Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>C(Cl)Cl.N1C=CC=CC=1>[O:12]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16])[CH3:11]
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2nc3ccccc3s2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2-amino-1,3-benzthiazole (700 mg, 4.7 mmol) in methylene chloride (20 ml) and pyridine (800 μl) was treated with 2,4-dimethoxybenzoyl chloride and stirred at 25° C. for 30 minutes. After this time, the reaction was treated with HCl (10 ml of 5 wt %) and the resulting precipitated collected by filtration. The solid was recrystallized from methanol to give 2-(2,4-dimethoxylbenzamido)-1,3-benzthiazole as colorless needles. (1.185 mg, 80% yield)
Reaction SMILES: [OH:1][P:2]([CH2:23][CH:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])([CH:4]([NH:12]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].B(Br)(Br)[Br:41].O>ClCCl>[BrH:41].[NH2:12][CH:4]([P:2]([CH2:23][CH:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([NH:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29])=[O:26])([OH:3])=[O:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrB(Br)Br
Reactant: C[C@H](NC(=O)C(Cc1ccccc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Solvent: O
Solvent: ClCCl
Product: Br
Product: C[C@H](NC(=O)C(Cc1ccccc1)CP(=O)(O)C(N)Cc1ccccc1)C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 50 mg (0.09 mmol) of N-[2-[[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]methyl]-1-oxo-3-phenylpropyl]-L-alanine in 2.5 ml of dichloromethane, cooled to −10° C., is added, under nitrogen, 0.45 ml of boron tribromide as a 1M solution in dichloromethane (0.45 mmol). The mixture is stirred for one hour at −10° C. and then for two hours at a temperature in the region of 20° C. 3 ml of water are added and the dichloromethane is evaporated off. The aqueous phase is washed with diethyl ether and evaporated to dryness. The product is taken up in water and then freeze-dried. 45 mg of product are recovered (yield=100%).
Reaction SMILES: S1C=CC=C1.[C:6]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][CH2:13]1.[H][H]>CO.C(O)C>[CH:6]1([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[CH2:16][CH2:17]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCC1
Reactant: c1cnc(NC2CCNCC2)nc1
Reactant: [H][H]
Solvent: CO
Solvent: CCO
Solvent: c1ccsc1
Product: c1cnc(NC2CCN(C3CCCC3)CC2)nc1

Procedure:
To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 2 parts of cyclopentanone, 5.5 parts of N-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-in-charcoal 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 4-methyl-2-pentanone and a small amount of trichloromethane. The whole is washed twice with a diluted sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered and dried, yielding 2.3 parts of N-(1-cyclopentyl-4-piperidinyl)-2-pyrimidinamine; mp. 118° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:19][C:20]1[C:21]([F:31])=[C:22]([F:30])[C:23](F)=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]>C1COCC1>[Br:19][C:20]1[C:21]([F:31])=[C:22]([F:30])[C:23]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 2-fluoro-aniline (177 mmol, 17.0 ml) in THF (80 mL) at −78° C. was added LiHMDS (265 mmol, 265 ml) and stirred for 30 min. To the reaction was added a solution of 5-bromo-2,3,4-trifluorobenzoic acid (78.4 mmol, 20.1 g) in THF (60 ml) at −78° C. The reaction was warmed to room temperature and stirred at the temperature over night. The reaction is concentrated and slowly 10% HCl (180 ml) is added. The mixture was extracted with ethyl acetate (100 ml×3), dried over MgSO4 and concentrated under reduced pressure. The crude material was taken in CH2CH2 (˜250 ml) and heated up to 45° C. for 10 min. Purification by trituration with CH2Cl2 gave 11 g (72%) of the desired product as a light yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[S:15][CH2:11][CH2:12][CH2:13][S:14]1
Reactant: COc1ccccc1C=O
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
A solution of 20.4 g (150 mmol) of o-anisaldehyde and 24 mL (239 mmol) of propane-1,3-dithiol in 300 mL of methylene chloride was cooled to 0° C. Boron trifluoride etherate (4.0 mL, 33 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was washed with 2×100 mL of 10% aqueous sodium hydroxide solution, 100 mL of water and 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 35.4 g (95% yield) of 2-(2'-methoxyphenyl)-1,3-dithiane, m.p. 127°-128° C.; 1H NMR (CDCl3) δ 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.87 (t, 1H), 2.92 (t, 1H), 3.05-3.2 (m, 2H), 3.85 (s, 3H), 5.69 (s, 1H), 6.87 (d, 1H), 6.97 (t, 1H), 7.25 (dt, 1 H), 7.59 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[S:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>N1C=CC=CC=1>[CH2:18]([N:20]([CH2:24][CH3:25])[C:21]([N:15]1[CH:16]=[N:17][C:13]([S:12][C:3]2[C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[N:14]1)=[O:22])[CH3:19]
Reactant: COc1c(C)c(C)cc(C)c1Sc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(Sc2c(C)cc(C)c(C)c2OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2,4,5-Trimethyl-6-methoxyphenylthio)-1,2,4-triazole (2.5 g) is dissolved in pyridine (60 ml) and diethyl carbamoyl chloride (1.4 g) is added dropwise to the solution. The mixture is stirred at room temperature for 1 h, then at 70° C. for 2 h. After distilling off pyridine, the residue is extracted with chloroform and dried with magnesium sulfate to obtain a crude product of 1-(diethylcarbamoyl)-3-(2,4,5-trimethyl-6-methoxyphenylthio)-1,2,4-triazole. This crude product is cooled to 0° C. and m-chloroperbenzoic acid (4 g) is added, followed by stirring at room temperature for 2 h and at 60° C. for 2 h. Subsequently, the resulting product is washed with a 10% aqueous solution of potassium carbonate and dried with magnesium sulfate. After distilling off the solvent, the residue is recrystallized from n-hexane/ethyl acetate; yield, 2.6 g (74%); m.p. 138°-139° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH2:26])=[C:24]([O:30][CH3:31])[CH:23]=1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH:26][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]4)=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1cc(Br)cc(C)c1N
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1cc(CC)n(-c2cccc3nc(Nc4c(C)cc(Br)cc4OC)n(C)c23)n1
Temperature: 110 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of 83 mg (0.287 mmol) of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole, 186 mg (0.862 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 20 hours. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate to give 112 mg (83%) of the title compound.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC(S(O[CH2:52][C:53](=[O:75])[C@@H:54]2[C@:71]3([CH3:72])[C@H:57]([C@H:58]4[C:68](=[CH:69][CH2:70]3)[C@:66]3([CH3:67])[C:61](=[CH:62][C:63](=[O:73])[CH:64]=[CH:65]3)[CH2:60][CH2:59]4)[CH2:56][C@H:55]2[CH3:74])(=O)=O)=CC=1>C(#N)C>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:29]4[CH2:30][CH2:31][N:32]([CH2:52][C:53](=[O:75])[C@@H:54]5[C@:71]6([CH3:72])[C@H:57]([C@H:58]7[C:68](=[CH:69][CH2:70]6)[C@:66]6([CH3:67])[C:61](=[CH:62][C:63](=[O:73])[CH:64]=[CH:65]6)[CH2:60][CH2:59]7)[CH2:56][C@H:55]5[CH3:74])[CH2:33][CH2:34]4)[N:13]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Reactant: c1c(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(NC34CC5CC(CC(C5)C3)C4)nc(NC34CC5CC(CC(C5)C3)C4)n2)CC1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
After adding 1.88 g (4.07 moles) of 2,4-bis(1-adamantylamino)-6-(1-piperazinyl)pyrimidine and 0.56 g of potassium carbonate to a solution containing 2.00 g (3.57 mmoles) of 21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of acetonitrile, the reaction mixture is stirred at 65° C. for 5 hours, then evaporated. The residue is distributed between 40 ml of chloroform and 10 ml of water. After separation the chloroform solution is dried, evaporated and the residue is purified by chromatography on a silica gel column. A 98:2 mixture of chloroform/methanol is used for elution and the product obtained is recrystallized from ether to give the title compound in a yield of 2.48 g (88.5%), m.p.: 210°-220° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:21])=O)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:28][C:29]([O-:31])=[O:30].[Na+]>C(OC(=O)C)(=O)C>[CH2:25]([O:24][C:22]([C:5]1[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][CH2:21][O:31][C:29](=[O:30])[CH3:28])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:27])=[O:23])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1S(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1SCOC(C)=O
Yield: 43.7 %

Procedure:
A suspension of 3.31 g (8.46 mm) of sulfoxide 34 and NaOAc (anhydrous, 1.10 g) in 9.1 mL of acetic-anhydride was stirred at reflux for 40 minutes. The acetic anhydride was removed at reduced pressure, and the residue diluted with 250 mL of CH2CL2 and 50 mL of H2O. The organic portion was washed with 10% aqueous HCl, 5% aqueous NaHCO3, and brine, dried (anhydrous MgSO4), filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc in hexane) to give acetate 35 (1.60 g, 44%).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([F:4])[F:3].O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(SC(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(SC(F)(F)F)cc2)CC1
Yield: 79.1 %

Procedure:
A solution of 2 g 4-trifluoromethylsulfanyl-phenol, 2.07 g t-butyl 4-hydroxy-1-piperidinecarboxylate, 3.2 g triphenyl phosphine and 5.4 g diethyl azodicarboxylate (40% toluene solution) in anhydrous tetrahydrofuran (40 mL) was heated for 24 hours under reflux in a stream of nitrogen. Water was added thereto, and the reaction solution was extracted with ethyl acetate, dried over sodium sulfate, and purified by NH silica gel chromatography (hexane/ethyl acetate) to give 3.07 g of the title compound.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14].C(OC(C)C)(C)C.C1(NC2CCCCC2)CCCCC1>CN(C=O)C.CCOC(C)=O>[C:1]([S:3][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(C)C[C@@H](Br)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)S[C@@H](CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
Thioacetic acid (4.2 g, 54.4 mmol) and DMF (100 mL, 1.0 mol) were combined, and the mixture cooled in an ice bath. Sodium carbonate (5.8 g, 54.4 mmol) was added. After 30 minutes, (R)-2-bromo-4-methylpentanoic acid (10.1 g, 51.8 mmol) in DMF (20 mL) was added dropwise and the mixture was stirred at 0° C. to room temperature over 6 hours. The mixture was diluted with 100 mL EtOAc and extracted with 100 mL of a 1:1 1N HCl: saturated aqueous NaCl solution. The layers were separated and the aqueous phase was extracted with additional EtOAc (100 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was dissolved into diisopropyl ether (45 mL, 320 mmol) and chilled at 0° C. Dicyclohexylamine (10.1 mL, 50.7 mmol) was added dropwise and the solid was allowed to crash out of solution. After stirring for an additional 30 minutes the material was filtered and washed with 75 mL cold diisopropyl ether. The recovered solid (14 g) was suspended in 100 mL EtOAc. 150 mL of 5% KHSO4 was added and the layers were separated. The organic was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was then azeotroped (3×25 mL toluene) to yield the title compound (6.1 g) as a dicyclohexylamine salt.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[F:15][C:16]([F:21])([F:20])C([O-])=O.[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[F:15][C:16]([F:21])([F:20])[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1=Cc2cc(C(F)(F)F)ccc2OC1(C)C
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A suspension containing 6-bromo-2,2,3-trimethyl-2H-1-benzopyran (38.0 g, 0.15 mol), potassium trifluoroacetate (62.0 g, 0.408 mol) and cuprous iodide (57.0g, 0.30 mol) in dimethylformamide (530 ml) and toluene (225 ml) was heated under nitrogen until a total of 70 ml of toluene was collected by distillation. Toluene was distilled off until the temperature of the reaction mixture reached 140° C. After a further four hours at this temperature the mixture was cooled to room temperature, water and diethyl ether were added, and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with heptane to give 18.82 g of 6-trifluoromethyl-2,2,3-trimethyl-2H-1-benzopyran as an oil, ms 242 (M+).
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[CH:44]1([NH:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=2)[CH2:46][CH2:45]1>>[CH:7]([OH:8])=[O:6].[CH:44]1([N:47]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[CH:50]=2)[C:36]([C:15]2[C@@H:14]3[NH:9][C@H:10]([CH2:17][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=2)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]3)=[O:37])[CH2:46][CH2:45]1
Reactant: COc1cccc(CNC2CC2)c1
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Product: COc1cccc(CN(C(=O)C2=C(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)C[C@@H]3CN(C(C)=O)C[C@H]2N3)C2CC2)c1
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and cyclopropyl-(3-methoxybenzyl)amine. LC-MS: Rt=0.87; ES+: 634.27.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cccnc1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3cccnc3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted with 3.0 g of 3-picolyl amine and 5 g of triethyl amine according to Example 76, the solvent was distilled off under reduced pressure and the residue was taken up in 70 ml of water. Three extractions followed with 60 ml of ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue crystallized under diisopropyl ether. Melting point: 152°-153° C.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:57])[CH2:56][CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][CH2:56][C:52]([F:57])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as colorless gum (13.3 mg, 69%). MS(m/e): 407.4 (MH+).
Reaction SMILES: C([O:5][C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12][O:11]1)[CH3:9])=[O:7])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:6]([C@H:8]([N:10]1[C:15](=[O:16])[C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12][O:11]1)[CH3:9])([OH:7])=[O:5]
Reactant: C[C@H](C(=O)OC(C)(C)C)N1OC[C@@H](O)[C@@H](O)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](C(=O)O)N1OC[C@@H](O)[C@@H](O)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a cooled (ca. 0° C.) stirred solution of the tert-butyl ester 8b (0.0467 g, 0.179 mmol) in CH2Cl2 (0.9 ml), trifluoroacetic acid (0.9 mL) was added in one portion. The reaction mixture was kept for 1 hour at room temperature and was evaporated in vacuo to dryness. The semisolid residue was triturated with dry ether and dried in vacuo to afford 0.0295 g (80%) of the product 9b as a white solid. 1H NMR (400 MHz) in CD3CN (J, Hz): δ 1.41 (3H, d, 3J=7.3, α-MeCH), 3.60 (2H, br. s, OH, OH, COOH), 4.14 (1H, dd, 2J=−11.6, 3J=2.3, 6-HA), 4.34 (1H, d, 3J=4.1, 4-H), 4.40 (1H, dd, 2J=−11.6, 3J=7.4, 6-HB), 4.49-4.45 (2H, m, 5-H), 5.01 (1H, q, 3J=7.3, α-CH), 5.31 (1H, br. s, COOH). 13C (100 MHz) in CD3CN: δ 14.45, 54.48, 70.05, 70.99, 77.77, 167.30, 171.82.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1SC.O[O:16][S:17]([O-:19])=O.[K+].[CH3:21]O>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[C:3]1[S:17]([CH3:21])(=[O:19])=[O:16]
Reactant: CSc1nnc(-c2ccccc2)n1C
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Product: Cn1c(-c2ccccc2)nnc1S(C)(=O)=O

Procedure:
A slurry of 4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole (0.360 g, 1.75 mmol) and oxone(r) monopersulfate compound (2.16 g, 3.51 mmol) were stirred rapidly in 5 mL MeOH overnight. The reaction was concentrated and the solids diluted with water, ice, and treated with 6 N NaOH until a pH>10. The resulting material was extracted 3×DCM, and the combined organic layers were dried over anhyd sodium sulfate, filtered, and concentrated to give 4-methyl-3-(methylsulfonyl)-5-phenyl-4H-1,2,4-triazole as a white solid. MS m/z=238 [M+H]+. Calc'd for C10H11N3O2S: 237.3.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:18][CH2:19][OH:20])[CH3:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:19][CH2:18][N:16]([C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=1)[CH3:17])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)OCCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
2.67 g of methacryloyl chloride in 5 ml of chloroform were added dropwise to 5 g of 2-[N-(p-nitrophenyl)-N-methylamino]-ethanol and 2.02 g of pyridine in 40 ml of chloroform while cooling. Thereafter, the resulting reaction solution was first stirred at room temperature and then refluxed for 3.5 hours. It was cooled to room temperature and then 40 ml of water were added to it, after which the chloroform phase was separated off and the aqueous phase was extracted with three times 20 ml of chloroform. After the combined chloroform phases had been dried with Na2SO4 and the chloroform evaporated off, the resulting product was washed with hexane and dried under reduced pressure. 2.6 g of 2-[N-(p-nitrophenyl)-N-methylamino]-ethyl methacrylate were obtained, the IR spectrum of the product in the form of a KBr pellet having bands at 2,950, 2,900, 1,720, 1,600, 1,510, 1,490, 1,320, 1,310, 1,160, 1,110 and 825 cm-1.