Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C(C)=CC(C)=CC=1C.[C:38]1([O:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[O:44]([C:45]([NH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[S:20](=[O:23])(=[O:22])[CH2:21][C:12]=3[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1nn(-c2cccc(N)c2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1nn(-c2cccc(NC(=O)Oc3ccccc3)c2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 1-(3-aminophenyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide hydrochloride (100 mg, 0.243 mmol) in THF (10 mL) are added 2,4,6 collidine (0.06 mL, 0.487 mmol), phenylchloroformate (0.04 mL, 0.365 mmol) then stirred at RT for 18 h. After this time, reaction mixture is concentrated under reduced pressure, diluted with water, and extracted with EtOAc. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 100 mg of the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[OH:26]>C(Cl)Cl>[OH:26][C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[NH:18][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(N)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C)cc2O)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Pyridine (810 μl) and then, a little at a time, p-toluenesulfonyl chloride (1.91 g, 10 mmol) are added to a solution of 2-amino-5-methylphenol (1.23 g, 10 mmol) in CH2Cl2 (20 ml). The reaction mixture is stirred at 40° C. for 4 h. The solvent is distilled off under reduced pressure, ethyl acetate is added to the residue and the solid is filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C#N)CC1
Yield: 79.9 %

Procedure:
In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60% ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80%).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2].[CH3:35][C:36]1([CH3:42])[O:40][C:39](=[O:41])[N:38]=[CH:37]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:38]3[CH2:37][C:36]([CH3:42])([CH3:35])[O:40][C:39]3=[O:41])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC1(C)C=NC(=O)O1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Product: CC(=O)N1CCN(c2cc(N3CC(C)(C)OC3=O)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 23.4 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (336 mg) described in Preparation Example 196 and 5,5-dimethyloxazolin-2-one (80.3 mg) described in Preparation Example 43, the title compound (91.3 mg) was obtained.
Reaction SMILES: CO[C:3]1([S:9]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH2:4]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.[BH4-].[Na+].[CH3:28][OH:29]>>[CH3:28][O:29][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([C:11]1[CH:12]=[C:13]([NH:14][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10]
Reactant: O=Cc1cccnc1
Reactant: COC1(S(=O)c2cccc(N)c2)C=CC=CC1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccccc1S(=O)c1cccc(NCc2cccnc2)c1
Yield: 82 %

Procedure:
3-(1-Methoxyphenylsulfinyl)aniline (145 mg, 0.59 mmol) and pyridine-3-carboxaldehyde (63 mg, 0.59 mmol) were reacted in anhydrous methanol (3.0 ml), followed by treatment with sodium borohydride (44 mg, 1.17 mmol) as previously described (Intermediate 3). Silica gel chromatography (2 mm Chromatotron® plate, eluting with 20/1 ethyl acetate/hexanes) afforded N-(3-(2-methoxyphenylsulfinyl)phenyl)pyrid-3-ylmethylamine (162 mg, 82%) as an oil. 1H NMR(400 MHz): 3.77(3H,s), 4.35(2H,br s), 6.61(1H,m), 6.83(1H,d,J=8.0), 6.96(1H,br t), 7.01-7.04(1H,m), 7.11(1H,dt,J=7.8, 1.0), 7.18(1H,t,J=7.8), 7.21-7.28(1H,br s), 7.35-7.41(1H,m), 7.63(1H,br d), 7.82(2H,dd,J=7.8, 1.5), 8.40-8.80(2H,br s); MS(ESI)m/z 339.1([M+H]+,100)
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)=[O:34]
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)Cc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.5 %

Procedure:
A mixture of 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.340 g (1.8 mmol) of 2-chlorophenylacetyl chloride, 0.20 g of triethylamine and 9 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 48 hours. An additional 0.27 g of 2-chlorophenylacetyl chloride is added and the mixture stirred at room temperature for 2.5 hr. The mixture is washed with 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from dichloromethane to give 0.27 g of crystals, m.p. 191°-194° C. Anal. Calc'd for C29H23ClN2 O2 : C,74.6; H,5.0; N,6.0; Cl,7.6. Found: C,74.4; H,4.9; N,5.9; Cl,7.8.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-amino-2-methylpropan-1-ol (CAS 124-68-5) (53 mg, 0.6 mmol), HATU (129 mg, 0.3 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide 18. LC/MS (ESI+): m/z 338 (M+H). 1H NMR (400 MHz, DMSO) δ 8.69-8.55 (m, 2H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.05 (d, J=39.6 Hz, 2H), 7.91 (d, J=7.7 Hz, 1H), 7.76 (s, 1H), 7.61 (t, J=7.7 Hz, 1H), 4.90 (t, J=6.0 Hz, 1H), 3.57 (d, J=6.0 Hz, 2H), 1.36 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]>Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OCCC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Product: COC(=O)C1(c2ccc(OCCC(=O)O)cc2)CC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (6.3 g, 20 mmol) in HCl (20%, 200 mL) was heated at 110° C. for 1 h. After cooling to room temperature, the resulting mixture was filtered. The solid washed with water and dried under vacuum to give 1-[4-(2-carboxy-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (5.0 g, 96%). 1H NMR (300 MHz, DMSO) δ 7.23-7.19 (m, 2H), 6.85-6.81 (m, 2H), 4.13 (t, J=6.0 Hz, 2H), 3.51 (s, 3H), 2.66 (t, J=6.0 Hz, 2H), 1.43-1.39 (m, 2H), 1.14-1.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[C@H:29]12[CH2:35][C@H:32]([O:33][CH2:34]1)[CH2:31][NH:30]2>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:20]([N:30]3[CH2:31][C@@H:32]4[CH2:35][C@H:29]3[CH2:34][O:33]4)=[O:21])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: O=C(Cl)Oc1ccccc1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)N3C[C@@H]4C[C@H]3CO4)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine, phenyl chloroformate and (1S,4S)-2-aza-5-oxabicyclo-[2.2.1]heptane, the title compound was prepared as white crystals (52% yield). MS: m/e=390(M+H+), mp 193-197° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 58.2 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added thereto. A solution of 6.0 g of icosyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4 g of diethyl 2-acetamido-2-icosylmalonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.C(O)(=O)C>[Fe].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[S:12][N:11]=[C:10]([C:6]3[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:14]=2[CH:15]=1
Reactant: COc1ccc(-c2nsc3ccc([N+](=O)[O-])cc23)cc1C
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Temperature: 65 °C
Yield: 98.1 %

Procedure:
A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2-benzisothiazole (63.0 g, 0.210 mol), 5% acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL) is heated to 65° C., treated portionwise with iron powder (58.6 g, 1.05 mol), stirred at 65° C., and filtered through quartz filter paper. The filtrate phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange oil (55.7 g, 98.1%) which is identified by NMR spectral analyses.
Reaction SMILES: [IH:1].[Cl:2][C:3]1[C:4](N)=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2.N([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:2][C:3]1[C:4]([I:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2N)OC1C(F)(F)F
Reactant: I
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2I)OC1C(F)(F)F
Temperature: 0 °C
Yield: 49 %

Procedure:
To a solution of 47% aqueous HI (11 mL, 59 mmol) dissolved in DMSO (11 mL) was added dropwise at 35° C. a solution of ethyl 6-chloro-5-amino-2-(trifluoromethyl)-2H-chromene-3-carboxylate (3.8 g, 11.8 mmol) in a mixture of 11 mL of DMSO and potassium nitrite (1.63 g, 23.6 mmol) with stirring. The resulted mixture was stirred at 35° C. for 15 min, and then it was transferred into 150 mL of a solution of potassium carbonate (10 g) in ice water. The product was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium carbonate, 5% aqueous sodium hydrosulfite, and brine, dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:9 EtOAc/hexane. The product was obtained as 2.5 g light yellow solid. A small amount of the product was further purified on reverse phase HPLC. It gave an off-white solid. m.p=117.0-119.0° C. LC-MS (ES+): 433.2(M+1, 100); 1H NMR(CDCl3/400 MHz) 7.93(s,1H), 7.36(d, J=8.4 Hz, 1H), 6.91(d, J=8.4 Hz, 1H), 5.65(q, J=6.8 Hz, 1H), 4.33(m, 2H), 1.36(t, J=6.8 Hz, 3H). 19F NMR(CDCl3/400 Hz) −78.50(d, J=6.8 Hz). 13C NMR (CDCl3/400 MHz) 163.3, 152.3, 140.9, 133.6, 132.2, 124.7, 123.2(q, J=287.7 Hz), 119.4, 117.6, 104.5, 70.3(q, J=33.4 Hz), 62.0, 14.4. MS(EI+) 432.0(M+, 20), 363.0(M-CF3, 100). High resolution MS(EI+) m/z calc. for Cl3H9ClF3IO3: 431.9271 (M+), found: 431.9238.
Reaction SMILES: C(O[C:4](=[O:24])[CH2:5][CH:6]([OH:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16])C.[CH2:25](Br)[CH:26]=[CH2:27].[Mg].[CH2:30]([CH:33]=CCC(O)CC(O)CCCCCCCCCCC)[CH:31]=C>>[CH2:25]([C:4]([OH:24])([CH2:5][CH:6]([OH:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH3:16])[CH2:33][CH:30]=[CH2:31])[CH:26]=[CH2:27]
Reactant: C=CCC=CCC(O)CC(O)CCCCCCCCCCC
Reactant: CCOC(=O)CC(O)CCCCCCCCC(C)C1CCCCC1
Reactant: C=CCBr
Agent: [Mg]
Product: C=CCC(O)(CC=C)CC(O)CCCCCCCCC(C)C1CCCCC1
Yield: 80 %

Procedure:
(4, ##STR16## R'=H, m=8) When 16.5 g (0.049 mole) of 3-hydroxy-12-cyclohexyltridecanoic acid ethylester, 20.6 g (0.17 mole) of allyl bromide and 24.3 g (0.20 mole) of magnesium was reacted as described for the preparation of -allyl-4,6-dihydroxyheptadec-1-ene, 14.9 g of a yellow oil was isolated in 80% yield which was used without purification; δ (CDCl3) 1.28(m,CH2) and 4.90-6.2(m,CH=CH2)
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:3])[CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc[n+]([O-])cc1
Product: COc1cc[nH]c(=O)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (36.3 mL) was added to 4-Methoxy pyridine N-oxide (1.09 g) and the resulting solution was warmed to 130° C. and stirred overnight. After 16 h of stirring, the crude mixture was concentrated on the rotavap. 10 mL of a 1:1 MeOH—H2O solution was added and the resulting mixture was stirred overnight. After 10 h, the mixture was concentrated to a solid. The solid was recrystallized in AcCN, filtered and rinsed with ether.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>CN(C)C=O.C(Cl)Cl>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(F)ccc1F
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1-n1cncn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A suspension of 2,5-diflurobenzonitrile (4.5 g, 32.35 mmol) and 1,2,4-triazole sodium salt (3.6 g, 40 mmol) in dimethylformamide (40 mL) was heated at 80° C. for 15 h. The reaction mixture was then cooled, diluted with CH2Cl2 (200 mL), washed with water (3×30 mL) and brine (30 mL), then dried (Na2SO4), filtered and concentrated to give a white solid which was purified by flash column chromatography (SiO2) using 1:1 to 3:1 ethyl acetate/Hexanes to afford the title compound (2.98 g, 49% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ: 8.70 (1H, s), 8.18 (1H, s), 7.76 (1H, dd, J=9.0, 4.8 Hz), 7.55 (1H, dd, J=7.3, 2.8 Hz), 7.51–7.47 (1H, m). LCMS (M+H) calcd for C9H6FN4: 189.17. found: 189.10.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:31](=[O:32])[CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:34][CH:35]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)c2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-fluorophenyl)ethanone (0.65 mL), potassium carbonate (0.75 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 57%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[C:16]#[N:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O>O1CCCC1>[N:7]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[C:21]([F:22])([F:23])[F:24])[CH2:16][NH2:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: N#Cc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 46.5 %

Procedure:
Next, to a suspension of lithium aluminum hydride (44.8 mg, 1.18 mmol) in tetrahydrofuran (5.0 mL) was added 3-piperidin-1-yl-4-(trifluoromethyl)benzonitrile (100.0 mg, 0.39 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 14 hours. To the mixture was added water and extracted with ethylacetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (methanol:ethylacetate=1:2) to afford [3-piperidin-1-yl-4-(trifluoromethyl)benzyl]amine (46.8 mg, 46% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]=[C:13]=S)=[CH:4][CH:3]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].N=C=N.O>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[NH:22][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: S=C=Nc1ccc(Br)c2ccccc12
Agent: N=C=N
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(Nc2nc3ccccc3[nH]2)c2ccccc12

Procedure:
A slurry of 1-bromo-4-isothiocyanatonaphthalene (1.0 g, 3.8 mmol), o-phenylene diamine (0.45 g, 4.2 mmol), and polymer-supported carbodiimide (9.0 g, 11 mmol, 1.27 mmol/g) in 72 mL THF was heated to 70° C. with a water-cooled reflux condenser for 3 h. The reaction was filtered, rinsing with dichloromethane. The solution was concentrated to a yellow solid, suspended in dichloromethane, and filtered, rinsing with a small quantity of diethyl ether to give N-(4-bromonaphthalen-1-yl)-1H-benzo[d]imidazol-2-amine as a white solid. MS m/z=338 [M+1]+. Calc'd for C17H12BrN3: 337
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH2:29][CH3:30])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[NH:12][C:11]2=[O:21])C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:35][CH2:34]1>C1COCC1>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:10]1([NH:9][C:8]([N:42]2[CH2:41][CH2:40][N:39]([CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH2:44][CH2:43]2)=[O:7])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21])[CH3:30]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOc1ccccc1C1(NC(=O)Oc2ccccc2)C(=O)Nc2ccc(OC)cc21
Solvent: C1CCOC1
Product: CCOc1ccccc1C1(NC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(OC)cc21
Yield: 65.7 %

Procedure:
1.9 g (4.5 mmol) of the intermediate from Step D and 1.75 g (9.5 mmol) 1-(1-methylpiperidine-4-yl)-piperazine were dissolved in 30 ml dry THF and refluxed for 90 minutes. The volatiles were removed in vacuo. The resulting residue was dissolved in ethyl acetate, washed with H2O and dried over magnesium sulfate and the solvent was removed in vacuo. The residue was treated with H2O and the resulting precipitate was separated to yield 1.5 g of the intermediate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[BrH:25]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH2:10][Br:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 36, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours and quenched at 0° C. with saturated aqueous Na2CO3. The mixture is extracted with EtOAc (3×25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 0.400 g of the desired product that is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).