Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11](O[C:14](=[O:15])[CH:5]21)=[O:12])C=C.[C:16]1([CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH2:23])[CH:17]=1>C1(C)C(C)=CC=CC=1>[C:16]1([CH2:24][N:25]2[C:11](=[O:12])[CH:6]3[CH:5]([C:4]4([CH2:11][CH:6]=[CH2:7])[CH2:10][CH:7]3[CH:8]=[CH:9]4)[C:14]2=[O:15])[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]2[C:11](=[O:12])[CH:6]3[CH:5]([C:4]4([CH2:9][CH:4]=[CH2:5])[CH2:10][CH:7]3[CH:8]=[CH:9]4)[C:14]2=[O:15])[CH:17]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCc1cccc(CN)c1
Solvent: Cc1ccccc1C
Product: C=CCC12C=CC(C1)C1C(=O)N(Cc3cccc(CN4C(=O)C5C6C=CC(CC=C)(C6)C5C4=O)c3)C(=O)C12
Temperature: 200 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a 1000 ml flask replaced with nitrogen 257.4 g (1.26 mol) of allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and 300 ml of xylene were charged. To the mixture was added 81.4 g (0.60 mol) of m-xylylenediamine over 1.5 hours with heating and stirring while refluxing xylene. The reaction was continued for 3 hours while separating and removing water produced by the reaction by a water separator, and then the solvent, xylene, was removed by distillation. Thereafter, the content of the flask was treated with heat at 200° C. under reduced pressure of 1 Torr for 1 hour while stirring, thus obtaining 301.8 g (yield:99%) of the target N,N'-m-xylylene-bis(allyl-bicyclo[2.2.1]hept-5-ene-2,3-dicarboximide), of which the chemical structure is shown by the following formula [6]. This compound is hereinafter abbreviated to BANI-mX. ##STR10##
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.C1(O)CCCCC1.[Al](OC(CC)C)(OC(CC)C)OC(CC)C.[K+].[Br-]>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Agent: CCC(C)O[Al](OC(C)CC)OC(C)CC
Agent: [Br-]
Agent: [K+]
Solvent: OC1CCCCC1
Product: Brc1ccc2cc3ccccc3cc2c1
Temperature: 155 °C
Reaction time: 48 h
Yield: 71 %

Procedure:
2-bromoanthraquinone (Formula XII, 35.2 g) was added to a 3-L, 3-necked flask fitted with a distillation head and receiver. The system was put under N2 and charged with cyclohexanol (1 L), and Al(O-sec-Bu)3 (375 mL). The mixture was heated until distillate began collecting in the receiver at a pot temperature of about 120° C. The distillation was continued until the pot temperature reached 162° C., and then cooled to 155° C. The reaction was stirred at 155° C. over 48 h, then cooled to 100° C. and poured into a large beaker containing methanol (MeOH) (1 L), water (400 mL) and concentrated HCl (200 mL). The off-white precipitate was collected on a filter frit (40-60 μm pores), washed with water (30 mL) and MeOH (1 L), and air-dried overnight. The product was dried further under vacuum to afford 22.4 g (71 percent yield). DSC data (scanned at 20° C./min): peak temp 220° C., ΔH=126 Jg−1. IR (KBr, strong abs only): 892, 741, 474 cm−1. 1H NMR (500 MHz, d6-Me2SO): δ 7.56 (m, 6 lines, 6-H, 8-H), 7.60 (dd, J=2.0 9.0 Hz, 7-H), 8.09 (m, 1-H, 3-H, 4-H), 8.39 (‘d’, J=1 Hz, 9-H), 8.57 (s, 5-H), 8.63 (s, 10-H).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:54])[C@@H:14]([NH:16][C:17](=[O:53])[C@@H:18]([O:22][C:23]([C:25]2(/[CH:31]=[CH:32]/[C:33]3[CH:42]=[C:41]4[C:36]([CH:37]=[CH:38][C:39]([C@H:43]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH3:44])=[N:40]4)=[CH:35][CH:34]=3)[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].[OH-].[Na+].Cl>O1CCCC1>[C:49]([O:48][C:46]([NH:45][C@@H:43]([C:39]1[CH:38]=[CH:37][C:36]2[C:41](=[CH:42][C:33](/[CH:32]=[CH:31]/[C:25]3([C:23]([O:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]4)=[O:54])=[O:53])=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[CH:34][CH:35]=2)[N:40]=1)[CH3:44])=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloroethyl ester (42 mg, 0.05 mmol) in tetrahydrofuran (2 mL) was stirred at 0° C. under nitrogen. An ice-cold aqueous solution of sodium hydroxide (0.1 M, 0.5 mL, 0.05 mmol) was added and the reaction mixture was stirred at 0° C. for 30 minutes. Additional sodium hydroxide solution (0.1 M, 1.0 mL, 0.1 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h. Additional sodium hydroxide solution (0.1 M, 1.0 mL, 0.1 mmol) was added and the reaction mixture was stirred at 0° C. for 90 minutes. Cold hydrochloric acid (1 M) was added to acidify the mixture to pH 2 and the solvent was evaporated. The residue was co-evaporated with tetrahydrofuran/toluene (1:1, 3×) and the residue was triturated with diethyl ether (2×) and the resulting solid was dried to afford (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (0.05 mmol) as a yellow solid and as a 1:1 mixture of diastereoisomers which was used crude in the next reaction. LCMS (m/z) 710.3 [M+H], Tr=2.80 min.
Reaction SMILES: [I-].[I-].[Sm+2].[CH3:4][CH:5]([C:8]1[CH:21]=[CH:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=1)[CH2:6][CH3:7].[CH3:22][C:23](=[O:26])[CH2:24][CH3:25]>>[CH3:4][CH:5]([C:8]1[CH:21]=[CH:20][C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][C:13]([C:23]([OH:26])([CH3:22])[CH2:24][CH3:25])=[N:12]3)[N:9]=1)[CH2:6][CH3:7]
Reactant: CCC(C)=O
Reactant: CCC(C)c1ccc2ccc3cccnc3c2n1
Agent: [I-]
Agent: [Sm+2]
Product: CCC(C)c1ccc2ccc3ccc(C(C)(O)CC)nc3c2n1

Procedure:
The title compound is prepared by following the General Procedure I with samarium diiodide and 2-(2-butyl)-1,10-phenanthroline, prepared as described by Example 16, and 2-butanone.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22][OH:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-{5-Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol (0.264 g, 0.85 mmol) and triethylamine (0.154 mL, 1.1 mmol) in CH2Cl2 (4 mL) at 0° C. is added methanesulfonyl chloride (0.077 mL, 1.0 mmol). The mixture is warmed to room temperature and stirred for 2 h. The mixture is concentrated to provide methanesulfonic acid 2-{5-methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethyl ester, which is used without purification. MS (m/e): 389 (M+1)
Reaction SMILES: CC1C=CC(S(O/[N:12]=[C:13]2\[CH2:14][CH2:15][CH2:16][C:17]3[O:21][CH:20]=[C:19]([C:22]([OH:24])=[O:23])[C:18]\2=3)(=O)=O)=CC=1.C([O-])(=[O:27])C.[K+].C(O)C>O>[O:27]=[C:13]1[NH:12][C:18]2[C:19]([C:22]([OH:24])=[O:23])=[CH:20][O:21][C:17]=2[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)O/N=C2\CCCc3occ(C(=O)O)c32)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCCc2occ(C(=O)O)c2N1
Yield: 35.8 %

Procedure:
A mixture of 1.0 g of (E)-4,5,6,7-tetrahydro-4-[[[(4-methylphenyl)sulfonyl]oxy]imino]-3-benzofurancarboxylic acid, 5.9 g of potassium acetate, 23 ml of ethanol and 39 ml of water is heated at reflux for 48 hours. The reaction mixture is concentrated in vacuo, 80 ml of methylene chloride added and the separated organic layer washed with water, brine and dried with Na2SO4. The organic layer is concen-trated in vacuo to a solid which is purified by chroma-tography on a preparative silica gel plate by elution with 0.5% acetic acid in ethyl acetate. The eluted band is washed with 1% acetic acid in ethyl acetate. The organic layer is dried with Na2SO4 and concentrated in vacuo to give 200 mg of off-white solid which is crystallized from ethyl acetate-hexane to give 165 mg of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[CH:15][O:16]C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCCC1.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH:15]=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=CC[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
5 g of 1-chloro-4-[trans-4-(2-methoxyvinyl)cyclohexyl]-benzene in 60 ml of tetrahydrofuran and 20 ml of 9 percent hydrochloric acid are stirred at 60° C. for 2 hours. After cooling to room temperature the aqueous phase is extracted with 100 ml of ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered and evaporated. The residue gave 4.6 g of [trans-4-(4-chlorophenyl)cyclohexyl]acetaldehyde.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].I[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1>C(O)C>[CH2:1]([NH:5][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:22]=2)=[CH:13][C:12]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Solvent: CCO
Product: CCCCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 54.4 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 1.9 ml (19.3 mmol) of n-butylamine and 750 mg (1.29 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 380 mg of ethyl 4′-(3-butylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=175° C., yield=59%).
Reaction SMILES: Br[C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([O:22][CH3:23])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[S:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[CH3:23][O:22][C:19]1[C:20]2[N:21]=[C:13]([C:4]3[N:3]([CH3:24])[C:2]([C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[N:6][C:5]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:14][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: COc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ncnc2sc(-c3c(-c4ccccc4)nc(-c4ccsc4)n3C)nc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)-7-methoxy[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 43) (50 mg), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg), thiophene-3-boronic acid (17 mg) and 2M potassium carbonate (0.25 mL) were heated in toluene (5 mL)/MeOH (1 mL) at 100° C. under an inert atmosphere. After 90 minutes the reaction mixture was cooled to ambient temperature, MgSO4 added, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 35% EtOAc/iso-hexane gave the title compound as a colourless solid (40 mg, 82%);
Reaction SMILES: C[O-].[Na+].C([N:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]1=[O:25])(C(OC)=O)=O>CO>[O:17]([CH2:16][C:15]([NH:14][CH:12]1[CH2:13][NH:10][C:11]1=[O:25])=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(=O)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(COc1ccccc1)NC1CNC1=O
Yield: 57.7 %

Procedure:
Sodium methylate (15 mg.) and absolute methanol (20 ml.) were added to 1-methoxalyl-3-(2-phenoxyacetamido)-2-azetidinone (1.1 g.), and the mixture was heated under reflux for 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in acetone, and then the insoluble material was filtered off. The filtrate was concentrated and allowed to stand cool, and then the precipitated crystals were collected by filtration. The crystals were washed with acetone and dried to give 3-(2-phenoxyacetamido)-2-azetidinone (456 mg.). Furthermore, the same compound (109 mg.) was recovered from the mother liquor. Total yield was 565 mg. Mp 153° to 155° C.
Reaction SMILES: [NH:1]1C=C[N:3]=[CH:2]1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[C:18]([NH:21][C@H:22]([C:25]([OH:27])=[O:26])CS)(=O)C>>[O:26]=[C:25]([CH2:22][N:21]([C:2](=[NH:1])[NH2:3])[CH3:18])[OH:27]
Reactant: c1c[nH]cn1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CN(CC(=O)O)C(=N)N

Procedure:
A creatine kinase buffer solution was prepared to contain 118.9 mmol/L of imidazole (molecular weight 68.1) (Calbiochem, San Diego, Calif.), 11.89 mmol/L of Mg Acetate(H2O)4 (mol. wt. 214.5) (J. T. Baker, Inc.), 23.8 mmol/L of D-Glucose (mol wt 180.2) (Pfanstiehl Labs, Inc.), and 23.77 mmol/L of N-acetyl-L-cysteine (mol wt 163.2) (Boehringer Mannheim Biochemicals, Indianapolis, Ind.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:3]12.[H-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>O1CCCC1.O.C(OCC)(=O)C>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH2:16][CH2:17][CH2:18][CH2:19][C@H:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CCCCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
In round-bottomed flask, (S)-methyl 6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazine-3-carboxylate (860 mg, 3.29 mmol) was dissolve in Tetrahydrofuran (Volume: 41 mL) to give a clear solution. The solution was cooled to 0° C. and NaH (197 mg, 4.94 mmol) was added. The reaction was allowed to stir at RT for 0.5 hour. The translucent solution was then cooled to −78° C. and LAH was added over two minutes. The reaction temperature was maintained between −30° C. and −20° C. for 3 hours while stirring, then cooled to −78° C. Methanol (3 ml, gas evolution) and water (1 ml) were added. The reaction was stirred at room temperature for 30 minutes. The crude product was added to 400 ml ethyl acetate. Water (100 ml) was added and the mixture stirred for 1 hr. The mixture was filtered through medium frit to remove tan solids which were discarded. The aqueous layer was extracted with ethyl acetate (1×100 mL). The organic fractions were combined, washed once with brine and dried with sodium sulfate and concentrated to yield 743 mg (97%) of the product as a white residue. [M+H] calc'd for C12H15N3O2, 234. found, 234.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:8][C:7](=O)[C:6]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:5]2[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:2][C:3]1[NH:8][CH2:7][C:6]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:5]2[N:4]=1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(N)nn12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(C)c2n1N=C(N)NC2

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazin-4(3H)-one, hydrochloride (5 g.) (prepared according to Example 8 of application Ser. No. 300,749 and lithium aluminium hydride (2.9 g.) in tetrahydrofuran were heated under reflux for 78 hours, and cooled. Water (11.6 ml.) was added cautiously followed by aqueous sodium hydroxide (2.9 ml., 15%). The solid was filtered off, the filtrate was evaporated and the residue was triturated with ethyl acetate. The product was crystallised from ethyl acetate and had m.p. 242°-246°.
Reaction SMILES: O.O.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:19]([OH:21])=O)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:25]1([CH2:24][CH2:23][NH:22][C:19](=[O:21])[C@H:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:10][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: NCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)NCCN1CCCCC1
Yield: 96.5 %

Procedure:
To a solution of 200.5 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine dihydrate (0.652 mmol) in tetrahydrofuran (1.5 mL), 101.7 mg of 1-(aminoethyl)piperidine (0.793 mmol), 89.7 mg of 1-hydroxybenzotriazole hydrate (0.664 mmol), and 146.1 mg of N,N′-dicyclohexylcarbodiimide (0.708 mmol) were added with stirring under ice cooling. The reaction mixture was stirred for 1 hour under ice cooling and for 1 hour at room temperature, and then concentrated under reduced pressure. Ethyl acetate (1 mL) was added to the residue. Insoluble materials were removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue (438 mg) was purified by column chromatography on alumina (alumina 2 g, chloroform), whereby 267 mg of the crude product was obtained. The crude product was purified by silica gel column chromatography [silica gel 10 g, about 15% ammonia/methanol-chloroform (1:100)], whereby 240.0 mg of N-t-butoxycarbonyl-β-cyclohexyl-L-alanine 2-(1-piperidinyl)ethyl amide was obtained as a colorless oil (yield 96%)
Reaction SMILES: [CH3:1][Li].[CH3:3][CH:4]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6][O:5]1.[NH4+].[Cl-]>C(OCC)C.[Cu]I>[CH3:3][CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][CH:6]([CH3:1])[O:5]1
Reactant: [Li]C
Reactant: CC1CC(=O)C=CO1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1CC(=O)CC(C)O1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.6M methyllithium in diethyl ether (20.9 mL, 33.4 mmol) was added to a stirred slurry of copper(I) iodide (4.25 g, 22.30 mmol) in diethyl ether (30 mL) at 0° C. and under nitrogen. The reaction was stirred at 0° C. for 20 min and then racemic 2-methyl-2H-pyran-4(3H)-one (1.25 g, 11.2 mmol) in diethyl ether (12.0 mL) was added over 10 min. The reaction was allowed to warm to RT and stirred 2 h. The reaction mixture was poured into sat NH4Cl (aq) and stirred 20 min. The solution was extracted with diethyl ether (4×60 mL) and the combined organics were washed with brine (˜80 mL), dried (MgSO4), filtered and concentrated to yield racemic (2R,6R)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (Cap-2, step b) (1.34 g) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.28-4.39 (m, 2H), 2.55 (ddd, J=14.1, 4.8, 1.5 Hz, 2H), 2.24 (ddd, J=14.1, 6.5, 1.5 Hz, 2H), 1.28 (d, J=6.3 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1
Reactant: Cc1ccccc1Br
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Yield: 88.9 %

Procedure:
A mixture of ethyl isonipecotate (69.25 g, 0.441 mol). -bromotoluene (75.44 g, 52.4 ml, 0.441 mol) and triethylamine (44.74 g, 61.5 ml, 0.441 mol) in 1000 ml methylene chloride was stirred at r.t. for 20 hr. The mixture was washed with brine and the organic layer was separated, dried and concentrated to give 97.016 g of ethyl 1-benzylpiperidine-4-carboxylate as a yellow oil. HNMR (CDCl)δ 1.2(t, 3H), 1.6-1.9 (m, 4H), 2.0 (dt, 2H), 2.2-2.3 (m, 1H), 2.85 (m, 2H), 3.5 (s, 2H), 4.1 (q, 2H), 7.2-7.36 (m, 5H) ppm.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[CH2:9]([Si:11]([CH2:21]C)([CH2:19]C)[C:12]1[O:16][CH:15]=[C:14](C=O)[CH:13]=1)C.C(OC(=O)C)(=O)C>>[CH2:1]([C:13]1[CH:14]=[CH:15][O:16][C:12]=1[Si:11]([CH3:9])([CH3:19])[CH3:21])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: [Li+]
Solvent: CC(=O)OC(C)=O
Product: CCc1ccoc1[Si](C)(C)C

Procedure:
Reacting 1-N-acetyl-20-(-N',N'-dimethyl)decyl diamine (prepare from 1,10-(-N',N'-dimethyl)decyl diamine with acetyl chloride) with lithium diisopropylamide, followed by 5-triethylsilyl-3-furaldehyde and acetic anhydride gives 4-[1-acetoxy-2(N-10-N',N'-dimethyl)aminodecyl)amido]ethyl-2-trimethylsilylfuran. Treatment of this intermediate with excess iodomethane followed by singlet oxygen oxidation gives r-[1-acetoxy-2-(N-10-(N',N',N'-trimethyl)aminodecyl)amido]ethyl-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(Br)cc2)nn1
Yield: 42.8 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (60 mg, 0.17 mmol); 1-azido-4-bromobenzene (51 mg, 0.26 mmol); CuSO4 (4.4 mg, 0.03 mmol); NaAsc (22 mg, 0.11 mmol); TBTA (20.0 mg, 0.04 mmol); in t-BuOH/EtOH/H2O (2:2:1); afforded the 44 as a white solid (40 mg, 42.6%). 1H NMR (DMSO-d6, 400 MHz): δ 9.00-8.99 (d, 1H, J=1.66 Hz); 8.74-8.71 (t, 1H); 8.63-8.61 (d, 1H, J=8.22 Hz); 8.54 (s, 1H); 7.60-7.56 (d, 2H, J=14.85 Hz); 7.345-7.341 (d, 1H, J=1.63 Hz); 7.11-7.07 (d, 2H, J=14.85 Hz); 4.69-4.66 (q, 1H); 4.40-4.38 (d, 2H, J=5.59 Hz); 4.20-4.13 (m, 2H); 3.66-3.66 (d, 1H, J=1.73 Hz); 3.52-3.51 (d, 1H, J=1.73 Hz); 3.33-3.12 (m, 2H); 1.23-1.20 (t, 3H). 13C NMR (100 MHz, DMSO-d6): 170.57, 167.51, 165.36, 154.07, 153.27, 146.56, 139.39, 136.25, 122.30, 121.54, 117.51, 116.23, 61.97, 53.46, 52.99, 51.76, 34.75, 33.50, 14.32.