheme 1,5′-O-tert-butyldimethylsilyloxy-5-bromomethyl-2′,3′ dideoxyuridine (3) can be contacted with a mixture comprising a copper reagent, for example copper iodide (CuI), an alkyne, for example 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, and a base, for example 1,8-diazobicyloclo[5.4.0]undec-7-ene (DBU), to form 5′-O-tert-butyldimethylsilyloxy-(5-(4-(N-trifluoroacetyl-2-aminoethoxy)but-2-yn-1-yl))-2′,3′-dideoxyuridine (4), where an acetylide anion is formed in the mixture comprising CuI, 3-(N-trifluoroacetyl-2-aminoethoxy)prop-1-yne, and DBU.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]([NH:7][C:8]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:14]2[C:15]([C:21](=[O:23])[CH2:20][CH2:19][O:18]2)=[CH:16][CH:17]=1)=[O:6])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCCC2=O
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A solution of methyl 2-tert-butylcarbonylamino-6-(2-carboxyethoxy)-benzoate (Intermediate 78, 2.73 g) in DCM (50 mL) was stirred at room temperature. DMF (5 drops) was added, followed by oxalyl chloride (2.0 g). After 30 minutes of stirring, the mixture was concentrated in vacuo and the residue was redissolved in DCM and evaporated to dryness. The residue was dissolved in DCM (50 mL) and aluminium chloride (3.38 g) was added. The resultant mixture was stirred at room temperature for 5 hours then diluted with more DCM and washed with ice/water. After separation, the aqueous phase was extracted with more DCM and the combined organic layers were washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 10-40% to give methyl 7-tert-butylcarbonylamino-4-oxochroman-8-carboxylate (1.16 g) as a white crystalline solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Cl:1][C:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2cccnc2n1-c1cccc(F)c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A solution of N-chlorosuccinimide (24 mg, 0.18 mmol) in DMF (0.1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (60 mg, 0.17 mmol) (5073-171) in N,N-dimethylformamide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The mix was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc/hexane) to give the desired product (26 mg, 40%). LCMS calculated for C20H22ClFN3O2(M+H)+: m/z=390.1. Found: 390.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][NH:30][CH3:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:30]([CH3:31])[CH3:29])=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: CNC
Product: CN(C)C(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and dimethylamine were coupled to give 111bp. 1H NMR (400 MHz, CDCl3) δ 7.15-7.31 (m, 3 H), 6.82-7.00 (m, 4 H), 5.13 (s, 2 H), 3.33 (m, 3 H), 2.94-3.13 (m, 6 H). LCMS (ESI) m/z: 429.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[N:15][CH:16]=[C:17]([C:20]#[N:21])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[NH:22]1C=N[N:24]=[N:23]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[N:15][CH:16]=[C:17]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1ncc(C#N)c(=O)n1CC2
Reactant: c1nnn[nH]1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)-c1ncc(-c3nnn[nH]3)c(=O)n1CC2
Yield: 57 %

Procedure:
In a manner similar to that described in Example 23C, 6,7-dihydro-9,10-dimethoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carbonitrile was converted to the corresponding tetrazole in 57% yield, m.p. 286°-288° (decomp) from acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1csc(-c2ccc(Cl)cc2)n1
Product: O=C(NCCc1csc(-c2ccc(Cl)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 23 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (13 mg, yield 23%). 1H NMR (400 MHz, CDCl3) δ 9.46 (m, 1H), 9.25 (m, 1H), 8.81-8.80 (t, J=2 Hz, 1H), 7.87-7.84 (m, 2H), 7.40-7.37 (m, 2H), 7.08 (s, 1H), 3.93-3.89 (m, 2H), 3.16-3.13 (m, 2H). MS (ESI) m/z: Calculated for C20H13ClF3N5O2S: 479.04. found: 480.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[C:6]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:5]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[C:6]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccccn2)c(OCC(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(O)c2ccccn2)c(OCC(F)(F)F)c1
Yield: 88 %

Procedure:
[4-nitro-2-(2,2,2-trifluoroethoxy)phenyl](pyridin-2-yl)methanol (4.5 g) was dissolved in ethanol (150 ml), and the solution was reduced by catalytic hydrogenation overnight with 10% palladium-carbon of 50% hydration (0.25 g). The catalyst was removed, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), to give [4-amino-2-(2,2,2-trifluoroethoxy)phenyl](pyridin-2-yl)methanol (3.6 g) as yellow crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]=[C:7]([CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)[O:6][N:5]=1.Cl.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32](Cl)=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([NH:3][C:4]2[N:8]=[C:7]([CH:9]3[CH:14]4[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]4)[CH2:10]3)[O:6][N:5]=2)=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1noc(C2CN3CCC2CC3)n1
Reactant: O=C(Cl)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CCN(Cc2ccccc2)CC1)Nc1noc(C2CN3CCC2CC3)n1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a suspension of sodium hydride (0.4 g) in N,N-dimethylformamide was added 3-amino-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.2 g) at 0° C. and the mixture was stirred for 1 hour. To the mixture was added (1-benzylpiperidin-4-yl)acetyl chloride hydrochloride (2.53 g) during 30 minutes at 0° C. After stirred for additional 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on alumina with chloroform to give 3-{(1-benzylpiperidin-4-yl)acetylamino}-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.11 g).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([CH:2]2[CH2:3][NH:4][CH2:5][CH2:6][N:1]2[C:7]2[C:8]3[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1ccc2ncnc(N3CCNCC3)c2n1
Reactant: O=C=Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)C1CNCCN1c1ncnc2ccc(Cl)nc12
Yield: 99.2 %

Procedure:
This compound was synthesized from 4-(piperazin-1-yl)-6-chloro-pyrido[3,2-d]pyrimidine (2.5 g, 10 mmole) and 3-chlorophenyl isocyanate (1.54 g, 10 mmole) using the procedure of example 69, resulting in the pure title compound (4.0 g, 99%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z): 403.1 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21]C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29](OC)=O>>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH2:21])[CH2:18][CH2:19]1)[CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Reactant: COC=O
Product: CN(CCCCCN1CCC(CN)CC1)Cc1ccccc1

Procedure:
A solution of N-benzyl-5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (3.7 g) in methyl formate (30 ml) was refluxed under heating for 12 hr. After cooling, methyl formate was evaporated, and tetrahydrofuran (40 ml) and 2M trifluoroborane-dimethyl sulfide solution (19 ml) were added to the residue, which was followed by refluxing under heating for 6 hr. The solvent was evaporated, and ethanol (40 ml) and hydrochloric acid (3 ml) were added to the reaction mixture, which was followed by refluxing under heating for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.60 g of N-benzyl-N-methyl-5-(4-aminomethylpiperidin-1-yl)pentylamine.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH2:6]([O:8][C:9]([CH2:11][C:12]([N:14]([CH2:22][CH3:23])[CH2:15][CH2:16][C:17]([O:19]CC)=O)=[O:13])=[O:10])[CH3:7]>C(O)C>[C:9]([CH:11]1[C:17](=[O:19])[CH2:16][CH2:15][N:14]([CH2:22][CH3:23])[C:12]1=[O:13])([O:8][CH2:6][CH3:7])=[O:10]
Reactant: CCOC(=O)CCN(CC)C(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CCN(CC)C1=O
Yield: 71 %

Procedure:
To an ethanol solution of sodium ethoxide which had been synthesized by adding 5.8 g of metallic sodium to 300 ml of ethanol, 62.2 g of ethyl N-ethoxycarbonylacetyl-3-ethylaminopropionate (Referential Example 34) was added. The resultant mixture was refluxed for 4 hours. After allowing the reaction mixture to cool down, ethanol was distilled off. Ethyl acetate and a dilute aqueous solution of hydrogen chloride were added. The resulting mixture was shaken. After washing the organic layer with water, it was dried and concentrated to obtain 36.3 g of 3-carboethoxy-1-ethylpiperidine-2,4-dione as an oily substance (yield: 71%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].C([O-])(=O)C.[Na+]>>[C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(SCCc2ccccc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C1NC(=O)C(=Cc2ccc(SCCc3ccccc3)cc2)S1
Yield: 11.8 %

Procedure:
4-(2-Phenylethylthio)benzaldehyde (12.4 mmol, 3.0 g), 2,4-thiazolidinedione (15.5 mmol, 1.81 g) and anhydrous sodium acetate (30.9 mmol, 2.54 g) were heated in an oil bath at 150° C. for 0.5 hour. The mixture was cooled and the resulting solid triturated with water (100 ml) and collected by filtration. The solid was recrystallized from methanol:ethyl acetate:acetone (1:1:2) to afford 500 mg of title product; m.p. 182°-183° C.