Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:32]=[CH:31][C:8]([C:9](=[O:30])[CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[C:20]2[C:21]([NH:25][CH2:26][CH2:27]C#N)=[N:22][O:23][N:24]=2)=[CH:7][CH:6]=1)C(C)=O.[C:33](=[O:36])(O)[O-:34].[Na+]>Cl.O>[NH2:1][C:5]1[CH:32]=[CH:31][C:8]([C:9](=[O:30])[CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[C:20]2[C:21]([NH:25][CH2:26][CH2:27][C:33]([OH:34])=[O:36])=[N:22][O:23][N:24]=2)=[CH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC#N)nc3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)Cn2c(-c3nonc3NCCC(=O)O)nc3ccccc32)cc1

Procedure:
A solution of 4-[1-(4-acetaminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine (0.061 g) in aqueous hydrochloric acid (5 ml, HCl conc.) is heated at reflux for two hours. The mixture is diluted with water and neutralized by addition of sodium bicarbonate. Extraction with ethyl acetate, drying over sodium sulphate, filtering and evaporation of the resulting filtrate to dryness gives the title compound in pure form, m.p. 174-177° C. 1H-NMR (400 MHz, d6-DMSO): 12.40 (s, 1H); 7.84 (m, 4H); 7.38 (m, 3H); 6.65 (m, 2H); 6.28 (S, 2H); 6.17 (s, 2H); 3.57 (m, 2H); 2.66 (t, 2H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=O)C)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].II.[N:29]1C=CC=CC=1>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:29])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: c1ccncc1
Reactant: CCCCCc1ccc([C@H]2CC[C@H](c3ccc(C(C)=O)cc3)CC2)cc1
Agent: II
Product: CCCCCc1ccc([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1
Reaction time: 2.5 h

Procedure:
14.0 g of trans-4-(4-n-pentylphenyl)-1-(4-acetylphenyl)-cyclohexane are heated for 2 hours on a steambath, together with 30 g of iodine and 100 ml of pyridine. After the evaporation of the pyridine under reduced pressure, the residue is dissolved in chloroform and purified over a short silica gel column. The eluate is evaporated and the 4-[trans-4-(4-n-pentylphenyl)-cyclohexyl]-benzoic acid remaining behind is brought to the boil for 2.5 hours with 30 ml of thionyl chloride. After distilling off the excess thionyl chloride, the 4-[trans-4-(4-n-pentylphenyl)-cyclohexyl]-benzoyl chloride is dissolved in 250 ml of dioxane and this solution mixed with 100 ml of 25% aqueous ammonia solution. The reaction mixture is poured into 1.5 liters of ice water and the precipitated 4-[trans-4-(4-n-pentylphenyl)-cyclohexyl]-benzamide filtered off and dried. The dry amide is dissolved at 40° in 170 ml of dimethyl formamide. To this solution are added dropwise at 50° , in the course of 30 minutes, 26 g of phosphorus oxide trichloride. After 1 hour the reaction mixture is poured into 300 ml of icewater. After extracting several times with 100 ml amounts of dichloromethane, washing of the extracts with 5% sodium bicarbonate solution and then with water, drying over sodium sulphate and evaporation, there is obtained trans-4-(4-n-pentylphenyl)-1-(4-cyanophenyl)-cyclohexane which is purified by recrystallisation from ethanol; m.p. 80°, c.p. 160°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:25]([CH:30]2[CH2:33][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:31]2)[O:24][N:23]=1)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11].O.Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:28][CH2:29]2)=[C:25]([CH:30]2[CH2:31][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:33]2)[O:24][N:23]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11]
Reactant: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)CC(CC(=O)O)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
tert-Butyl 4-(2-chloro-4-methylphenylcarbamoyl)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]butanoate (131 mg) and water (0.8 mL) were mixed. After an addition of 25 w/w % hydrogen bromide in acetic acid (1.64 mL) to the reaction mixture, the mixture was stirred at RT for 1.5 hr. Sodium acetate and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform=1/9) to give the title compound (97.3 mg). The specific optical rotation value of the title compound was [α]D25=+32.7° (c=1.00, methanol). The title compound was analyzed using a chiral column. The retention time of the title compound was 6.8 min., and the optical purity thereof was 95.1% ee. The condition for the analysis using the chiral column was as follows:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]([F:39])([F:38])[C:29]1[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:35]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:27])[F:38])[N:34]=2)=[O:36])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)n1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)n2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-trifluoromethyl-pyridine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].C(Cl)(=O)N.C(NC(Cl)=O)C.CN(C)C(Cl)=O.C([S:28][CH:29]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:43][CH3:44])[CH:39]=2)[CH:34]=1)[C:30]([OH:32])=[O:31])(=O)N.C(NC(SC(C1C=CC2C(=CC=C(OC)C=2)C=1)C(O)=O)=O)C.CN(C)C(SC(C1C=CC2C(=CC=C(OC)C=2)C=1)C(O)=O)=O>>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([S:28][CH:29]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:43][CH3:44])[CH:39]=2)[CH:34]=1)[C:30]([OH:32])=[O:31])=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc2cc(C(SC(N)=O)C(=O)O)ccc2c1
Agent: CCNC(=O)Cl
Agent: CCNC(=O)SC(C(=O)O)c1ccc2cc(OC)ccc2c1
Agent: CN(C)C(=O)Cl
Product: CCN(CC)C(=O)SC(C(=O)O)c1ccc2cc(OC)ccc2c1

Procedure:
When diethylcarbamylchloride is replaced in the above procedure by carbamyl chloride (prepared in situ from potassium cyanate and anhydrous hydrogen chloride in anhydrous chloroform), ethylcarbamyl chloride or dimethylcarbamyl chloride, then the products prepared are α-carbamylthio-6-methoxy-2-naphthylacetic acid, α-ethylcarbamylthio-6-methoxy-2-naphthylacetic acid or α-dimethylcarbamylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:28]([CH:27]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:30][CH3:31])[CH3:29]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: CCC(Br)CC
Product: CCC(CC)Oc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
Using the compound obtained in Example 136 and 3-bromopentane, white powdery 3-{2-[3-(1-ethylpropoxy)-4-methoxy phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][O:14][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCOCc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution consisting of 3-(2-hydroxy-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (0.250 g, 1.24 mmol) and THF (2 mL) at 0° C. was added sodium hydride (0.0459 g, 0.124 mmol). The reaction was stirred at 0° C. for 0.5 h, then treated with tetrabutylammonium iodide (0.0459 g, 0.124 mmol) and 4-chlorobenzyl bromide (0.383 g, 1.86 mmol), warmed to rt and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl (1.0 mL), diluted with ethyl acetate (40 mL) and extracted with 1 N NaOH (40 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound as a yellow oil (0.302 g, 74%). 1H NMR (d6-DMSO): 7.40 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.42 (s, 2H), 3.88 (t, J=8.0 Hz, 2H), 3.53-3.44 (m, 2H), 3.40 (t, J=6.2 Hz, 2H), 2.62-2.53 (m, 1H), 1.84-1.74 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C@H:25]([OH:31])[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:39][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][C@H:25]([OH:31])[CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1
Reactant: CCC(CC)[C@@H](O)CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)[C@@H](O)CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 103.2 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(R)-hydroxypentylthio}pregna-5,7,16-triene (54.9 mg, 0.0797 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=9:1, developed once) to give the title compound as a colorless oil (37.9 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH:12]2OCC[O:27][CH:11]12.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:27]
Reactant: CCCCCC(O)C=C[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOCC
Product: CCCCCC(O)C=C[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC
Reaction time: 8 h

Procedure:
A mixture of 9-ethylenedioxy-15-hydroxyprost-13-enoic acid methyl ester (35 mg), methanol (3 ml) water (0.5 ml) and p-toluenesulfonic acid (10 mg) is allowed to stand at room temperature overnight, taken up in ether, washed to neutrality with water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield 15-hydroxy-9-oxoprost-13-enoic acid methyl ester γmaxFilm 3450, 1745 cm-1, identical to the compound of the same name described in British Pat. No. 1,218,998, cited above.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:20][CH2:19]1>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:20][CH2:19]1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2cccc(Cl)c2Cl)CC1
Product: Clc1cccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)c1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2,3-dichlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(2,3-dichlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1[C:24](OC)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:10][C@H:9]1[CH:24]=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1C=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (9.01 g) in toluene (70 ml) was added dropwise 1.5 molar solution of diisobutylaluminum hydride (61.2 m mol) in tetrahydrofuran (40.8 ml) at -78° C. After the mixture was stirred at -78° C. for 1.5 hours, saturated aqueous potassium sodium tartrate was added to the reaction mixture and the mixture was filtered through Celite. The solid was washed with ethyl acetate and the combined organic solution was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of ethyl acetate and n-hexane (1:2-2:1) as an eluent to give (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-formylpyrrolidine (5.51 g) as pale yellow crystal.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:44][C:45]1[O:49][N:48]=[C:47]([CH3:50])[N:46]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[O:49][N:48]=[C:47]([CH3:50])[N:46]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cc1noc(CCl)n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1noc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as light-red solid. MS(m/e): 371.2 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[C:32]([C:30]1[CH:29]=[CH:28][C:27]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[C:26]([CH3:25])[CH:31]=1)#[N:33]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1cc(C#N)ccc1B(O)O
Product: Cc1cc(C#N)ccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 14 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-methyl-4-cyanophenylboronic acid (available from Aldrich Chemical Company, Inc.; 64 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-methyl-biphenyl-2-carboxylic acid (13 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.75-7.83 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[O:10][CH2:9][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:11][O:12]1
Reactant: O=Cc1cccc(F)c1F
Reactant: CCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCC1COC(c2cccc(F)c2F)OC1

Procedure:
Quantities: compound from Example 8 (27 g, 0.155 mol), 2,3-difluorobenzaldehyde (21.5 g, 0.15 mol) and 4-toluenesulphonic acid (100 mg). The experimental procedure was as described in Example 11 except using dry benzene instead of dry toluene.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[C:4]=1[CH:5]=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33](Br)(Br)[Br:34]>ClCCl>[Br:32][C:33]([Br:34])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCc1cccc(CC)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc(CC)c1C=C(Br)Br
Reaction time: 0.08 h

Procedure:
To a solution of 3.80 g (23.4 mmol) 2,6-diethyl-benzaldehyde and 12.3 g (47 mmol) triphenylphosphine in 100 ml dry dichloromethane cooled to −20° C. was added drop-wise a solution of 9.32 g (28.1 mmol) tetrabromomethane in 70 ml dichloromethane. The reaction temperature was kept below 5° C. After the addition the reaction mixture was kept at −10° C. for 5 minutes and then for 30 minutes at ambient temperature. The reaction mixture was poured onto water, extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography on silica gel with a heptane/ethyl acetate gradient as eluent: 4.50 g 2-(2,2-dibromo-vinyl)-1,3-diethyl-benzene as colourless liquid: MS (EI): 319.9 and 318.0 and 316.0 (M+.), 239.1 and 237.1 ((M-Br)+.), 158.2 ((M-Br2)+., 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][CH3:20])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([O:17]C)=[O:16])[CH:10]=2)=[N:6][CH:7]=1.[Li+].[OH-].O1CCCC1>O>[Cl:1][C:2]1[C:3]([NH:19][CH3:20])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNc1nc(Nc2cc(C(=O)OC)nn2C)ncc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(Nc2cc(C(=O)O)nn2C)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a 100 mL round bottom flask equipped with a stir bar was added 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate, 0.28 g of LiOH, 15 mL of tetrahydrofuran and 10 mL of water. The reaction was stirred at room temperature for 18 hours. The tetrahydrofuran was removed in vacuo and the aqueous layer was acidified to pH 5 with 1N HCl. The aqueous layer was partitioned with ethyl acetate and the organic layer washed with brine, dried over MgSO4, filtered and concentrated to give 0.58 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylic acid which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]([O:41][CH2:42][CH2:43][CH3:44])=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36]([O:38][CH3:39])=[O:37])[C@@H:31]([CH3:40])[CH2:30][CH2:29]4)[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:40][C@H:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][CH:35]=[C:26]([C:24]3[CH:23]=[N:22][N:21]([CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH:25]=3)[C:27]=2[O:41][CH2:42][CH2:43][CH3:44])[N:32]1[C:36]([O:38][CH3:39])=[O:37]
Reactant: CCCOc1c(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ccc2c1CC[C@H](C)N2C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1c(-c2cnn(C3CCNCC3)c2)ccc2c1CC[C@H](C)N2C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate (0.090 g, 0.176 mmol) in dichloromethane (2.0 mL) and the reaction mixture stirred at rt for 1 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-methyl 2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-propoxy-3,4-dihydroquinoline-1(2H)-carboxylate (0.070 g, 97%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.48 Hz, 3H), 1.05-1.13 (m, 3H), 1.48 (dq, J=13.05, 6.50 Hz, 1H), 1.63-1.87 (m, 5H), 1.88-2.03 (m, 2H), 2.05-2.19 (m, 2H), 2.53-2.66 (m, 2H), 2.72-2.90 (m, 1H), 3.04 (br d, J=12.61 Hz, 2H), 3.54 (br t, J=6.60 Hz, 2H), 3.67 (s, 3H), 4.11-4.32 (m, 1H), 4.37-4.57 (m, 1H), 7.21-7.31 (m, 1H), 7.31-7.40 (m, 1H), 7.81 (s, 1H), 8.06 (s, 1H). MS (ESI, pos. ion) m/z 413 [M+H]+. MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([OH:11])[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:13][C:14]1[CH:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[OH:11][C@:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C@H:2]1[NH:1][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:13])[CH:23]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: COC(=O)[C@@]1(O)CCC[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a solution of methyl (1R,2R)-2-amino-1-hydroxycyclopentanecarboxylate (2.1 mmol) in CH2Cl2 (8 mL) and saturated sodium bicarbonate (8 mL) was added 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (0.88 g, 1.1 eq). The reaction was allowed to stir for 18 h at room temperature, and then taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified using ilica chromatography eluting with a gradient of 50% -70% ethyl acetate/hexanes afforded methyl (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (0.2 g, 20%). MS: 470.1 (M+H)+