Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([OH:22])[CH2:15]2>>[Cl-:1].[CH2:12]([O:11][C:4]1[N:5]=[C:6]([O:8][CH2:9][CH3:10])[N:7]=[C:2]([N+:14]23[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]2)[CH:16]([OH:22])[CH2:15]3)[N:3]=1)[CH3:13]
Reactant: OC1CN2CCC1CC2
Reactant: CCOc1nc(Cl)nc(OCC)n1
Product: CCOc1nc(OCC)nc([N+]23CCC(CC2)C(O)C3)n1
Product: [Cl-]

Procedure:
The operation was carried out in the same manner as in Preparation Example 1 but using 4.07 g (0.02 mols) of a 2-chloro-4,6-diethoxy-1,3,5-triazine and 2.54 g (0.02 mols) of a 3-quinuclidinol to obtain 6.51 g (yield, 98.4%) of white crystals of a 1-(4,6-diethoxy-1,3,5-triazin-2-yl)-3-hydroxyquinuclidinium chloride represented by the following general formula (XII)
Reaction SMILES: C(OC([N:11]1[CH:17]2[CH:15]([CH:16]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:14]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:13](=[O:31])[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:14]2[C:13](=[O:31])[CH2:12][NH:11][CH2:17][CH:15]2[CH2:16][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1C2C1N(C(=O)OCc1ccccc1)CC(=O)N2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CNCC(=O)N1Cc1ccc(F)cc1

Procedure:
The lower Rf isomer of ethyl 5-benzyloxycarbonyl-2-(4-fluorobenzyl)-3-oxo-2,5-diazabicyclo[4.1.0]heptane-7-carboxylate (7.5 g, 17.5 mmol) and 10% palladium on carbon (940 mg; 0.05 mmol) in ethanol (200 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum to provide the title compound. The structure was assigned by the analysis of HMQC, gHMBC and ROESY spectra. 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J=8.4, 5.3 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 5.22 (d, J=15.0 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.95 (d, J=14.8 Hz, 1H), 3.64-3.80 (m, 1H), 3.61 (d, J=4.5 Hz, 2H), 2.95-3.06 (m, 2H), 2.84 (dd, J=16.1, 9.4 Hz, 1H), 2.59 (dd, J=16.1, 2.4 Hz, 1H), 1.26 (t, J=7.2 Hz, 3H). ES MS (M+1)=295.32.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O>C(#N)C>[C:22]1([CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][N:5]2[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(CC(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 58.23 %

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 500 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (11.46 g, 83 mmol), anhydrous potassium carbonate (28.75 g, 208 mmol) and acetonitrile (220 mL). To the resulting mixture was slowly added a solution of 2,2-diphenylethyl methanesulfonate (23 g, 83 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. A mixed solution of dichloromethane and water was added for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=30:1 (volumetric ratio)) to produce 1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-ol (13.6 g) in a yield of 58.23%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][N:3]=1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9]#[N:10])=[CH:4][N:3]=1
Reactant: Clc1ccncc1
Reactant: Cc1ncc(CC#N)cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C(C#N)c2ccncc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (1.0 g, 7.51 mmol) and 4-chloropyridine hydrochloride (1.13 g, 7.51) in dioxane (20 mL) in a dried flask was degassed and filled with nitrogen. t-BuOK (18.8 mL, 1M in THF) was added. The mixture was stiffed at 100° C. for 4 h and cooled to room temperature, quenched by cooled sat. aq. NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (MeOH: EtOAc=1:10) to give 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)acetonitrile (700 mg, crude).
Reaction SMILES: ClC(OC(C)C)=O.[CH3:8][N:9]1CCOCC1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].Cl.CN.C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:8][NH:9][C:29](=[O:31])[CH2:28][N:25]1[C:26](=[O:27])[N:21]2[CH:20]=[N:19][C:18]([C:15](=[O:17])[NH2:16])=[C:22]2[N:23]=[N:24]1
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Agent: CN
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. After 1 hour, methylamine hydrochloride (142 mg, 2.100 mmol) then triethylamine (0.292 mL, 2.100 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 16 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL), then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane), recrystallized from acetonitrile and triturated with ether to furnish the desired product as a pale pink solid. Yield: 82 mg, 0.33 mmol, 31%. LCMS (ES+) m/z 252 (M+H)+ at solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (1H, s), 8.14 (1H, br q), 7.83 (1H, br s), 7.69 (1H, bs), 4.89 (2H, s), 2.60 (3H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[H-].[Na+].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH:17]=[CH:18][C:11]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
147 mg (0.60 mmol) of the compound from example XIX are dissolved in 10 ml of THF, 48 mg (1.21 mmol) of sodium hydride (in THF) are added and the mixture is then stirred at RT for one hour. 242 mg (1.27 mmol) of p-toluenesulfonyl chloride are then added, and the reaction solution is stirred at 60° C. for another hour. The suspension is filtered through CELITE (diatomaceous earth), the filtercake is washed with THF and a little DCM/methanol 10:1 and the filtrate is concentrated using a rotary evaporator. The residue in the flask is taken up in DMSO and purified by RP-HPLC chromatography (gradient: acetonitrile/water).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:26]([O:30][C:31](=[O:42])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>C(#N)C>[C:26]([O:30][C:31](=[O:42])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:41])[C@H:38]([CH3:40])[NH:39][C@@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 13.1 %

Procedure:
A solution of ethyl 2-bromo-9-phthalimidononanoate [prepared according to Chem. Pharm. Bull. 34, 2078 (1986)] (3 g), L-alanyl-L-proline tertiary butylester (1 g) and triethylamine (0.8 ml) in acetonitrile (200 ml) is subjected to 60 hours' reflux. Acetonitrile is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The solution is dehydrated with anhydrous sodium sulfate, and thereafter is concentrated to obtain an oily residue. When this substance is applied to a silica gel chromatography (ethyl acetate:n-hexane=3:1) for separative purification, 310 mg of N-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]-L-alanyl-L-proline tertiary butylester is obtained as a colorless oil from the first effluence.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1([CH3:39])[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36](=[O:37])[C:33]2[CH:34]=[CH:35][C:30]([CH3:39])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75.0 mg) and triethylamine (41.5 μL) in THF (1.24 mL) was added 4-toluoyl chloride (39.4 μL). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (104.3 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (200 ml) is cooled to 5° C. 4-Fluoroacetophenone (20 ml, 0.16 mol) is added keeping the temperature below 10° C. The mixture is cooled to 0-5° C. and potassium nitrate (25 g, 0.25 mol) is added portionwise over 2 hours keeping the temperature within this range. Following the addition the mixture is stirred in the cold for additionally 2 hours. The mixture is poured on ice (600 g) and the crude product is filtered off. Column-chromatographic purification on silica gel using a mixture of ethyl acetate and petroleum ether (1:9) as the eluent affords pure 1 g (18.2 g, 60%). Mp 48-49° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])=[CH:2]1.I[CH3:16].[C:17]([O:21][C:22](N1C2C(=CC=CC=2)C(CC#N)=C1)=[O:23])(C)(C)[CH3:18]>>[CH2:17]([O:21][C:22]([CH:16]1[C:2]2[NH:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[C:10]([CH3:14])([CH3:13])[CH2:11][NH:12]1)=[O:23])[CH3:18]
Reactant: CC(C)(CN)c1c[nH]c2ccccc12
Reactant: CI
Reactant: CC(C)(C)OC(=O)n1cc(CC#N)c2ccccc21
Product: CCOC(=O)C1NCC(C)(C)c2c1[nH]c1ccccc21

Procedure:
4,4-Dimethyl-2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylic acid ethyl ester was prepared in a manner similar to that described in Example 66A by replacing tryptamine-HCl with 2-(1H-indol-3-yl)-2-methylpropylamine, which was synthesized using 2 equivalents of iodomethane during alkylation of (1-tert-butoxycarbonylindol-3-yl)acetonitrile as described in Example 32B; MS(ESI): 273(MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-chlorophenyl 4-hydroxyphenyl ketone (349 mg) were mixed and stirred at 180° C. for 20 minutes. The reaction mixture was purified by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 26 mg of the title compound (yield: 12%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: CSC(=NC#N)SC
Reactant: COc1ccnc(CSCCN)c1
Solvent: CCO
Product: COc1ccnc(CSCCN=C(NC#N)SC)c1
Reaction time: 8 h

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-4-methoxypyridine (3.15 g) in ethanol (25 cc) was added over 1 hour to a stirred solution of dimethyl N-cyanodithioimidocarbonate (2.215 g) in ethanol (30 cc) at 22° and the mixture was allowed to stand overnight at room temperature. Nitrogen was passed through the suspension and the mixture was filtered to give N-cyano-N'-[2-((4-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea m.p. 91.5°-92.5°. (3.9 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[N:21]=1>C(O)(C)C>[Br:22][C:20]1[N:21]=[C:16]([NH:14][C:11]2[CH:12]=[N:13][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3nc(Br)cn(C)c3=O)cn2)CC1
Yield: 25.4 %

Procedure:
A mixture of 6-(4-methylpiperazin-1-yl)pyridin-3-amine (1 g, 5.2 mmol) prepared according to US 2009/0318448, 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.7 g, 6.2 mmol), and isopropanol (20 mL) was stirred at reflux for 16 h. After the reaction was completed, the solvent was removed to give 331a as a brown solid (500 mg, 30%). MS: [M+H]+ 379.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[C:8]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.Br[CH:20]([C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[O:24][N:23]=1)[CH3:21]>C1COCC1>[Cl:33][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([CH:20]([CH3:21])[CH2:12][C:11]3[N:7]([CH3:6])[C:8]([C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:26]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nnc(-c2ccncc2)n1C
Reactant: CC(Br)c1noc(-c2cccc(Cl)c2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Yield: 9.6 %

Procedure:
84 microl (0.21 mmol, 2.5 M) n-BuLi was added dropwise to a solution of 37 mg (0.21 mmol) 4-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine in 2.1 ml THF at 0° C. After 20 min a solution of 60 mg (0.21 mmol) 3-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole was added dropwise. The reaction mixture was allowed to reach room temperature and stirred over night. NH4Cl(sat) was added and the mixture was extracted twice with EtOAc. The organic phase was dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 7.7 mg (10%) of the desired product. 1H NMR (CDCl3), d (ppm): 1.57 (d, 3 H) 3.16 (m, 1 H) 3.38 (m, 1 H) 3.71 (s, 3 H) 3.84 (d, 1 H) 7.46 (t, 1 H) 7.55 (m, 1 H) 7.58 (m, 2 H) 7.98 (m, 1 H) 8.10 (t, 1 H) 8.77 (d, 2 H)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>CCO.N1CCCCC1>[F:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:23][C:22]3[CH:25]=[CH:26][C:19]([OH:18])=[CH:20][CH:21]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(Nc2ccc(F)cc2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(F)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
5-amino-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-fluorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH3:13])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: Cc1ccc(CCl)cc1
Reactant: OCCNCCO
Product: Cc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol). Yield 9.8 g (99%); MS: 209.9 (M+H)+.
Reaction SMILES: [NH:1]([C:8](=[O:43])[C:9]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH:33]C(=O)OC(C)(C)C)=[O:25])=[CH:22][CH:21]=1)([C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24]([C:23]1[CH:41]=[CH:42][C:20]([C:9]([CH3:10])([C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:43])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:21][CH:22]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)Nc1ccccc1)(C(=O)Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-1-methyl-2-oxoethyl]benzoyl}amino)phenyl]-carbamate (14 mg, 0.024 mmol) in CH2Cl2 (3 mL) at room temperature was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature 30 min and concentrated. Purification by reverse phase HPLC (10% to 95% MeCN in water) gave 2-(4-{[(2-aminophenyl)amino]carbonyl}-phenyl)-2-methyl-N,N′-diphenylmalonamide (12 mg, TFA salt, 84%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.77 (s br, 1H), 9.18 (s br, 2H), 7.87 (d, J=6.2 Hz, 21-1), 7.45-7.42 (m, 6H), 7.34-7.28 (m, 5H), 7.17-7.04 (m, 5H), 6.18 (s br, 21-1), 2.05 (s, 3H); ESIMS calcd 479.2 (M++H), found 479.2 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH:19]([CH:21]=O)=O>C(#N)C>[N:10]12[CH:21]3[N:7]([CH2:6][CH2:5][N:4]4[CH:19]3[N:1]([CH2:12][CH2:11]1)[CH2:2][CH2:3]4)[CH2:8][CH2:9]2
Reactant: CCNCCNCCNCCN
Reactant: O=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C1CN2CCN3CCN4CCN1C2C43

Procedure:
1,4,7,10-tetraazadodecane (1.1.4) trihydrobromide in acetonitrile with potassium carbonate was reacted with glyoxal to form 1,4,7,10-tetraazatetracyclo-[5,5,2,04,13,010,14] tetradecane (1.1.23). Following separation the pure product was obtained by low pressure distillation. This was dissolved in acetonitrile and benzylbromide was added to form 1,7-dibenzylonium-1,4,7,10-tetraazatetracyclo[5,5,2,04,13,010,14] tetradecane (1.1.24). Following recrystallization from ethanol this was reacted with sodium borohydride. HCl was added, followed by water and NaOH, and the product extracted with chloroform. Following evaporation of solvent the solids were dissolved in methanol and HBr was added to obtain 1,7-dibenzyl-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane (1.1.25) as the hydrobromide salt. This was dissolved in water and reduced using H2 and a Pd-C catalyst to remove the benzyl groups. Purification of the title compound was by crystallization of the hydrobromide salt. The base form was obtained by low pressure distillation following addition of base.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[ClH:31].[CH2:38]([N:37]([CH3:36])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2Cl)C3)cc1
Reactant: CCCCNC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2Cl)C3)cc1
Product: Cl

Procedure:
This product was synthesized as described in general procedure 2 except 4-(6-(2-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate was used instead of 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylbutan-1-amine instead of piperidine to afford N-(4-(2-(butyl(methyl)amino)ethyl)phenyl)-6-(2-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine hydrochloride. 1H-NMR 400 MHz (CDCl3) δ 8.44 (dd, J=7.4, 1.1 Hz, 1H), 8.12 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.46-7.39 (m, 3H), 7.24-7.19 (m, 3H), 7.12 (t, J=7.4 Hz, 1H), 7.04 (d, J=7.4 Hz, 2H), 6.75 (dd, J=7.8, 1.5 Hz, 1H), 4.85 (t, J=2.2 Hz, 1H), 3.18-3.12 (m, 2H), 2.79-2.76 (m, 2H), 2.61-2.59 (m, 2H), 2.41 (t, J=7.4 Hz, 1H), 2.31 (s, 3H), 1.51-1.47 (m, 2H), 1.36-1.30 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). LCMS m/e 498 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[N:14]\[OH:15])/[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:15]/[N:14]=[C:5](/[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13])\[C:4]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([Cl:1])[C:3]=1[OH:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2cc(F)ccc2F)c(O)c1Cl
Product: COc1ccc(/C(=N\OC(C)=O)c2cc(F)ccc2F)c(O)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 19 g of E-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone oxime and 10 ml of acetic anhydride was warmed at 60° C. for 30 minutes. On cooling the mixture solidifies. The residue is partitioned between ethylacetate and 10% NaHCO3. The ethylacetate extract is washed with water, dried over Na2SO4 and evaporated to give E-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 130°-131° C.