Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][CH2:3][C:4]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[NH+:13][CH:14]=[CH:15][N:5]12.[C:23]([O-:26])(O)=O.[Na+]>C(Cl)Cl>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2([CH2:3][N:2]3[CH2:11][CH2:12][CH2:4][CH2:3][C:23]3=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3=[N:13][CH:14]=[CH:15][N:5]23)=[CH:17][CH:18]=1
Reactant: NCC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCCN1CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Reaction time: 0.5 h

Procedure:
To a stirred biphasic mixture of a solution of 5-(aminomethyl)-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-1-ium chloride (25 mg) in CH2Cl2 (3 mL) and aqueous saturated NaHCO3 (3 mL) was added a solution of 5-bromobutyryl chloride (34 mg) in CH2Cl2 (1 mL). After 30 minutes layers were separated. Organic layer was dried over Na2SO4 and concentrated. The residue was then dissolved in DMF (0.5 mL) and NaH (12 mg, 60% in mineral oil) was added and stirred for 30 minutes. The reaction was then quenched with water, diluted with DMF and filtered. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 5-55% MeCN/water containing 0.1% TFA over 20 min at 20 mL/min) afforded title compound as a white solid. HRMS. Found, 408.0718; calcd for (M+H)+, 408.0706. 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1 H); 7.52-7.43 (m, 4 H); 7.39-7.34 (m, 2 H); 7.16 (d, J=1.54 Hz, 1 H); 7.13-7.09 (m, 2 H); 4.57 (d, J=14.04 Hz, 1 H); 4.38 (d, J=14.28 Hz, 1 H); 2.52-2.46 (m, 2 H); 2.09-1.95 (m, 2 H), 1.62 (p, J=7.47 Hz, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:24][CH3:25])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 51.6 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 4-ethoxyphenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 27 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(4-ethoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34 mg, 52%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.44 (t, 3H, J=7.0 Hz), 1.49 (s, 9H), 1.96-2.05 (m, 2H), 2.17-2.30 (m, 1H), 2.86-3.04 (m, 2H), 4.06 (q, 2H, J=6.9 Hz), 4.23-4.36 (m, 2H), 4.90-5.00 (m, 1H), 6.97 (d, 2H, J=8.8 Hz), 7.15 (d, 2H, J=9.0 Hz), 8.54 (s, 1H), 8.54 (s, 1H). Mass spectrum (ES) MH+=440. HRMS Calcd. for C23H30N5O4 (MH+): 440.2293. Found: 440.2292.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=1[C:29]([CH:31]1[CH2:33][CH2:32]1)=[O:30]
Reactant: CON(C)C(=O)C1CC1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1ccc(N)c(C(=O)C2CC2)c1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a stirred solution of p-tolyl-carbamic acid tert-butyl ester (1.0 g, 4.8 mmol) in Et2O (10 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (6.5 mL, 11.1 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopropanecarboxylic acid methoxy-methyl-amide (0.92 g, 6.3 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (15 mL) and TFA (15 mL) and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 0.80 g crude (2-amino-5-methyl-phenyl)-cyclopropyl-methanone as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1)=[CH:11][CH:10]=3.[CH3:28][C:29]1([CH3:44])[O:34][CH2:33][CH2:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.O1CCOCC1>CCOC(C)=O.O>[CH3:28][C:29]1([CH3:44])[O:34][CH2:33][CH2:32][C:31]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)=[CH:11][CH:10]=4)=[CH:30]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CCO1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncc(F)c3)ccc1Oc1cnc(Cl)cc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)C=C(c2cc3c(cn2)Oc2ccc(-c4cncc(F)c4)cc2[C@@]32COC(N)=N2)CCO1
Reaction time: 0.5 h

Procedure:
A glass microwave reaction vessel was charged with (S)-3-chloro-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.250 g, 0.653 mmol; prepared as described in Method BB41), 2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.311 g, 1.306 mmol), bis(di-tert-butylphenylphosphine)dichloropalladium (II) (0.041 g, 0.065 mmol), dioxane (3 mL) and water (0.8 mL). The reaction mixture was exposed to MW radiation at 105° C. for 30 min in a microwave reactor. The mixture was diluted with EtOAc and water. The organic layer was washed with saturated sodium carbonate and dried over sodium sulfate. The crude material was initially purified by silica gel chromatography using 2-10% MeOH (2M NH3)-CH2Cl2) followed by further purification by SFC chromatography to give (S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: S([CH:5]([CH2:17]C(OCCCCCCCC)=O)[C:6]([O:8]CCCCCCCC)=[O:7])(O)(=O)=O.[Na].[O-2].[Zn+2:31].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>C1(C)C=CC=CC=1>[C:6]([O-:8])(=[O:7])[CH:5]=[CH2:17].[Zn+2:31].[C:32]([O-:36])(=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)O
Reactant: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Agent: [Na]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]

Procedure:
U.S. Pat. No. 5,789,616 disclosed a process comprising adding at the first an anionic surfactant, sodium dioctyl sulfosuccinate, in toluene, following with adding successively zinc oxide, fatty acid and acrylic acid, and, after completion of the reaction, drying by distillation at a reduced pressure, and pulverizing and sieving the thus produced crude product to yield a modified zinc acrylate powder having a particle size characterized in that 64% of particles<44 μm, 54% of particles<10 μm, and 41% of particles<5 μm, while the part that had a particle size of>105 μm and must be removed by sieving was estimated to be 31%. The anionic surfactant, i.e. sodium dicotyl sulfosuccinate, used in this technique to be added at the first stage of the reaction might cause the swelling of the content in the reaction mixture such that in the subsequent addition of acrylic acid, might lead to local thickening and hence difficulty for stirring, and therefore, the reaction could be completely only through slow addition of raw material and postponing the reaction time. This might be the cause that made the zinc acrylate powder thus produced coarser and the particle size distributions non-uniform. On the other hand, it had an advantage that the trouble of sticking the wall of the reactor and the drying tank in the course of drying could be avoided.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:5][C:6]([OH:8])=[O:7].Cl.[CH3:14][CH2:15]O>>[CH2:14]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH2:3][CH2:2][O:8][C:6](=[O:7])[CH2:5]1)[CH3:15]
Reactant: O=C(O)CN(CCO)CC(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CN1CCOC(=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To N-(2-hydroxyethyl)iminodiacetic acid (3.55 g, 20 mmol) in 500 mL EtOH was added concentrated HCl (1.7 mL, 21 mmol). The mixture was stirred for 24 h at rt and concentrated. The residue was partitioned in diethyl ether (200 mL) and NaHCO3 (150 mL, 10% wt). After layer separation, the organic phase was washed with aqueous NaHCO3 (2×100 mL) and dried over Na2SO4 and concentrated and dried under high vacuum. To this crude product in 250 mL of dioxane was added 1.5 mL of HCl and the mixture was heated to reflux for 24 h. After removal of the solvent, the residue was chromatographed (dichloromethane/methanol) to afford a dark yellow oil (1.45 g). 1H-NMR (CD3OD, 300 MHz) δ (ppm): 4.40 4.37 (m, 2H), 4.18-4.11 (m, 2H), 3.60 (s, 2H), 3.29 (s, 2H), 2.89-2.86 (m, 2H), 1.25-1.20 (m, 3H); 13C-NMR δ (ppm) 169.4, 167.0, 68.6, 60.9, 57.0, 54.5, 48.2, 14.2. (ESI) m/z: 188 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][C:5](C(O)=O)=[C:4](C)[CH:3]=1.[C:16](OC)([O:20][CH3:21])([O:18]C)[CH3:17]>CN1C(=O)CCC1>[CH3:14][S:11]([C:10]1[C:9]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:5][C:17]([C:16]([O:20][CH3:21])=[O:18])=[C:3]([CH3:4])[CH:2]=1)(=[O:13])=[O:12]
Reactant: COC(C)(OC)OC
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 100.0 g of 4-chloro-5-methanesulfonyl-2-methylbenzoic acid and 68.1 g of trimethyl orthoacetate in 322 ml of NMP was refluxed until the acid had reacted completely. After the excess orthoester had been distilled off, 96.5 g of sodium methanesulfinate were added, and the mixture was stirred at 90° C. for 18 h. Conventional work-up gave methyl 4,5-bis-methanesulfonyl-2-methylbenzoate.
Reaction SMILES: [Cl:1][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:14][C:13]2[CH:12]=[N:11][C:10]3[N:15](CC4C=CC(OC)=CC=4)[N:16]=[CH:17][C:9]=3[C:8]=2[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O.O1CCOCC1>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:14][C:13]2[CH:12]=[N:11][C:10]3[NH:15][N:16]=[CH:17][C:9]=3[C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)C(Cl)c2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(C(Cl)c1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 65 °C
Yield: 82.2 %

Procedure:
To 2-chloro-1-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone (0.60 g, 1.34 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, 1,4-dioxane (5 mL) and toluene (5 mL) were added and the solvent removed under reduced pressure to give the crude product. The crude product was then partitioned between dichloromethane (20 mL) and water (20 mL). The organic layer was separated, washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, gradient 60% EtOAc in hexane to 80% EtOAc in hexane) to give the pure desired product, 2-chloro-1-(8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone as a white foamy solid (0.360 g, 83%). LCMS [M+H]: 327.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]1=2.[N+:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[C-:14].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:12][CH:14]=[N:13][C:15]=3[C:16]([O:18][CH3:19])=[O:17])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(O)c1ccc2occc2c1
Reactant: [C-]#[N+]CC(=O)OC
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1ccc2occc2c1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of benzo[b]furan-5-carboxylic acid (1.30 g) and of methyl isocyanoacetate (834 mg) in N,N-dimethylformamide (10 ml) were added diethyl cyanophosphate (1.33 ml) and triethylamine (3.6 ml) at room temperature, and the mixture was stirred overnight. After removing the solvent under reduced pressure, an aqueous citric acid solution and ethyl acetate were added to the residue, the organic layer was collected, washed successively with an aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to obtain a crude product of methyl 5-(5-benzo[b]furyl)oxazol-4-carboxylate (1.14 g).
Reaction SMILES: [NH:1]1[C:7](=[O:8])[C:6](=[N:9]O)[CH2:5][CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.C(O)(=O)C.[H][H]>CO.[Pd]>[NH2:9][CH:6]1[C:7](=[O:8])[NH:1][C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[CH2:4][CH2:5]1
Reactant: O=C1Nc2ccccc2CCC1=NO
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC1CCc2ccccc2NC1=O
Temperature: 50 °C
Yield: 67.3 %

Procedure:
5 g (26,3 mmol) of 4,5-dihydro-1H-benzo[b]azepine-2,3-dione 3-oxime is taken in 50 ml of methanol then 6,3 g (105 mmol) acetic acid is added. The reaction mixture is left to stir at 50° C. and 5 bar hydrogen pressure for 21 hours in the presence of 1,1 g Pd catalyst (5% on charcoal, containing 50% water). The reaction mixture is evaporated after filtration and the residue is dissolved in 16,5 ml water. 9,5 ml dichloromethane is added and the pH value is adjusted to pH 12–14 with NaOH (32%). After phase separation the aqueous layer is extracted two times with 5,5 ml dichloromethane each. The organic phases are dried over sodium sulfate and evaporated to give 3,12 g 3-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, yield 67,4%, HPLC 94,5 area %, RT=2.45.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C1(C)C(C)=CC=CC=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)(=O)C.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: C1CNCCN1
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CN1c2ccccc2N=C(N2CCNCC2)c2cscc21

Procedure:
A mixture comprising 2.6 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine (U.S. Pat. No. 3,951,981 -- Ex. 7), 8.6 g. of piperazine, 3 drops of acetic acid and 15 ml. of xylene is stirred and refluxed for 4 hours. The reaction mixture is evaporated, washed with water and the residue is dissolved in 50 ml. of 2N acetic acid. The solution is filtered, the filtrate is made alkaline with ammonium hydroxide and extracted with benzene. The extracts are dried over magnesium sulfate, filtered and evaporated producing an amber oil. This oil is dissolved in 20 ml. of ethanol and a mixture of 2.1 g. of fumaric acid in 40 ml. of ethanol is added. The solid is collected and recrystallized from 125 ml. of methanol giving the desired product as the fumarate salt, m.p. 205°-206° C. (dec.).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18](O)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:55]([O:57][C:58](=[O:77])[CH2:59][CH:60]([C:67]1[CH:76]=[C:75]2[C:70]([CH2:71][CH2:72][NH:73][CH2:74]2)=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=1)[CH3:56]>CN(C)C=O>[CH2:55]([O:57][C:58](=[O:77])[CH2:59][CH:60]([C:61]1[CH:62]=[CH:63][N:64]=[CH:65][CH:66]=1)[C:67]1[CH:76]=[C:75]2[C:70]([CH2:71][CH2:72][NH:73][CH:74]2[C:18](=[O:19])[CH2:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:21])[O:9][C:10]=3[CH:16]=2)=[CH:69][CH:68]=1)[CH3:56]
Reactant: CCOC(=O)CC(c1ccncc1)c1ccc2c(c1)CNCC2
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
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: CCOC(=O)CC(c1ccncc1)c1ccc2c(c1)C(C(=O)Cc1ccc3nc(Nc4ccccc4C)oc3c1)NCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-o-tolylaminobenzoxazole-6-acetic acid (0.124 g) and diisopropylethylamine (0.17 g) in dimethylformamide (2 mL) was treated with a solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.183 g) in dimethylformamide. After 10 minutes at room temperature this yellow solution was added dropwise to a rapidly stirred solution of 3-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-3-(pyrid-4-yl)-propionic acid ethyl ester, enantiomer A {0.219 mmoles, Reference Example 17(a)} in dimethylformamide. After stirring at room temperature for 2.5 hours the reaction mixture was evaporated. The residual oil was dissolved in a mixture of acetonitrile, water and trifluoroacetic acid (25:75:0.1) and treated with dimethylformamide and trifluoroacetic acid to bring to pH2. This mixture was subjected to preparative HPLC {Hypersil Elite C18 column, 10 cm×2.1 cm, using a mixture of acetonitrile, water and trifluoroacetic acid (25:75:0.1) as the mobile phase followed by a 1% acetonitrile/minute gradient) to give the title compound. LC-MS:MS (ES)=575 (M+H)+, 573 (M−H)−.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:22]([O:26][C:27]([N:29]([C:31]1[CH:36]=[C:35]([CH2:37][O:38][Si](C(C)(C)C)(C)C)[CH:34]=[CH:33][N:32]=1)[CH3:30])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C.O>O1CCCC1>[C:22]([O:26][C:27]([N:29]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[CH:33][N:32]=1)[CH3:30])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cc(CO)ccn1
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of tetra-n-butylammonium fluoride trihydrate(1.3 g, 4.2 mmol) in tetrahydrofuran (20 mL) was added to a solution of 2-(N-tert-butoxycarbonyl-N-methylamino)-4-(tert-butyldimethylsilyloxymethyl)pyridine (Reference compound No. 6-1, 1.4 g, 3.7 mmol) in tetrahydrofuran (20 mL) for 5 minutes at room temperature, and the mixture was stirred for 15 minutes. Ethyl acetate (50 mL) and water (100 mL) were added to the reaction mixture, the whole was separated, and then the aqueous layer was extracted with ethyl acetate (50 mL). These organic layers were combined, then it was washed with brine (100 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, then the resulting residue was purified by silica gel column chromatography to give 450 mg of the title reference compound as a reddish brown oil. (Yield 50%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.Br[CH2:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:9][CH2:10][CH2:11][S:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1nnnn1C
Yield: 66.7 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (4.6 g) and 1,3-dibromopropane (4 g) are dissolved in acetone (50 ml). To the mixture is added potassium carbonate (5.5 g), and the mixture is refluxed for 3 hours. After acetone is distilled off, water is added to the residue, and the precipitated crystals are separated by filtration and recrystallized from ethanol to give 1-methyl-5-[3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiopropyl]thio-1,2,3,4-tetrazole (3.6 g) as colorless prisms, m.p. 141.5°-143.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.BrC1C=CC(CNCC(OC)OC)=CC=1[Cl:41]>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:18][CH:19]([O:20][CH3:21])[O:22][CH3:23])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:41]
Reactant: COC(CN(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Reactant: COC(CNCc1ccc(Br)c(Cl)c1)OC
Product: COC(CN(Cc1ccc(Br)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC

Procedure:
The title compound was prepared by the protocol described for N-(4-Bromo-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzenesulfonamide (2), starting from (4-Bromo-3-chloro-benzyl)-(2,2-dimethoxy-ethyl)-amine (7). Rt=1.93 min (Method C). Detected mass: 430.3/432.3 (M−OMe−).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (4.5 g, 18.44 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (11.01 g, 55.33 mmol) in dichloroethane (50 mL), acetic acid (6.64 g, 110.6 mmol) was added and reaction stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (11.72 g, 55.28 mmol) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the desired compound (5.2 g, 66.24%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=1
Reactant: Cc1nc(Cl)cc(-c2cc(Cl)ccc2C)n1
Reactant: Nc1ccc(Cl)cc1
Product: Cc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2C)n1
Yield: 97 %

Procedure:
Following the method described in Example 38 (alternate method), 4-chloro-6-(5-chloro-2-methyl-phenyl)-2-methyl-pyrimidine and 4-chloroaniline provided the title compound (97% yield). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3), 2.53 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.35-7.44 (m, 4H, Ar), 7.49 (d, 1H, J=2.2 Hz, Ar), 7.78 (d, 1H, J=8.8 Hz, Ar), 9.72 (s, 1H, NH).