Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:37]([CH3:40])(=[O:39])=[O:38])[C:14]1[C:33]([CH:34]2[CH2:36][CH2:35]2)=[CH:32][C:17]2[C:18]([C:28](=[NH:31])[NH:29][OH:30])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:20][C:16]=2[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:34]1([C:33]2[C:14]([N:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[S:37]([CH3:40])(=[O:38])=[O:39])=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[C:18]([C:28](=[NH:31])[NH:29][OH:30])[C:17]=3[CH:32]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCCCO)c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A solution of Example 11C (0.1193 g, 0.202 mmol) in tetrahydrofuran (5 mL) was treated with 1 M tetrabutylammonium fluoride in tetrahydrofuran (0.607 mL, 0.607 mmol), and the resulting yellow solution was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, the yellow oily residue was taken up in dichloromethane (10 mL), filtered, and purified on a silica gel column (12 g) eluting with a gradient of 99.5/0.5 dichloromethane/methanol to 95/5 dichloromethane/methanol over 30 minutes to afford the title compound (0.095 g, 99%).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:26][CH2:27][CH3:28].[Na+].[Cl-]>CN(C)C=O>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH2:26][CH2:27][CH3:28])[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCI
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.51 g (S)-5-dibenzylaminopiperidin-2-one (see 5.1) are placed in 5 ml dimethylformamide. While cooling with the ice bath 120 mg sodium hydride (60% in mineral oil) are added. The reaction mixture is then stirred for 30 minutes at ambient temperature. While cooling with the ice bath 0.289 ml 1-iodopropane are added. The reaction mixture is then stirred overnight at ambient temperature, then combined with a saturated NaCl solution. The product is extracted with ethyl acetate. 0.569 g product are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][C:8]2[N:17]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:16](=[O:27])[C:15]3[C:10](=[C:11]([O:28][CH3:29])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:17]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:23][CH2:22]3)[C:16](=[O:27])[C:15]3[C:10](=[C:11]([O:28][CH3:29])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:30][CH:31]=1
Reactant: COc1cccc2c(=O)n(CCCC3CCNCC3)c(COc3ccc(Cl)cc3)nc12
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(COc3ccc(Cl)cc3)nc12
Temperature: 25 °C

Procedure:
A solution of 2-(4-chloro-phenoxymethyl)-8-methoxy-3-(3-piperidin-4-yl-propyl)-3H-quinazolin-4-one (150 mg, 0.31 mmol), N-(3-chloropropyl)-piperidine hydrochloride (222 mg, 0.63 mmol), K2CO3 (87 mg, 0.63 mmol), Kl (105 mg, 0.63 mmol) was heated at 80° C. in THF/H2O (3:1 mixture, 30 mL) for 17 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc. The organic solution was separated and was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was chromatographed on SiO2-gel using EtOAc/NEt3 (10:1) to give the desired product as an oil. API-MS: 567.2 (M+1). 1H NMR (300 MHz, d4-MeOH): d 7.75 (d, 1 H), 7.5 (t,1 H), 7.38 (d, 1 H), 7.3 (d, 2 H), 7.1 (d, 2 H), 5.25 (s, 2 H), 4.1 (m, 2 H), 4.0 (s, 3 H), 2.9 (m), 2.4-2.1 (m), 1.9-1.1 (m).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9]CC)=O)[CH:4]=[N:3][CH:2]=1.[OH-].[NH4+:13]>CO>[N:1]1[CH:6]=[C:5]([C:7]([NH2:13])=[O:9])[CH:4]=[N:3][CH:2]=1
Reactant: CCOC(=O)c1cncnc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl pyrimidine-5-carboxylate (6.10 g, 40.0 mmol) in methanol (40 mL) was stirred with ammonium hydroxide (4.30 mL, 110 mmol) in a sealed tube at 50° C. for 10 hours. The reaction mixture was then concentrated and the residue was stirred in ethanol/ethyl acetate (v/v 1/4, 50 mL) at ambient temperature for 2 hours. The white precipitate was collected by filtration and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 7.85 [s (broad), 1H], 8.33 [s (broad), 1H], 9.18 (s, 2H), 9.32 (s, 1H) ppm; MS (DCI/NH3) m/z 124 (M+H)+, 141 (M+NH4)+.
Reaction SMILES: [N:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N+:2]=[N-:3].[CH2:19]([OH:22])[C:20]#[CH:21]>>[OH:22][CH2:19][C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:21]=1
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Product: CC(C)(C)OC(=O)NCc1ccccc1-n1cc(CO)nn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 38 %

Procedure:
tert-butyl 2-azidobenzylcarbamate, 12, (5.4 g, 21.7 mmol) was dissolved in neat propargyl alcohol (10 mL). The reaction mixture was stirred at 90° C. for 18 h. The reaction mixture was then concentrated in vacuo and the resulting residue dissolved in diethyl ether. Upon standing, triazole 13 crystallized. The crystals were collected by filtration yielding 2.5 g (38%) of 13: 1H NMR (400 MHz, CDCl3) δ 7.82, (s, 1H), 7.64-7.35 (m, 3H), 7.34-7.30 (m, 1H), 5.35, (bs, 1H), 4.87, (s, 2H), 4.15 (s, 2H), 1.42 (s, 9H); ESI+ MS: m/z (rel intensity) 249 (100, M-tBu).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N+:9]([O-])=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:21][CH:11]1[C:10]2[C:15](=[C:2]([NH2:1])[C:3]3[C:8]([N:9]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:14](=[O:16])[CH2:13][CH2:12]1)(=[O:20])[CH3:19]
Reactant: Nc1c2c([n+]([O-])c3ccccc13)CCCC2=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCC(=O)c2c1nc1ccccc1c2N
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of 9-amino-3,4-dihydroacridin-1(2H)-one N-oxide (5.4 g) and acetic anhydride (60 ml) was heated to reflux and then concentrated. The residue was stirred in saturated sodium bicarbonate solution for one hr. The mixture was filtered and the filter cake was washed with water and dried under vacuum at 40° C. for three hrs to yield 1.93 g of product, mp 208° C. (dec). An additional 1.38 g, mp 208° C. (dec), of product was obtained by extraction of the tiltrate with ethyl acetate, evaporation of ethyl acetate extract, and trituration of the residue with diethyl ether; total 52% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[N:9]2[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:5][CH:4]=1
Reactant: O=C1Cc2ccc(CO)cc2N1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCN1C(=O)Cc2ccc(CO)cc21
Yield: 80.4 %

Procedure:
A mixture of 6-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (150 mg), 1-bromo-3-methoxypropane (211 mg), potassium carbonate (254 mg) and potassium iodide (229 mg) in acetonitrile (6 ml) was refluxed for 15 hours. Further, 1-bromo-3-methoxypropane (70.3 mg) and potassium carbonate (127 mg) were added and the mixture was refluxed for 3 hours. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform to chloroform/methanol=10/1) to give 6-(hydroxymethyl)-1-(3-methoxypropyl)-1,3-dihydro-2H-indol-2-one (174 mg) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][CH:6]=1.[C-:14]#[N:15].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:14]#[N:15])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 15 in dimethylformamide (0.3 M) at room temperature under nitrogen was added potassium cyanide (1.2 eq). The reaction was stirred at room temperature overnight. The reaction was diluted with H2O then extracted with ethyl acetate (3×). The organic phases were combined, washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (26%) 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 4H), 3.74 (s, 2H), 3.70 (s, 3H) 3.64 (s, 2H).
Reaction SMILES: CS(O[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=O)=O.[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N+:32]([O-:34])=[O:33])[CH:26]=3)[N:40]2[C:39]2[CH:41]=[CH:42][C:36]([F:35])=[CH:37][CH:38]=2)=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(F)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Product: O=[N+]([O-])c1cc(C2CCC(c3ccc(Cl)c([N+](=O)[O-])c3)N2c2ccc(F)cc2)ccc1Cl
Temperature: 45 °C
Yield: 23.8 %

Procedure:
The product from Example 28C (2.9 g, 5.2 mmol) and 4-fluoroaniline (5.0 mL, 52.0 mmol) were combined, neat, and heated at 45° C. for 20 h then cooled and poured into water and extracted into dichloromethane. The organics were concentrated the residue was purified by chromatography on silica gel with a 120 g column, eluting with 0-5% ethyl acetate/hexanes to give 0.59 g (24%) of a thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)[CH3:2].[C:21]([Si:25]([CH3:41])([CH3:40])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)([CH3:24])([CH3:23])[CH3:22].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:40])[CH3:41])=[CH:28][CH:29]=3)=[CH:38][CH:37]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCO)cc1)OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OC

Procedure:
(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl)-2-methoxy-propionic acid ethyl ester and 4′-(tert-butyl-dimethyl-silanyloxy)-biphenyl-4-ol (Example 196, Step A) were treated under Mitsunobu procedure B (DIAD, toluene), to afford the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[C:16]2[C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[NH2:21].[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([NH:21][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[C:16]=2[CH:8]=1)=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCC3
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
Triethylamine (2.0 mL, 14 mmol) was added to a cooled (0° C.) solution of 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (0.86 g, 4.6 mmol). The reaction mixture was stirred for 10 minutes at 0° C. and then trimethylacetyl chloride (0.60 mL, 4.8 mmol) was added. The ice bath was removed and the reaction mixture was stirred for 30 min and then concentrated. The crude material was dissolved in chloroform and washed with 10% aqueous ammonium hydroxide, water, and brine, dried (Na2SO4) and concentrated. The crude material was recrystallized from acetonitrile to provide 2,2-dimethyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-propionamide (0.80 g). Mp 210-211° C.; Anal. Calcd. for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.33; H, 7.64; N, 5.07.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]=O.N1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1cccc(Br)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: Nc1cccc(Oc2ccc(F)cc2)c1
Temperature: 210 °C

Procedure:
In a dry microwave vessel with stir bar, 3-bromoaniline (316 μL, 0.029 mol) and 4-flourophenol (716 mg, 0.064 mol) were added to anhydrous pyridine (10 mL) under nitrogen. To this was added potassium carbonate (1.6 g, 120 mol) and copper(II) oxide (1.2 g, 145 mol). The microwave vessel was sealed then heated in the microwave at normal absorbance at 210° C. for 40 min. The cooled reaction was filtered through a bed of Celite with ethyl acetate. The filtrate was then washed 3 times with concentrated aqueous NaHSO4 and twice with concentrated aqueous NaCl. The organic layer was then dried over magnesium sulfate, filtered and concentrated. Purification over silica using an eluent of hexane and ethyl acetate with a gradient of 0-23% ethyl acetate over 45 min gave 3-(4-fluoro-phenoxy)-phenylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2].[C:24]([O:29][CH3:30])(=[O:28])[C:25]([CH3:27])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:25]([C:24]([O:29][CH3:30])=[O:28])[CH3:27])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C)=O
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Product: COC(=O)C(C)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-nitro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-nitro-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.S(O)(=O)(=O)C.S(O)(=O)(=O)C.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32]>C(O)C>[NH2:33][C:31]1[N:30]=[N:29][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:32]=1
Reactant: N=C(N)NN
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(-c2nnc(N)nc2-c2ccc(C)cc2)cc1

Procedure:
A stirred mixture of 4,4′-dimethylbenzil (2.38 g; 0.01 mol), aminoguanidine bismesylate (3.33 g; 0.0125 mol) and ethanol (10 cm3) was heated under reflux until no starting material remained (4 hrs) when a cream solid was deposited. The mixture was evaporated to half volume and basified with 880 ammonia+water (1:1; 4 cm3). On standing, bight yellow prisms were deposited. The product was filtered off, washed with ethanol+water (1:1) and dried in vacuo at 450.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:26])=[NH:25])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.Cl.[C:31](=[NH:36])(OCC)[CH3:32].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:31]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:26])=[NH:25])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[NH:36])[CH3:32]
Reactant: N=C(N)c1cccc(/C=C/CNc2ccc(OC3CCNCC3)cc2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(NC/C=C/c3cccc(C(=N)N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 217.1 %

Procedure:
To a solution of 3-[3-[N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (345 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (185 mg) and triethylamine (0.52 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 30% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (272 mg, yield 72%) as a yellow amorphous solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6]1.[Na].[N:22]1[NH:23][C:24](=[O:31])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12.[I-].[K+]>[OH-].[K+].C(#N)C>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:23]3[C:24](=[O:31])[N:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]4=[N:22]3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reactant: O=c1[nH]nc2ccccn12
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CC#N
Product: O=c1n(CCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)nc2ccccn12

Procedure:
The hydrochloride salt of 1-(3-chloropropyl)-4-[3-(trifluoromethyl)phenyl]piperazine, 6.41 g. (0.0187 mole) is dissolved in dilute KOH solution and the free base which is formed is extracted into ether. The ether solution is washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford the desired free base. A suspension of 2.61 g. (0.0166 mole) of the sodium salt of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one and 5.09 g (0.0166 mole) of 1-(3-chloropropyl)-4-[3-(trifluoromethyl)phenyl]piperazine in 100 ml. of acetonitrile is treated with approximately 50 mg. of potassium iodide, and refluxed for 24 hrs. The mixture is then cooled and filtered, and the filtrate concentrated to an oil under reduced pressure. The residual oil solidifies when triturated with ether. This solid is recrystallized twice from ethanol to give 4.34 g. (58%) of product, m.p. 207.5°-209.5°.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+:17]>>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:6][CH:5]=1.[Na+:17]
Reactant: CC(C)=Cc1ccc(C(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=Cc1ccc(C(C)C(=O)[O-])cc1

Procedure:
Stoichiometric amounts of 2-(4-dimethylvinylphenyl)propionic acid and 1 N aqueous sodium hydroxide were stirred at room temperature for 30 minutes. The mixture was washed with 2×50 ml portions of ether and the aqueous solution evaporated to dryness to give the title compound as a white solid, m.p. 166°-168°. I.R. C=O stretch 1550-1560 cm-1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Solvent: ClCCl
Product: COCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (101 mg, 0.348 mmol) and piperidinomethyl polystyrene resin (110 mg) in 2 mL of dry CH2Cl2 was added methoxyacetyl chloride (97%, 34 μL, 1.05 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2 Removal of CH2Cl2 afforded methoxyacetic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenylamide 38 (70 mg, 56%).
Reaction SMILES: CS(O[CH:6]([C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH2:7][N:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])(=O)=O.[N-:52]=[N+:53]=[N-:54].[Na+]>CN1C(=O)N(C)CCC1.CCOC(C)=O>[C:34]([O:33][C:31](=[O:32])[N:8]([CH2:7][CH:6]([N:52]=[N+:53]=[N-:54])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:39]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])([CH3:36])([CH3:37])[CH3:35]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl methanesulfonate from the previous reaction was dissolved in DMPU (15 mL) and treated with NaN3 (140 mg, 2.15 mmol). The reaction was stirred at room temperature for 15 hours and then diluted with EtOAc (75 ml). The solution was washed with H2O (5×40 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified with 20% EtOAc/hexanes to afford tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.52 (15% EtOAc/hexanes). LCMS=605.3 (M+1-BOC)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.80 (s, 1H), 7.67 (s, 1H), 7.48 (s, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.01-7.11 (m, 2H), 6.89 (m, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.22-4.69 (m, 3H), 3.28 (s, 3H), 2.61-3.16 (m, 3H), 1.34 (s, 9H), 1.13-1.18 (m, 6H).