Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:13])O.[N-:14]=[N+:15]=[N-:16].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl.O>[N:14]([C:5]1([CH3:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[O:8][CH2:7][CH2:6]1)=[N+:15]=[N-:16]
Reactant: CC1(O)CCOc2ccc(I)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(N=[N+]=[N-])CCOc2ccc(I)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-iodo-4-methylchroman-4-ol (1.0 g, 3.4 mmol) and NaN3 (0.7 g, 10.3 mmol) in CHCl3 (15 ml), at 0° C., was added TFA (1.3 ml, 17.2 mmol) as a solution in 10 ml of CHCl3 dropwise via addition funnel. The addition was carried out over 2 h and stirring continued for an additional 2 h at 0° C. The mixture was warmed to r.t. and stirred over night. The mixture was diluted with 30 ml of water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 4-azido-6-iodo-4-methylchroman as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=2.07 Hz, 1H), 7.50 (dd, J=8.71, 2.07 Hz, 1H), 6.66 (d, J=8.71 Hz, 1H), 4.27 (m, 2H), 2.06 (m, 2H), 1.68 (s, 3H). MS (ESI+) for C10H10IN3O m/z 273.0 (M+H)+ loss of azide. The crude azide was dissolved in THF (15 ml) followed by the addition of trimethylphosphine (4 ml, 1.0 M in THF) at r.t. After 15 min. 3 ml of water was added and stirring continued at r.t. for 2 h until complete as indicated by LC/MS. The solvent was removed in vacuo and the residue diluted with water (75 ml) and extracted with CH2Cl2 (3×50 ml). The organic layer was dried over Na2SO4 and concentrated in vacou to yield 6-iodo-4-methylchroman-4-amine (0.900 g, 91%) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.07 Hz, 1H), 7.40 (dd, J=8.60, 2.18 Hz, 1H), 6.59 (d, J=8.50 Hz, 1H), 4.25 (m, 2H), 2.01 (m, 2H), 1.53 (s, 3H). MS (ESI+) for C10H12INO m/z 273.2 (M+H)+ loss of NH3.
Reaction SMILES: Cl.[NH2:2][NH2:3].C([C:6](CC)([C:10]([C:12]([O-:14])=[O:13])=O)[C:7]([O-:9])=O)C.[Na+].[Na+].[CH2:19](O)[CH3:20]>>[CH2:19]([O:14][C:12]([C:10]1[CH:6]=[C:7]([OH:9])[NH:3][N:2]=1)=[O:13])[CH3:20]
Reactant: NN
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cc(O)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 ml of ethanol were added 20.6 g (0.30 mol) of the hydrazine hydrochloride and 63.0 g (0.30 mol) of sodium diethyloxalacetate. This mixture was stirred at room temperature for 2 hours, and then heated with refluxing and stirring for 3 hours. After the ethanol was distilled off, 100 ml of water was added to the residue. The resulting mixture was stirred at room temperature for 1 hour, and the crystals yielded were taken out by filtration and washed with water.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[C:9](=[O:12])([O-])[O-].[K+].[K+].[CH2:15]([P:17](Cl)(Cl)=[S:18])[CH3:16]>Cl[Hg]Cl.C(#N)C>[CH2:15]([P:17](=[S:18])([O:12][C:9]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)[O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CCP(=S)(Cl)Cl
Reactant: Oc1cccc(F)n1
Agent: Cl[Hg]Cl
Agent: [K+]
Solvent: CC#N
Product: CCP(=S)(Oc1cccc(F)n1)Oc1cccc(F)n1
Reaction time: 2 h
Yield: 52 %

Procedure:
Into a three liter flask were placed 523 grams (4.6 moles) of 6-fluoro-2-pyridinol, 638 grams (4.6 moles) potassium carbonate, 1.0 grams HgCl2 and two liters of acetonitrile. The mixture was stirred at 50°-55° C. for two hours and allowed to cooled. The mixture was stirred while 269 grams (2.1 moles) of ethylphosphonothioic dichloride was added dropwise. An exotherm from 25° C. to 55° C. was obtained. The mixture was stirred at 50° C. for five hours and allowed to cool. The insolubles were filtered off and the solvent removed under reduced pressure at 45° C. The resulting oil was taken up in 1.5 liters of methylene chloride and washed once with one liter of water, once with one liter of aqueous 2% NaOH and again with one liter of water. The product layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure at 45° C. The resulting oil was poured into 250 milliliters of cold n-hexane and stirred. The solid product was filtered off and dried to give a 52% yield of the desired O,O-bis(6 -fluoro-2-pyridinyl) ethylphosphonothioate, m.p. 46°-48° C. (compound No. 1).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][OH:4].[C:15]1(=O)OCC[O:16]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:5]([CH:2]1[CH2:3][O:4][C:15](=[O:16])[NH:1]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1OCCO1
Reactant: CCCCCCCCCCC(N)CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC1COC(=O)N1
Yield: 91.5 %

Procedure:
26.465 g of 2-aminododecanol and 12.32 g of ethylene carbonate were heated at approximately 110° C. for 48 hours (preparation of the cyclic urethanes can be carried out without a solvent or in toluene solution)as a solvent. The reaction was followed by tlc and at the completion of the reaction the contents were cooled, dissolved in ethyl acetate and the organic solution was washed with brine and water. After drying, the filtrate was concentrated and the oily residue was kugelrohr distilled to give 27.33 g (96.56%) of colorless liquid, which slowly solidified, m.p. 31.5-32.5° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:36]([NH:38][C:39]1([C:43]([NH2:45])=[O:44])[CH2:42][NH:41][CH2:40]1)[CH3:37]>COCCOC.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:6]2[N:5]=[C:4]([CH3:25])[N:3]=[C:2]([N:41]3[CH2:42][C:39]([NH:38][CH2:36][CH3:37])([C:43]([NH2:45])=[O:44])[CH2:40]3)[N:7]2[N:8]=1
Reactant: CCNC1(C(N)=O)CNC1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2nc(C)nc3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)C1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 2.00 g, 5.13 mmol) in DME (30 ml) at 23° C. was added diisopropylethylamine (0.940 ml, 5.36 mmol) over 5 minutes. In a separate flask, a solution of 3-ethylaminoazetidine-3-carboxylic acid amide hydrochloride salt (I-2A-1h; 1.16 g, 5.37 mmol) in water (10 ml) was treated with diisopropylethylamine (1.90 ml, 10.8 mmol) over 5 minutes. The aqueous solution was then added to the DME solution over a 10-minute period while maintaining the reaction temperature below 28° C. After 2 hours, water (20 ml) was added over 5 minutes, and an orange solid precipitated from the reaction. The solid product was collected by filtration, washed with additional water, and then air dried by pulling low house vacuum across the sample to afford 2A-1 (2.15 g, 84%) as an off-white solid: +ESI MS (M+1) 496.4; 1H NMR (400 MHz, CD3OD) δ 7.46-7.35 (m, 4H), 7.31 (d, J=7.7 Hz, 2H), 7.21 (d, J=7.7 Hz, 2H), 5.14 (br d, J=8.3 Hz, 1H), 4.77 (br d, J=8.3 Hz, 1H), 4.61 (br d, J=8.3 Hz, 1H), 4.22 (br d, J=8.3 Hz, 1H), 2.54 (q, J=7.1 Hz, 2H), 2.45 (s, 3H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([OH:13])=O)[C:9]=2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:10]3[C:9]=2[C:17](=[O:19])[N:23]([CH:24]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]2=[O:26])[C:11]3=[O:13])=[CH:20][CH:21]=1
Reactant: O=C(O)c1cccc(OCc2ccc(Cl)cc2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccc(Cl)cc4)c3C2=O)C(=O)N1
Yield: 48.5 %

Procedure:
A mixture of 3-(4-chloro-benzyloxy)-phthalic acid (1.9 g, 6.2 mmol), alpha-amino-glutarimide hydrochloride (1.1 g, 6.5 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(4-chloro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (1.2 g, 49% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 6.64 min (99.9%); mp, 239-241° C.; 1H NMR (DMSO-d6) δ 2.00-2.07 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.12 (dd, J=6, 12 Hz, 1H, CH), 5.38 (s, 2H, CH2), 7.48-7.86 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.91, 48.75, 69.18, 115.66, 116.65, 120.16, 128.50, 129.02, 132.52, 133.25, 135.22, 137.03, 155.27, 165.30, 166.74, 169.89, 172.75. Anal Calcd For C20H15N2O5Cl: C, 60.24; H, 3.79; N, 7.02; Cl, 8.89. Found: C, 60.41; H, 3.63; N, 7.02; Cl, 8.72.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([O:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26]COCC)=[O:25])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.COC1C=CC(O)=CC=1>C(O)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([C:17]([O:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCOCC)cc2)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C

Procedure:
98.5 g (0.2 mole) of ethoxymethyl 4-(4-(6-acryloyloxyhexyloxy)bezoyloxy)benzoate (16) were dissolved in 400 ml of ethanol and 5 g (0.02 mole) of pyridinium 4-toluensulfonate and 20 mg of 4-methoxyphenol were added. The mixture was heated at 60° C. for 15 h. After cooling down at room temperature the product crystallized. It was collected, washed with 300 ml of ethanol, and dried in a desiccator 55.3 g of a white powder (67%) were obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[C:7]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC1CN(Cc2ccccc2)CCC12CNc1ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CNCCC12CNc1ccccc12
Yield: 37.1 %

Procedure:
3′-Methyl-1′-(phenylmethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] (10 mmol, 2.9 g), acetic acid (30 mL) and Pd/C (5%, 600 mg) were added to a Parr bottle. The mixture was subjected to hydrogen gas at 30 psi for 20 h, after which time the solution was filtered over celite, concentrated and purified by reverse phase chromatography, 10-50% acetonitrile/water (0.1% TFA) over 14 min to give 3′-methyl-1,2-dihydrospiro[indole-3,4′-piperidine] (750 mg) as the TFA salt as an off white solid. MS (ES) m/e 203 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 0.62 (d, J=7.03 Hz, 3H) 1.83 (d, J=14.31 Hz, 1H) 2.00 (td, J=13.87, 4.14 Hz, 1H) 2.13 (dd, J=7.15, 4.39 Hz, 1H) 2.77 (d, J=11.80 Hz, 1H) 2.94 (d, J=11.54 Hz, 1H) 3.17 (d, J=1.51 Hz, 1H) 3.31 (d, J=13.30 Hz, 1H) 3.40 (d, J=10.79 Hz, 1H) 3.61 (d, J=11.04 Hz, 1H) 6.79 (d, J=7.78 Hz, 1H) 6.88 (t, J=7.28 Hz, 1H) 7.03 (d, J=7.28 Hz, 1H) 7.12 (t, J=7.15 Hz, 1H) 8.74 (br. s., 1H) 8.87 (br. s. 1H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.[Na+].Cl[C:14]([F:19])([F:18])C([O-])=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:10][O:9][C:7]([C:5]1[N:4]([CH3:11])[N:3]=[C:2]([O:1][CH:14]([F:19])[F:18])[CH:6]=1)=[O:8]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1cc(O)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC(F)F)nn1C
Temperature: 80 °C
Yield: 40.6 %

Procedure:
A solution of 2.00 g (12.8 mmol) of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (preparation: Chem. Ber. 1974, 107, 1318-1328) in 28 ml of N,N-dimethylformamide is admixed with 5.09 g (32.0 mmol, 96%) of chlorodifluoroacetic acid sodium salt and 2.66 g (19.2 mmol) of potassium carbonate, and the reaction mixture is heated at 80° C. overnight. The reaction mixture is added to 300 ml of water and extracted several times with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated by evaporation in vacuo on a rotary evaporator. Chromatographic purification gives 1.07 g of methyl-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (40%).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[CH3:32][C@H:33]1[CH2:38][NH:37][CH2:36][C@@H:35]([CH3:39])[NH:34]1>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:37]3[CH2:36][C@H:35]([CH3:39])[NH:34][C@H:33]([CH3:32])[CH2:38]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H](C)N1
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
A dimethyl sulfoxide solution (0.8 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (76.5 mg, 0.19 mmol) and cis-2,6-dimethylpiperazine (87.5 mg, 0.77 mmol) was heated at 140° C. and stirred for 2.5 hours. The resulting mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the resulting mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (91.1 mg, 100%) as a light brown solid.
Reaction SMILES: ON1C(=O)C2=CC=CC=C2C1=O.C(N(CC)CC)C.[N+]([C:23]1[CH:24]=[CH:25][C:26]2[N:32]3C(CCl)=NN=[C:31]3[CH2:30][N:29]=[C:28](C3C=CC=CC=3Cl)[C:27]=2[CH:45]=1)([O-])=O>CC(N(C)C)=O>[NH:32]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:45][C:27]=2[CH:28]=[N:29][CH:30]=[CH:31]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-nitro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-nitro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo][4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:17]=[C:16]([C:27](O)=[O:28])[C:15]=2[CH3:30])=[CH:10][CH:9]=1.C(N(CC)CC)C.[Cl-].[C:39]([C:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]1)([OH:41])=[O:40]>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:17]=[C:16]([C:27]([N:45]3[CH2:44][CH2:43][C:42]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:39]([OH:41])=[O:40])[CH2:47][CH2:46]3)=[O:28])[C:15]=2[CH3:30])=[CH:12][CH:13]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(O)C1(c2ccccc2)CC[NH2+]CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCC(C(=O)O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 67 %

Procedure:
A 2 M solution of oxalyl chloride in dichloromethane (3 eq., 0.19 mL, 0.377 mmol) was added to 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq., 48 mg, 0.126 mmol) in dichloromethane (5 mL). Next, 2 drops of anhydrous N,N-dimethylformamide was added the reaction was stirred for 2 h. The reaction was concentrated in vacuo. The reaction mixture was dissolved in dichloromethane (5 mL). Triethylamine (3 eq., 0.05 mL, 0.377 mmol) and 4-carboxy-4-phenylpiperidin-1-ium chloride (1.5 eq., 45.7 mg, 0.189 mmol) was added and the reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-10% methanol/dichloromethane with 1% acetic acid to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxylic acid (48 mg, 67%). (77) 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.87-2.09 (m, 2H) 2.15 (s, 3H) 2.61 (t, J=16.18 Hz, 2H) 3.21 (t, J=12.03 Hz, 1H) 3.47 (t, J=11.94 Hz, 1H) 4.26 (d, J=13.61 Hz, 1H) 4.57 (d, J=13.56 Hz, 1H) 7.05 (d, J=8.34 Hz, 2H) 7.12-7.45 (m, 10H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[C:19](Cl)(=[O:21])[CH3:20].CCOC(C)=O>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
To a solution of N-methyl-4-nitroaniline (200 mg, 1.31 mmol) in THF (5 ml) were successively added Et3N (0.364 ml, 2.63 mmol), acetyl chloride (0.14 ml, 1.97 mmol) and DMAP (8.0 mg, 0.066 mmol) at RT. The reaction mixture was stirred at RT for 2 h then diluted into AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (275 mg) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=1.17 min; LC-MS: m/z 195.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 2.05 (br. s., 3H), 3.37 (s, 3H), 7.36-7.46 (m, 2H), 8.27-8.36 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1nc(C(Cl)(Cl)Cl)ns1
Yield: 86 %

Procedure:
A solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 14.0 grams (0.18 mole) acetyl chloride in 200 milliliters xylene was refluxed at about 140° C. for 15 hours. The product precipitated (11.2 grams, 86% yield) after concentration in vacuo to approximately 50% of the original volume. A pure product of m.p. 193° C. was obtained by recrystallization from ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[OH:29])=[CH:3][CH:4]=1
Reactant: COc1cccc(C=O)c1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: -78 °C
Yield: 96.6 %

Procedure:
p-Dibromobenzene (7.08 g, 30.0 mmole) was added to 50 ml of anhydrous tetrahydrofuran under nitrogen and the slurry was cooled to -78° C. A solution of n-butyllithium in hexane (1.67M, 18.0 ml, 30 mmole) was added dropwise over 15 minutes. After stirring for ten minutes at -78° C., 3.8 ml (4.1 g, 30 mmole) of m-anisaldehyde was added dropwise over five minutes. After stirring for 15 minutes, the reaction was quenched with 10 ml of saturated aqueous ammonium chloride solution and was allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 50 ml portions of 1.0M aqueous sodium bisulfite, followed by 50 ml of 1.0 M sodium hydroxide, 100 ml of water, and 100 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 8.5 g (97%) of crude (4-bromophenyl)(3-methoxyphenyl)-methanol.
Reaction SMILES: O[C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(O)c3c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccc2sc3ncnc(Cl)c3c2c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0^[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate (2.10 g, 7.28 mmol, 1.00 equiv) in POCl3 (23 mL) was stirred for 1 h at 90° C. in an oil bath. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue dissolved in EtOAc was poured into a cooled saturated aqueous sodium bicarbonate, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1:5) to afford ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0^[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate (1.61 g, 72%) as a white solid. LCMS (ES, m/z): 307 and 309 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C=O.[C:12](O)(=[O:14])C>O>[OH:14][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Agent: C=O
Solvent: O
Product: OCn1nnc2ccccc21
Yield: 90 %

Procedure:
A mixture of benzotriazole (60 g, 0.5 mole), formalin (40 ml, 40% by volume), acetic acid (50 ml) and water (100 ml) (gave a white color precipitate after few minutes) was allowed to stand for over two hours at room temperature. The product which had precipitated was filtered off, and dried and recrystallized from 1200 ml of hot (80°-85° C.) not boiling water to give 68 g of (90% yield) the desired product; mp 148° C. (lit. 148°-151° C.).
Reaction SMILES: [CH:1](OC)([O:4][CH3:5])[O:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:20][C:21]1[N:26]=[CH:25][C:24](C=O)=[CH:23][CH:22]=1>CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH:1]([O:4][CH3:5])[O:2][CH3:3])=[CH:25][N:26]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
Trimethyl orthoformate (643 μl, 5.9 mmol) and p-toluene sulphonic acid monohydrate (102 mg, 0.54 mmol) were added to 6-bromo-pyridine-3-carbaldehyde (1 g, 5.37 mmol) dissolved in MeOH (40 ml). The mixture was stirred for 24 h at room temperature and then partitioned between water and Et2O. The organic extract was washed with water, 5% Na2CO3, dried over Na2SO4 and evaporated under vacuo to give 1.2 g of 2-bromo-5-dimethoxymethyl-pyridine as a brown oil.
Reaction SMILES: C([N:8]1[C:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=3)[C:15](=[O:26])[CH2:14]2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH:20]=3)[CH:15]([OH:26])[CH2:14]2)[N:8]=[CH:9]1
Reactant: CC(C)Cc1ccc2c(c1)C(c1cncn1Cc1ccccc1)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1ccc2c(c1)C(c1c[nH]cn1)CC2O

Procedure:
3-(3-Benzyl-3H-imidazol-4-yl)-5-isobutylindan-1-one (0.5 g) is dissolved in ethanol (15 ml). The reaction solution is hydrogenated at 50° C. with 10% palladium on carbon as catalyst until no more hydrogen is consumed. The mixture is filtered to remove the catalyst, and the filtrate is evaporated under reduced pressure. The crude product contains cis- and trans-isomers. The isomers are purified by flash chromatography.