Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[CH3:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=1
Reactant: OCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCCCCCCCCCO)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
With 100 ml of 2-butanone were mixed 20.0 g (79.6 mmol) of 11-bromoundecane-1-ol, 11.0 g (72.5 mmol) of methyl p-hydroxybenzoate, and 10.0 g (72.4 mmol) of potassium carbonate. The whole was refluxed for 48 hours. Upon cooling the reaction mixture to room temperature, a large amount of precipitate appeared. The precipitate was collected by filtration under washing with hexane and dried to obtain 20.2 g of methyl p-(11-hydroxyundecyloxy)benzoate (1) (yield: 86.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nccs2)CC1
Temperature: 90 °C
Yield: 94.3 %

Procedure:
A solution of 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.205 g, 0.58 mmol) and 2-(tri-n-butylstannyl)thiazole (0.239 g, 0.64 mmol) in 6 mL of dry DMF was degassed with a stream of Ar bubbles for 10 min. To this solution was added (Ph3P)4Pd (0.067 g, 10 mol %) and CuI (0.011 g, 10 mol %), and then the reaction vessel was sealed and heated at 90° C. for 18 h. The cooled mixture was concentrated and then it was partitioned with EtOAc-water. The organic phase was washed (brine), dried (MgSO4) and evaporated. Flash chromatography of the residue (SiO2/hexane-EtOAc, 3:2) afforded the title compound (0.195 g, 94%) as a yellow solid:
Reaction SMILES: [OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:18]1([C:24]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[C:33]([F:36])([F:35])[F:34])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:21]2[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])[CH2:19][CH2:20]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(Cl)nn1
Product: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a brown solid (51% yield). m.p. 186-189° C. 1H NMR (300 MHz, CDCl3) δ 8.20, 8.04, 7.75, 7.22, 7.07, 6.98, 4.06-3.98, 3.91-3.71, 3.47-3.23, 2.45, 0.96. 13C NMR (75 MHz, CDCl3) δ 166.3, 164.1, 160.1, 160.0, 130.1, 127.2, 116.9, 116.6, 115.0, 114.7, 112.4, 79.4, 46.4, 44.5, 44.3, 41.9, 41.3, 34.4, 25.7. MS (ES+) m/z 498 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([OH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:38]([O:44][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCO
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCOC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with hexanol, mp 66°-68° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[C:8]([CH3:12])[N:9]=[C:10](O)[C:5]=2[N:4]([CH2:13][CH3:14])[N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:10]1[C:5]2[N:4]([CH2:13][CH3:14])[N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[C:8]([CH3:12])[N:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCn1nc(C)c2nc(C)nc(O)c21
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1nc(C)c2nc(C)nc(Cl)c21
Yield: 85.8 %

Procedure:
A mixture of 16 g (0.083 mol) of 3,5-dimethyl-1-ethyl-7-hydroxy-1H-pyrazolo[4,3-d]pyrimidine and 18.5 g (0.087 mol) of phosphorus pentachloride in 120 ml of phosphorus oxychloride is stirred under reflux five hours. The solution is evaporated in vacuo. The residue is redissolved in ether and percolated over neutral alumina to yield 15 g of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine, a low-melting waxy solid (40°-50° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C:5](=[O:7])[NH:4][C@@H:3]1[C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:36][C@H:37]([C:44]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH2:50])=[O:49])=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][C:5](=[O:7])[NH:4][C@@H:3]1[C:8]([NH:36][C@H:37]([C:44]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH2:50])=[O:49])=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:10]
Reactant: C[C@@H]1CC(=O)N[C@@H]1C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H]1CC(=O)N[C@@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
cis-3-Methylpyroglutamic acid [A. B. Mauger, J. Org. Chem. 46, 1032 (1981)] (1.5 g) was dissolved in DMF (30 ml), and HOBT (1.6 g) was added to the solution, followed by addition of DCC (2.81 g) under cooling at 0° C. The mixture was stirred at the same temperature overnight. The above-mentioned DMF solution of L-histidyl-L-prolinamide was added to the mixture, and the mixture was stirred at 5° C. overnight. After the resulting precipitation was filtered off, the filtrate was concentrated to dryness under reduced pressure and the residue was subjected to silica gel column chromatography with chloroform-methanol-ammonia water (40:10:1) as eluent. The eluted fractions were combined and concentrated to dryness to give Nα -(cis-3-methylpyroglutamyl)-L-histidyl-L-prolinamide (2.2 g) as powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[C:14]([NH:21][CH3:22])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+].C1N=CN(C(N2C=NC=C2)=O)C=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:12][C:13]2[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[N:21]([CH3:22])[C:23]1=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: CC#N
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])ccc1Cl)C2
Temperature: 50 °C
Yield: 96 %

Procedure:
20.796 g {5-[(2-Chloro-5-nitro-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-methyl-amine were dissolved in 500 ml acetonitrile, 25.375 g potassium carbonate and 19.847 g N,N-carbonyldiimidazole (CDI) were added, and the solution was heated at 50° C. for 24 hrs. The solvent was dried over sodium sulfate, evaporated, and the residue was extracted with diethyl ether to give the title product in 96% yield.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[CH3:21])(=[O:3])[CH3:2].Cl.[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:31][CH2:30][CH2:29][C:28]1[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=1)=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C)c2[nH]c1=O
Reactant: NCCc1ccc(F)cc1
Agent: Cl
Product: CC(=O)c1c(NCCc2ccc(F)cc2)c2cc(Cl)cc(C)c2[nH]c1=O
Yield: 77.8 %

Procedure:
3-Acetyl-6-chloro-8-methyl-4 -methylsulfoxy -2-quinolinone (2.98 g, 0.01 mol) and p-fluorophenethylamine hydrochloride (1.76g, 0.01 mol) were used, but the reaction was carried out as the above process of example 42 to obtain the desired product (2.9g, yield: 71%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of crude 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (13.33 mmol, 75% pure) in DCM (10 mL) was added Et3N (1.4 mL, 10 mmol) and 1-methylpiperazine (1.1 mL, 10 mmol). After stirring for 3 h at rt, aq. NaHCO3 was added, and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 10% MeOH/DCM) to provide 2.21 g of product as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:15][CH2:16]2)=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCC(Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCC(Oc3ccc(N)cc3)CC2)cc1
Yield: 76.6 %

Procedure:
N-2-(4-Nitrophenoxy)ethyl-4-(4-nitrophenoxy)piperidine (1.50 g, 3.87 mmol) was hydrogenated in THF/MeOH (1:1, 60 mL) at 50 psi over 10% Pd/C (0.5 g) for 16 hours. The mixture was filtered through solka floc and the filtrate was concentrated. Purification by flash chromatography (8% MeOH/CHCl3) gave 0.97 g (80%) of N-2-(4-aminophenoxy)ethyl-4-(4-aminophenoxy)piperidine as a yellow oil. 1H NMR (DMSO-d6): δ 6.65 (d, 4H), 6.50 (d, 4H), 4.60 (br s, 4H), 4.05 (m, 1H), 3.90 (t, 2H), 2.78 (m, 2H), 2.60 (t, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.55 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncc([N+](=O)[O-])cc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3,5-dinitropyridine were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Direct filtration of the reaction mixture afforded a red solid which was recrystallized in ethanol to afford the title compound (7%) as a red solid: mp, 194.0°-195.0° C.; 13C NMR (DMSO-d6) δ152.2, 150.7, 134.7, 134.1, 131.2, 128.2, 127.1, 126.7, 123.9, 119.1, 114.8, 112.7, 111.4, 59.7, 44.9, 22.8; HRMS calculated for C17H18N6O4 370.1391, found 370.1358. Anal. calcd. for C17H18N6O4.1/2H2O: C, 53.82; H, 5.04; N, 22.15. Found: C, 53.55; H, 4.58; N, 21.98.
Reaction SMILES: [C:1]([O:6][CH:7](OCC=C)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:19]([O:22]C1C=CC(CCO)=CC=1)[CH:20]=[CH2:21].C(Br)C=C>>[C:1]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:19][CH:20]=[CH2:21])=[CH:13][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOc1ccc(CCO)cc1
Reactant: C=CCOC(Cc1ccccc1)OC(=O)C(=C)C
Solvent: C=CCBr
Product: C=CCOc1ccc(CCOC(=O)C(=C)C)cc1

Procedure:
Allyloxyphenethyl methacrylate, 82% purity, was prepared in the manner of Example 3 from 2-(4-allyloxyphenyl)ethyl alcohol. The starting 2-(4-allyloxyphenyl)ethyl alcohol was prepared by alkylation of the corresponding phenolic alcohol with allyl bromide.
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH3:25][C:26]1([CH3:37])[O:30][C:29]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:28]=2[O:27]1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][CH2:35][C:33]2[CH:32]=[CH:31][C:29]3[O:30][C:26]([CH3:37])([CH3:25])[O:27][C:28]=3[CH:34]=2)[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)Oc2ccc(C=O)cc2O1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)Oc2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2O1

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 83 mg of 2,2-dimethyl-benzo[1,3]dioxole-5-carbaldehyde (0.47 mmol) (described in example S119), 89 mg of 2-(3,4-dichloro-phenyl)-ethylamine (0.47 mmol) and 26 mg of sodium borohydride (0.70 mmol). The isolated colorless liquid (133 mg, 81%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.66 (s, 6H), 2.76 (m, 2H), 2.86 (m, 2H), 3.68 (s, 2H), 6.66 (s, 1H), 6.68 (d, J=7.4 Hz, 2H), 7.04 (dd, J=8.2 and 2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[NH:33])[CH2:27][CH2:26]2)=[CH:11][CH:10]=1.[OH-].[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[N:25]2[CH2:26][CH2:27][CH:28]([N:31]([CH3:36])[C:32]([NH:34][CH3:35])=[N:33][C:5](=[O:7])[CH3:6])[CH2:29][CH2:30]2)=[CH:11][CH:10]=1
Reactant: CNC(=N)N(C)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=NC(C)=O)N(C)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
0.48 ml of acetic anhydride dissolved in 5 ml of methylene chloride is added to a solution of 2 g (0.005 mole) of N-[1-[1-[(4-fluorophenyl)methyl]-2-(1H)-benzimidazolyl]-4-piperidinyl]-N,N'-dimethylguanidine in 20 ml of methylene chloride, cooled to 5° C. Stirring is continued for 2 h and the mixture is then poured into concentrated sodium hydroxide. The phases are separated, the organic phase is dried with MgSO4, is filtered and is evaporated down. On addition of acetone, the product crystallizes. It is purified by chromatography on a silica column (eluent 9/1 methylene chloride/methanol) N-[1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-4-piperidinyl]-N,N'-dimethyl-N"-acetylguanidine is obtained.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH2:10])=[NH2+:9])#[N:6].C(N(CC)CC)C.BrBr.[S-:23][C:24]#[N:25].[K+]>CO>[NH2:25][C:24]1[S:23][N:10]=[C:8]([C:7](=[N:11][O:12][CH3:13])[C:5]#[N:6])[N:9]=1
Reactant: N#C[S-]
Reactant: CON=C(C#N)C(N)=[NH2+]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C#N)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 174.9 %

Procedure:
To a solution of 2-cyano-2-(methoxyimino)acetamidinium acetate (12.5 g) dissolved in methanol(100 ml) was added triethylamine(23.4 ml). Thereafter, bromine (12.9 g) was added slowly in small portions at -15° C., and the mixture was stirred for 5 minutes at -15°~-10° C., Potassium thiocyanate(3.7 g) dissolved in methanol(55 ml) was then added dropwise to the mixture at temperatures of -10° to -5° C., and the mixture stirred for 2 hours at 0° C. The reaction mixture was poured into ice water (1.2 l), and stirred for 30 minutes. The precipitates were filtered and dired to give the above-indicated compound (12.2 g) in pale brown.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:21](=[O:23])[CH3:22])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 4-(4-bromophenyl)piperidine (400 mg, 1.70 mmol) in dichloromethane (20 mL) was added triethylamine (340 mg, 3.40 mmol) and acetic anhydride (500 mg, 5.10 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue. The material was partitioned between water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was washed two additional times with ethyl acetate (30 mL). The combined organics layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (260 mg, 60% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2H), 6.91 (d, 2H), 4.63 (d, 1H), 3.77 (d, 1H), 3.00 (t, 1H), 2.57-2.42 (t, 2H), 1.97 (s, 3H), 1.75-1.68 (m, 2H), 1.47-1.40 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][O:20][CH3:28])=[CH:15][C:14]=3[C:21]([F:22])([F:24])[F:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(CO)cc3C(F)(F)F)[C@@H]2C1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.08 mmol) and proton sponge (26 mg, 0.12 mmol) in dry CH2Cl2 (1.0 mL) was added trimethyloxonium tetrafluoroborate (11.5 mg, 0.08 mmol). The reaction was stir for 16 hr and then quenched with 1M aq.HCl. The reaction was extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pink oil. The oil was purified by flash chromatography (silica gel, 0–40% EtOAc in hexanes) to yield 13 mg of the desired product as a colorless oil. MS (ESI) 401 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])O)[C:6]=2[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1.Br.[ClH:23].CCOCC>CO>[ClH:23].[CH2:16]([C:9]1[N:10]([CH:11]=[C:12]([CH3:14])[CH3:15])[C:6]2[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CC(C)(C)O
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1C=C(C)C

Procedure:
4-Amino-2-butyl-α,α,6,7-tetramethyl-1H-imidazo[4,5-c]pyridine-1-ethanol (about 200 mg) was combined with concentrated hydrobromic acid (50mL) and heated at reflux overnight. The reaction mixture was concentrated under vacuum. The residue was taken up in methanol then diluted with ether. The resulting precipitate was collected then partitioned between methylene chloride and 10% sodium hydroxide. The organic layer was separated, dried over magnesium sulfate then concentrated to provide an oil. The oil was taken up in methanol then combined with 0.05 mL of concentrated hydrochloric acid followed by dilution with ether. The resulting precipitate was collected, rinsed with ether and dried to provide 60 mg of the desired product as a white solid, m.p. 205° C.(dec.). Analysis: Calculated for C16H24N4 +1.6 HCl: % C, 58.10; % H, 7.80; % N, 16.94; Found: % C, 57.95; % H, 7.87; % N, 16.89.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[Cl:27])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:29]1([CH2:38][C:39](O)=[O:40])[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[Cl:27])=[N:16][N:17]=1)(=[O:11])=[O:12])[C:39](=[O:40])[CH2:38][N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2Cl)s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2Cl)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2-chloro-4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.25 (s, 0.4H), 9.16 (brs, 1H), 8.62–8.57 (m, 1H), 8.54–8.48 (m, 1H), 8.42–8.36 (m, 1H), 7.33 (s, 0.6H), 7.24 (s, 0.4H), 4.66 (s, 1.2H), 4.47 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.06 (s, 1.2H), 3.57 (t, 1.2H), 3.45–3.40 (m, 2H), 3.28 (t, 0.8H), 1.75 (s, 1.8H), 1.74 (s, 1.2H), 1.24 (t, 1.2H), 1.18 (t, 1.8H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(C#N)c2)CC1
Yield: 77.9 %

Procedure:
3-Cyanophenyl boronic acid (1.8 g, 12.2 mmol) and 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.0 g, 15.2 mmol;) are dissolved in acetonitrile (60 ml) and 0.4 M aqueous sodium carbonate (60 ml). The solution is degassed and treated with palladium tetrakistriphenyl phosphine (0.81 g, 0.7 mmol) at 90° C. for 1 hour. The reaction is cooled, filtered warmed and the filtrate is concentrated to an oil. The oil is extracted with methylene chloride (3×) and the solvent is removed under vacuum. The residue is chromatographed (15% ethyl acetate/hexane) to give the title compound as a white solid (2.7 g, 9.5 mmol). 1H NMR (CDCl3, 300 MHz) δ 7.63 (s, 1H), 7.55 (m, 2H), 7.44 (t, 1H), 6.10 (br, 1H), 4.09 (m, 2H), 3.63 (t, 2H), 2.50 (br, 2H). EI MS M++1: 285.