Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])C)[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[CH2:26]([N:28](CC)CC)C.CN=C=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([NH:28][CH3:26])=[O:24])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CCN(CC)CC
Agent: CN=C=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2.03g (6.53 mmole) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of triethylamine in 30 mL of dry THF at -10° C. and under a nitrogen atmosphere was added dropwise over 10 minutes 0.40 mL (6.78 mmole) of methylisocyanate. The mixture was slowly warmed to room temperature. After 4 hours it was poured in water and extracted 3× with CH2Cl2. The organic portions were combined, dried over MgSO4, filtered and concentrated in vacuo to afford a product which was recrystallized from CH2Cl2 /ethyl acetate/hexanes to give 1.70 g of the title compound as white crystals. (m.p. 194.5°-196° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Yield: 99.3 %

Procedure:
1.63 g (6.83 mmol) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 50 ml of ethanol, treated with 350 mg of PtO2.H2O and hydrogenated (1 atm) for 7 h. The reaction was filtered and evaporated to give 1.65 g (99%) of 4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 244 (MH1, 1Cl).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].C1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])(=[O:26])[CH3:25]
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)NCCC(C)c1ccccc1-c1ccccc1
Reaction time: 3 h

Procedure:
A mixture of 2.25 g of 3-p-biphenylyl-butylamine, 20 ml of benzene, 1 ml of pyridine and 1 ml of acetic anhydride is stirred for 3 hours at 25°. 1-Acetamido-3-p-biphenylylbutane is obtained after working up in the customary manner.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].[N+:22]([C-:25]([CH:28]=O)[CH:26]=O)([O-:24])=[O:23].[Na+].O>CC(O)=O>[N+:22]([C:25]1[CH:26]=[N:1][C:2]2[N:6]([N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]=2[C:20]#[N:21])[CH:28]=1)([O-:24])=[O:23]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=C[C-](C=O)[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2cc([N+](=O)[O-])cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (83 mg, 0.3 mmol) in HOAc (2 mL) was added sodium 2-nitro-1,3-dioxopropan-2-ide (47 mg, 0.3 mmol). After stirring at RT for 1 hr, water (2 mL) was added. The mixture was partitioned between EA (25 mL) and brine (25 mL). The combined organic layers were washed with brine (25 mL×2), dried over Na2SO4 and concentrated to afford 90 mg of 6-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (84%) as a yellow solid. MS (ESI) m/e [M+1]+ 358.2.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][N:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ccncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
p-Anisaldehyde (320 g, 2.35 mol, 1.0 equiv; Aldrich, St. Louis, Mo.) and 4-aminopyrimidine (246 g, 2.58 mol, 1.1 equiv; AK Scientific, Inc., Union City, Calif.) were dissolved in anhydrous DCM (8.0 L). To this solution under N2 atmosphere at room temperature was added a solution of Ti (Oi-Pr)3Cl (1348 g, 5.17 mol, 2.2 equiv; Aldrich) in anhydrous DCM (1 L) in one portion and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 10° C. and NaBH(OAc)3 (1495 g, 7.05 mol, 3.0 equiv; Aldrich) was added in portions over 30 min followed by the addition of acetic acid (10 mL). (Note: A mild exotherm of 10-19° C. was observed). Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction was monitored using LC/MS. Product formation was observed along with many other peaks. Upon completion the reaction mixture was quenched slowly and carefully pouring over a well-stirred saturated aqueous NaHCO3 (30 L). The crude product was then extracted with dichloromethane (3×12 L) and the organic extracts were combined, washed with brine (5 L), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was initially triturated with hexanes to obtain a solid. The crude solid was further triturated with MTBE to remove most of the impurities. The crude product was purified using column chromatography eluting with MeOH/ethyl acetate (2:98 to 5:95) to afford N-(4-methoxybenzyl)pyrimidin-4-amine (INTERMEDIATE OO) as a white solid with >99% purity (129 g, 26% yield). 1H NMR (400 MHz, DMSO) δ ppm 8.40 (s, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.82 (t, J=6.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 6.98-6.77 (m, 2H), 6.48 (s, 1H), 4.43 (s, 2H), 3.72 (s, 3H). m/z (ESI) 216.0 (M+H)+
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:12][C:11]1([CH3:19])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 1-octyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, methacryloyl chloride and triethylamine in methylene chloride to afford the title compound as a colorless oil. Analyses by nmr, ir and ms give data consistent with the desired structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:9]=[N:8][N:7]=1.BrCC1C=CC(C(OCC)=O)=CC=1.[NH:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31]1.N1C2C=CN=CC=2N=C1>>[CH:11]1([N:10]2[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[N:30]=[CH:31]3)=[N:7][N:8]=[N:9]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClCCCCc1nnnn1C1CCCCC1
Reactant: c1cnc2nc[nH]c2c1
Agent: CCOC(=O)c1ccc(CBr)cc1
Agent: c1cc2[nH]cnc2cn1
Product: c1cnc2c(c1)ncn2CCCCc1nnnn1C1CCCCC1

Procedure:
Utilizing the procedure described in Example 1(a) employing 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in lieu of ethyl 4-bromomethylbenzoate and imidazo[4,5-b]pyridine in lieu of imidazo[4,5-c]pyridine yielded an impure mixture of isomers. The mixture was purified by column chromatography (silica gel, 5% ethanol in chloroform) to yield a less polar isomer which was recrystallized from diethyl ether-chloroform to yield 3-[4-(1-cylohexyl-1H-tetrazol-5-yl)butyl]-3H-imidazo[4,5-b]pyridine as a colorless crystalline solid, having a melting point of 94°-95° C. and the following physical characteristics:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:24]4[CH:25]=[N:26][C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:30][C:28]1[CH:29]=[C:24]([N:22]2[CH2:21][CH2:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:13][C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[C:15]=3[CH2:23]2)[CH:25]=[N:26][C:27]=1[O:31][CH3:32]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (766.2 mg, 1.66 mmol) was dissolved in a TFA/CH2Cl2 (1/2) solution and stirred at rt for 1 h. The reaction mixture was concentrated under vacuum, the residue was diluted with CH2Cl2, the organic layer washed with NaOH 1N then brine, dried over Na2SO4, filtered and evaporated to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine. LCMS: [M+H]+=362.1, Rt(3)=1.28 min.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1)=[N+:2]=[N-:3].[H-].[Na+].I[CH3:24].O>CN(C=O)C>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([O:20][CH3:24])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CC(N=[N+]=[N-])CCN(c2c([N+](=O)[O-])cnn2C)C1
Reaction time: 0.17 h

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (0.85 g, 3.0 mmol) in DMF (5 mL) cooled to 0° C. under nitrogen, was added sodium hydride (60% in mineral oil, 133 mg, 3.3 mmol) and the resulting mixture was stirred for 10 min. Iodomethane (0.37 mL, 6.0 mmol) was added and the mixture stirred at room temperature for 16 hr. Water (200 mL) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-azido-3-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as an oil (0.76 g). This azide (0.76 g, 2.6 mmol) in THF (15 mL) and water (3 mL) was treated with triphenylphosphine (0.71 g, 2.7 mmol). The mixture was heated at 65° C. for 16 hr and the solvents were removed under reduced pressure to afford 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was suspended in DCM (40 mL) and di-tert-butyl dicarbonate (1.13 g, 5.2 mmol) and DIPEA (1.36 mL, 7.8 mmol) were added. After stirring at room temperature for 16 hr the solvent was removed under reduced pressure and the residue dissolved in DCM (40 mL). Water (20 ml) was added and the organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.84 g, 74% over three steps) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=4.3 Hz, 1H), 5.39 (d, J=7.9 Hz, 1H), 4.21-3.94 (m, 1H), 3.84 (s, 3H), 3.56-3.42 (m, 2H), 3.35-3.03 (m, 6H), 2.28-1.89 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([S:8][CH:9]1[NH:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH2:22][CH2:23][CH2:24]OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([S:8][CH:9]1[N:12]([CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(SCc2ccccc2)N1
Reactant: O=S(=O)(OCCCc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(SCc2ccccc2)N1CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A solution of 4-(benzylthio)azetidin-2-one (1.1 g, 5.5 mmol) in dry THF (10 ml) was added dropwise over 10 minutes to a suspension of NaH (0.13 g, 5.6 mmol) in dry THF (5 ml) at -20° C. under a N2 atmosphere. A solution of 3-phenyl-1-(trifluoromethanesulfonyloxy)propane (1.5 g, 5.6 mmol) in dry THF (10 ml) was added dropwise over 10 minutes at -55° C. After stirring for 1 hour, the mixture was poured into ice/water (50 g), filtered through hyflo, the THF evaporated under reduced pressure and the residue taken up in ethyl acetate. The solution was washed with brine (×2), dried (MgSO4), evaporated under reduced pressure and purified by flash chromatography on silica gel eluted with 5:1 petroleum ethemethyl acetate to give the title compound as a yellow oil (1.4 g, 81%). 1H NMR δ (CDCl3) 2.58 (2H, m, CH2), 2.58 (2H, t, J=15 Hz, CH2Ph), 2.9, 3.2 (each 2H, m, H-3 & NCH2), 3.73 (2H, s, SCH2), 4.51 (1H, m, H-4), 7.2 (10H, m, 2×Ph--H)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].Cl.[CH2:9]([C:16]([NH2:18])=[NH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.ClCCCl>[CH3:5][O:4][C:2]([NH:18][C:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[NH:17])=[O:3]
Reactant: COC(=O)Cl
Reactant: N=C(N)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)NC(=N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
137.2 parts of methyl chloroformate and a solution of 162.7 parts of potassium hydroxide in 180 parts of water are added via two inlets to a mixture of 246 parts of benzylmethanamidine hydrochloride in 530 parts of 1,2-dichloroethane and 85 parts of water, at from 10° to 15° C., in the course of 35 minutes. The mixture is stirred at 25° C. for 20 minutes, the organic phase is separated off and the aqueous phase is extracted twice more with 1,2- dichloroethane. The organic extracts are concentrated to give 259.8 parts (93% of theory) of N-methoxycarbonylbenzylmethanamidine of nD25 1.5247.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH2:26](I)[CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC(C)C(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCCCI
Agent: [Na]
Solvent: CCO
Product: CCCCC(CC(C)C(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 10 °C

Procedure:
4,4-Diethoxycarbonyl-2-methylbutyric acid benzyl ester [prepared by Michael condensation of benzylmethacrylate and malonic ester as per J. Am. Chem. Soc., 52, 4598 (1930)] (3.36 g, 10 mmole) is added to a solution of 0.23 g of sodium in ethanol (3 ml) chilled to 10° C. Butyl iodide (1.85 g, 10 mmoles) is added and the mixture is refluxed for four hours. The solvent is removed in vacuo and the mixture is distilled in vacuo to yield 4,4-diethoxycarbonyl-2-methyloctanoic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[S:34][C:35]2[CH:41]=[C:40]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:38][C:36]=2[N:37]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([CH3:32])[S:34][C:35]=2[CH:41]=1)(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2ccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)cc2s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-methylbenzo[d]thiazole-6-sulfonyl chloride (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CO
Product: COCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 10.5 gm (0.03 mol) of diamine 15, 4.0 gm (0.03 mol) of benzyl chloride, and 15 gm of MeOH were charged to the flask and heated to reflux. After 1.5 hours, GC showed 5-10% benzyl present along with amine. The reaction was allowed to reflux overnight (ca. 15 hr). GC showed the benzyl chloride consumed and some amine still present. Benzyl methyl ether was formed as a by-product of the reaction. Excess amine and other residue was removed by vigorous washing of the crude product in ether. After rotary evaporation, 10 gm (70% crude yield) of Quat 5 was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[C:11]([CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)([CH3:13])=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:8][C:7]1[C:2]([NH:20][C@H:17]2[CH2:18][CH2:19][C@@H:14]([C:11]([CH3:13])=[CH2:12])[CH2:15][CH2:16]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: C=C(C)C1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Temperature: 25 °C

Procedure:
1.6 g (0.009 mol) of 4,5-dichloro-6-ethylpyrimidine and 1.2 g (0.009 mol) of 4-isopropenylcyclohexylamine were stirred with 1.8 g (0.013 mol) of K2CO3 in 10 ml of DMF at 80° C. for 6 hours. After cooling to room temperature, the mixture was placed in water and extracted with ether. The organic phase was washed with water, dried and filtered, and the filtrate was chromatographed on silica gel with petroleum ether/ethyl acetate 7:3 in order to separate the cis/trans isomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[CH3:17][O:16][C:14]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:19][CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: COC(=O)c1cccc(-c2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(NCCNC(=O)OC(C)(C)C)c2)c1
Temperature: 55 °C
Yield: 16.3 %

Procedure:
A mixture of methyl 3′-aminobiphenyl-3-carboxylate (3.0 g, 13.22 mmol, 1.00 equiv.), tert-butyl 2-bromoethylcarbamate (3.0 g, 13.22 mmol, 1.00 equiv.) potassium carbonate (3.6 g, 26.09 mmol, 2.00 equiv.), and N,N′-dimethylformamide (20 mL) was heated at 50-60° C. for about 16 hours. Additional tert-butyl 2-bromoethylcarbamate (3.0 g, 13.22 mmol, 1.00 equiv) was added and the mixture was heated an additional 14 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with water, dried over sodium sulfate, filtered, and concentrated to afford a crude product that was purified by silica gel chromatography (petroleum ether/ethyl acetate (8:1) to give the title product as light-yellow oil (800 mg; yield=16%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(F)c(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-5-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90° C. for 1 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](OS(C)(=O)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:14]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCCc1ccccc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCn2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-phenyl-1H-imidazole (1 g, 8.75 mmoles) in DMF (8 mL) is added NaH 60% dispersion in mineral oil (455 mg, 11 mmoles). The reaction mixture is stirred at room temperature for 1 hour, then methanesulfonic acid phenethyl ester (example 4D) (1.84 g, 9.12 mmoles) is added. The reaction mixture is then heated at 60° C. for 2 hours. Water is added, and the aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) (100:0) then (98:2) to give 1-phenethyl-4-phenyl-imidazole.