Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[O-:3]O.[CH:5]12[CH2:13][CH:9]([C:10]1([CH3:12])[CH3:11])[CH2:8][CH2:7][CH:6]2[CH3:14].[C:15](Cl)(=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22]>O>[C:15]([O:25][OH:3])(=[O:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22].[CH:5]12[CH2:13][CH:9]([C:10]1([CH3:12])[CH3:11])[CH2:8][CH2:7][CH:6]2[CH3:14]
Reactant: [O-]O
Reactant: CC(C)(C)CCCCCC(=O)Cl
Reactant: [OH-]
Agent: CC1CCC2CC1C2(C)C
Agent: [K+]
Solvent: O
Product: CC(C)(C)CCCCCC(=O)OO
Reaction time: 0.08 h

Procedure:
One liter capacity four-necked flask equipped with an agitator is charged with 216.4 g of a 35% KOH aqueous solution, and added under agitation with 289.7 g of 52.9% pinane hydroperoxide, while retaining the solution temperature at 20° C. Further 143.1 g of neodecanoic acid chloride is added dropwise over 10 min., while agitating and retaining the solution temperature at 20° C. After agitation of 1 hr., 170 g of cold water is added to the solution, and additional agitation is effected for 5 min. Then, the solution is left still for phase separation. Water phase is removed by separation to leave an oily phase. The oily phase is washed with 300 g of 5% NaOH aqueous solution, subsequently three times with water, and dried over anhydrous magnesium sulfate. Thus, 325.2 g of pinane peroxyneodecanoate solution of a purity of 54.5% is obtained. Yield is 72.8 mol%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(N(CC)CC)C.C1C=CC=CC=1>O>[N:1]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CCCCC2)n1

Procedure:
A mixture comprising 2.1 g of piperidine, 4 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine and 20 ml of benzene was refluxed for 12 hours. The reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O.ClCCl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: NC1CCOCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200.0 mg, 0.63 mmol) in DMSO (1.5 mL) was added tetrahydro-2H-pyran-4-amine (127.8 mg, 1.26 mmol), DIEA (163.3 mg, 1.27 mmol) under nitrogen atmosphere. After stirring overnight at 100° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.01%-0.1% ethyl acetate in petroleum ether to afford methyl 2-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-4-ylamino)quinoxaline-6-carboxylate as a light yellow solid (180.0 mg, 75%).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6](Cl)[N:5]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14]>CC(C)=O.O>[CH2:12]([NH:15][C:4]1[N:9]=[C:8]([NH:15][CH2:12][CH2:13][CH3:14])[N:7]=[CH:6][N:5]=1)[CH2:13][CH3:14]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCNc1ncnc(NCCC)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
A 2 M NaOH solution (82 mL, 162.68 mmol) was added in a dropwise manner to a suspension of 2,4,6-trichloro-1,3,5-triazine (XVIII) (15.00 g, 81.34 mmol) and n-propylamine (13.4 mL, 162.68 mmol) in acetone (300 mL) and water (15 mL) at 0° C. The reaction mixture was heated at 50° C. for 3 h and then cooled. Water (100 mL) was added to the reaction mixture; the resultant precipitate was filtered, washed with water, ethyl ether and dried to yield 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (15.88 g, 85% yield).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[C:28]([C:32]1[CH:33]=[C:34]([CH:40]=[C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:42]=1[OH:43])[CH:35]=[CH:36][C:37](Cl)=[O:38])([CH3:31])([CH3:30])[CH3:29]>C1C=CC=CC=1>[C:44]([C:41]1[CH:40]=[C:34]([CH:33]=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:42]=1[OH:43])[CH:35]=[CH:36][C:37]([N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:4][CH2:5]1)=[O:38])([CH3:46])([CH3:47])[CH3:45]
Reactant: CC(C)(C)c1cc(C=CC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 16.8 g. (50 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate dihydrochloride and 200 ml. anhydrous pyridine is added dropwise at 5°-10° C., in the course of 40 minutes, a solution of 14.8 g. 3,5-di-tert.-butyl-4-hydroxycinnamoyl chloride and 50 ml. anhydrous benzene. The reaction mixture is stirred for 4 hours at 20° C., the benzene and pyridine are substantially distilled off in a vacuum and the residue is stirred into about 1 liter ice water. The separated, greasy precipitate is taken up in methylene chloride and the methylene chloride phase is washed with aqueous sodium carbonate solution, dried with anhydrous sodium sulphate and evaporated to dryness in a vacuum. The crude base is dissolved in ethanol, gassed with hydrogen chloride and finally precipitated as the hydrochloride by the addition of diethyl ether. The yield is 17.3 g. (62% of theory) of the desired product which, after stirring up with diethyl ether, melts at 193°-195° C. (decomp.).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][NH:11][C:12]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][N:22]2[C:27](=[O:48])[CH2:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20])=[O:13])[CH2:5]1)[CH:2]=[CH2:3].[CH2:49]([Br:52])[CH:50]=[CH2:51]>>[Br-:52].[CH2:1]([N+:4]1([CH2:51][CH:50]=[CH2:49])[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][NH:11][C:12]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][N:22]2[C:27](=[O:48])[CH2:28][C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:20])=[O:13])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: C=CC[N+]1(CC=C)CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: [Br-]

Procedure:
The title compound was prepared by a method similar to Example 128, using (2R)-N-{((3R)-1-allyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-pyrrolidine-2-carboxamide and allyl bromide. The compound was obtained as a white foamy substance.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:18][CH:17]([CH3:19])[CH:16]([C:20]#[N:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.O>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH:17]([CH3:19])[CH:16]([CH2:20][NH2:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1CN(Cc2ccccc2)CC1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccccc2)CC1CN
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a mixture of LAH (0.019 g, 0.499 mmol) in THF (5 mL) was added 1-benzyl-4-methylpyrrolidine-3-carbonitrile (0.050 g, 0.250 mmol, Tyger) at about 0° C., then the resulting mixture was stirred at about 25° C. for about 4 h. EtOAc (2 mL) and water (3 mL) were added and the precipitate formed was filtered off. The filtrate was concentrated to give (1-benzyl-4-methylpyrrolidin-3-yl)methanamine (0.05 g, 39%): LCMS (Table 2, Method 1) Rt=0.22 min.; MS m/z: 205 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.CO.[CH3:17][Si](C=[N+]=[N-])(C)C>C1COCC1>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:17])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCCC2=O
Yield: 99.8 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (10.0 g, 52.6 mmol) in THF (52.6 mL) and MeOH (10.64 mL, 263 mmol) at rt was added trimethylsilyldiazomethane (2.0 M in diethyl ether, 79 mL, 158 mmol) dropwise until the solution turned yellow and gas evolution ceased. The reaction was then concentrated under reduced pressure to give methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (10.72 g, 52.5 mmol, 100% yield) as a brown solid. MS ESI calcd for C12H12O3 [M+H]+ 205, found 205. 1H NMR (500 MHz, DMSO) δ 7.94 (d, J=8.1 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J=8.1, 1.6 Hz, 1H), 3.86 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.66-2.61 (m, 2H), 2.09-2.00 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]([C:35](=[O:36])[NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCNCC2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)Nc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 36 mg (0.1 mmol) [4-(4-Isopropyl-phenylcarbamoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester, 16.5 mg (0.12 mmol) 4-fluorophenyl isocyanate and 32 mg (0.31 mmol) NEt3 in 1 mL DCM was shaken at room temperature over night. After evaporation to dryness the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and HCOOH. The product containing fractions were evaporated to yield 38.5 mg (77%) of the title compound. MS (m/e): 499.3 [(M+H)+].
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[CH2:5]([O:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[C:15]([O:26]C)[N:16]2[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[C:12]([NH2:28])[N:11]=1)[CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.CS(C)=O>CN(C=O)C>[NH2:28][C:12]1[N:11]=[C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:26])[N:16]2[CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH:2]([CH3:4])[CH3:3])[CH2:21]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(C(C)C)C3)c2n1
Reaction time: 18 h
Yield: 30.6 %

Procedure:
2-Iodopropane (0.1 mmol) was weighed into a vial and an aliquot (0.3 ml, 0.1 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine (802 mg, 2.398 mmol) suspended in DMF (7.2 ml) was added. DIPEA (40 μl, 0.229 mmol) was added and the tube was capped and shaken to aid dispersion then allowed to stand at room temperature (18 hours). DMSO (400 uL) was added and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.5 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The material was redissolved in methanol (0.5 ml), and applied to a 0.5 g aminopropyl SPE (preconditioned with methanol, 2 CV). The cartridge was eluted with methanol (2 ml), the solvent was removed to give the title compound (11.1 mg). LCMS (System A): tRET=0.62 min; MH+ 363
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].C(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: CC1=C(C(=O)OCc2cccc(Cl)c2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Solvent: CC(C)O
Product: C/C(N)=C/C(=O)OCc1cccc(Cl)c1
Yield: 69 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoaceic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 3-chlorobenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3-chlorobenzyl ester of melting point 104° C (from ethanol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25]([CH3:27])C)=O.[Cl:34][C:35]1[N:40]=[CH:39][C:38]([CH2:41][N:42]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:43][CH2:44]O)=[CH:37][CH:36]=1.[S:50]1C=CC=C1CC(O)=O>C1COCC1>[Cl:34][C:35]1[N:40]=[CH:39][C:38]([CH2:41][N:42]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:43][CH2:44][S:50][C:25](=[O:24])[CH3:27])=[CH:37][CH:36]=1
Reactant: CC(C)CN(CCO)Cc1ccc(Cl)nc1
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCN(Cc1ccc(Cl)nc1)CC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a stirred, cold (0° C.) solution of 3.11 grams (0.012 mole) of triphenylphosphine in 200 mL of THF was added dropwise 2.28 grams (0.011 mole) of diisopropyl azodicarboxylate. The reaction mixture was stirred at 0° C. for five hours and at that time a solution of 1.37 grams (0.0056 mole) of 2-{[(6-chloro(3-pyridyl))methyl](2-methylpropyl)amino}ethan-1-ol and 0.94 gram (0.012 mole) of thiolacetic acid in 50 mL of THF was added dropwise. After complete addition the reaction mixture was stirred at 0° C. for one hour. The reaction mixture was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with mixtures of n-heptane and ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.07 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC[O:29]CC>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:29]
Reactant: Brc1cccnc1
Reactant: CCOCC
Reactant: COC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COC1CCCCC1(O)c1cccnc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 2.5 M n-butyllithium in hexane (13.2 ml, 33 mmol) at -78° C. was added diethyl ether (15 ml) followed by a solution of 3-bromopyridine (4.7 g, 30 mmol) in ether (90 ml) over a period of 10 minutes. After 1 hour at -78° C. a solution of (±)-2-methoxycyclohexane (3.84 g, 30 mmol) in ether (20 ml) was added dropwise during 10 minutes. After 2 hours at -78° C. and 30 minutes at 0° C. the reaction mixture was warmed to 20° C. and then poured onto ice (150 g). The mixture was extracted with ether (2×50 ml) and then the combined organic extracts were extracted with 1 N hydrochloric acid (50 ml). This aqueous extract was washed with ether (20 ml) and then treated with 2 M sodium hydroxide solution (25 ml) and extracted with ether (3×100 ml). The organic extracts were combined, washed with brine then dried over anhydrous sodium sulphate. Concentration in vacuo afforded (±)-2-methoxy-1-(pyrid-3-yl)cyclohexanol (5.0 g, 24 mmol) as a 4:1 mixture of cis and trans isomers;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2ccc(F)cc2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(F)cc4)C3)CC2)cc1
Yield: 30.6 %

Procedure:
The title compound (D196) (50 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(4-fluorophenoxy)pyrrolidin-1-yl)nicotinic acid (D138) (110 mg, 0.320 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (72.86 mg, 0.320 mmol).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:38])[CH:36]=2)[CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:38][C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][N:29]=[C:28]2[Cl:27])=[CH:33][CH:34]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccnc(Cl)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nccc2ccc(CBr)cc12
Temperature: 25 °C
Yield: 97 %

Procedure:
N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide (0.39 g, 1.13 mmol) are added to a solution of 1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride (70 mL). The resulting mixture is heated to reflux for 6 hours then cooled to room temperature and diluted with methylene chloride. The organic layer is washed with 1N NaOH and brine, then dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes to give the product (1.4 g, 5.46 mmol) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[N:21]([CH3:38])[CH:22]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[C:32]([CH2:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:35][CH3:36])[CH:24]=3)[C:17]([CH3:39])=[CH:16][N:15]=2)=[C:9]([CH3:40])[CH:8]=1)(C)(C)C.O>ClCCl.FC(F)(F)C(O)=O>[CH2:35]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][CH3:34])[C:27]=1[NH:26][C:25]([C:23]1[CH:24]=[C:20]([C:18]2[C:17]([CH3:39])=[CH:16][N:15]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:41])=[O:5])=[CH:8][C:9]=3[CH3:40])[N:19]=2)[N:21]([CH3:38])[CH:22]=1)=[O:37])[CH3:36]
Reactant: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3C)ncc2C)n(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)O)cc3C)ncc2C)n(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]-5-methyl-pyrimidin-2-ylamino}-3-methyl-benzoic acid tert-butyl ester (438 mg, 0.790 mmol) in dichloromethane (20 ml), trifluoroacetic acid (1.2 ml) was added. The mixture was stirred at room temperature overnight. Water was added and the mixture extracted with ethylacetate. The organic solvent evaporated to dryness to give 393 mg of the title compound in quantitative yield.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26][CH2:27][CH:28]2[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:30](=[O:36])[CH:29]2[NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CCOCC.O1CCOCC1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([O:26][CH2:27][C@H:28]2[N:31]([CH2:32][C:33]([O:35][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:34])[C:30](=[O:36])[C@H:29]2[NH:37][C:38]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2CC(=O)O)cc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2CC(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A solution of 2.68 g of diphenyldiazomethane in 59 ml of ether was added to a solution of 6.55 g of 4-{[(4-methylphenyl)-sulfonyloxy]-methyl}-3-(triphenylmethylamino)-2-oxo-azetidin-1-yl-acetic acid in 70 ml of dioxane and after stirring for 3 hours at 20° C. 448 mg of diphenyldiazomethane were added. The mixture was stirred at 20° C. for 16 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica and was eluted with a 10-0.5 methylene chloride-ether mixture to obtain 7.5 g of diphenylmethyl racemic cis 4-{[(4-methylphenyl)-sulfonyloxy]-methyl)-3-triphenylmethylamino-2-oxo-azetidin-1-yl-acetate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)C(=O)[O:17][N:16]=2)=[N:12][O:13][N:14]=1.[N:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:30]=[O:31].[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:32]([NH:29][C:30]([NH:8][CH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)=[N:12][O:13][N:14]=1)=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (15 mg, 0.035 mmol) and TEA (15 pt, 0.10 mmol) were dissolved in DCM (0.5 mL) and then 2-isocyanato-2-methylpropane (24 μL, 0.21 mmol) was added. The reaction was stirred for 16 h at room temperature. A solution of sodium hydroxide in water (0.50 mL, 1.0; N) was added and the mixture stirred at room temperature for 2 h. Acidification with acetic acid and purification by preparative LCMS gave the desired product (12 mg, 68%). MF=C15H18ClFN6O3; LCMS calculated for C15H19ClFN6O3 (M+H)+: m/z=385.0.