Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:21]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[O:37][NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:26]1([CH2:25][N:22]2[CH2:23][CH2:24][C@@H:20]([N:8]([C:9]3[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:18])[NH:38][O:37][CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36][O:31]4)=[CH:13][N:14]=3)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:21]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)O)cn1)[C@@H]1CCN(CC2CCCC2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(CC2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (77 mg, 0.66 mmol), HOBt (89 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) in DMF (4.5 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform-MeOH=10-1) to give tert-butyl [(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl)carbamate (181 mg, 69%) as an amorphous powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[CH3:24][NH2:25].Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:15])[N:25]([CH3:24])[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CN
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(C)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with methylamine hydrochloride(1.35 g, 20.0 mmol). Purification on silica gel, eluting with 2:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from EtOAc/2-propanol to give 120 as a white solid (m.p. 245-246° C.).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:29][CH2:28][C:12]2([NH:17][C:16]3[CH:18]=[C:19]([C:21]4[CH:22]=[N:23][NH:24][C:25]=4[CH3:26])[S:20][C:15]=3[C:14](=[O:27])[NH:13]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH:9]1[CH2:29][CH2:28][C:12]2([NH:17][C:16]3[CH:18]=[C:19]([C:21]4[CH:22]=[N:23][NH:24][C:25]=4[CH3:26])[S:20][C:15]=3[C:14](=[O:27])[NH:13]2)[CH2:11][CH2:10]1
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(O[Si](C)(C)C(C)(C)C)CC1)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(O)CC1)N2
Temperature: 50 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-6′-(5-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclohexane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (<0.450 mmol) in THF (4 mL) was added N,N,N,N-tetrabutylammonium fluoride (1.0 M in THF, 1.08 mL, 1.08 mmol). The mixture was stirred at room temperature for 16 h and at 50° C. for 1 h. The mixture was partitioned between EtOAc (20 mL) and aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (5 mL×2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 85:15 EtOAc/MeOH) followed by trituration with EtOAc (5 mL) to give the title compound (32.1 mg, 22%) as a pale yellow solid:
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[C:6](#[N:9])[CH:7]=[CH2:8].[C:10]([NH:14]C(C)(C)CS(O)(=O)=O)(=[O:13])C=C>O>[NH2:9][C:10]([NH2:14])=[O:13].[C:1]1([CH:2]=[CH:3][CH:8]=[C:7]([OH:13])[CH:6]=1)[OH:5]
Reactant: C=CC#N
Reactant: C=CC(=O)NC(C)(C)CS(=O)(=O)O
Reactant: C=CC(=O)O
Solvent: O
Product: NC(N)=O
Product: Oc1cccc(O)c1

Procedure:
Thoroughly mixed were 50 parts of an anionic water-soluble polymer (a 20 wt. % aqueous solution; viscosity: 300 cps) having a monomer composition of 55 mole % acrylic acid, 40 mole % acrylonitrile and 5 mole % of 2-acrylamido-2-methylpropanesulfonic acid and obtained by radical-polymerizing the monomers in an aqueous system, 10 parts of urea, 1 part of resorcin and 250 parts of water. The pH of the resultant mixture was adjusted to 3.3 with a 20% aqueous NaOH solution. Then, as core materials, 200 parts of phenylxylylethane ("Hisol SAS-296", product of Nippon Petrochemical Co., Ltd.) containing 3 wt. % of Crystal Violet Lactone and 0.8 wt. % of Benzoyl Leuco Methylene Blue, both dissolved in the phenylxylylethane, were added. The resultant mixture was emulsified using a Homo-Mixer at 9,000 rpm. Three minutes later, there was obtained a stable o/w-type emulsion having an average droplet size of 4.0 micrometers. Twenty-five parts of formalin (a 37% aqueous solution of formaldehyde) were then added to the above system. The system was heated to 60° C. with stirring. While continuing the stirring, the system was held at this temperature for 4 hours to provide microcapsules having dense wall films, which were made of a urea-formaldehyde resin, around the core material. The system was then cooled, and a 28% aqueous ammonia solution was added little by little with stirring to raise the pH of the system to 8.5. Thus, the smell of formaldehyde was completely wiped off from the system. The thus-obtained microcapsule slurry had a solid content of 43 wt. % and a low viscosity of 85 cps. No substantial viscosity changes were observed on the slurry over a pH range of from pH 3.3 (at the time of condensation) to pH 8.5 (after removal of formaldehyde).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].BrBr>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C2=NNC(=O)CC2)cc1Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Br

Procedure:
3 In acetic acid heated to 70° C. was suspended 6.3 g. of 6-(3-bromo-5-chloro-4-methylphenyl)-4,5-dihydro-3(2H)pyridazinone, and to this suspension was added dropwise with stirring 3.7 g. of bromine. After completion of the addition, the reaction mixture was treated in the manner as in Example 1 - 3 to give 6.2 g. of the desired product of m.p. 247° - 250° C.
Reaction SMILES: [N-]=C=O.C[C:5]1[C:6](N=C=O)=[CH:7][C:8]([N:11]=[C:12]=[O:13])=[CH:9][CH:10]=1>>[NH:11]([CH:12]=[O:13])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: [N-]=C=O
Product: O=CNc1ccccc1

Procedure:
41.4 parts, by weight, of an isocyanate mixture consisting of 40%, by weight, of a tolylene diisocyanate mixture (2,4- and 2,6-isomers in proportions of 65:35) and 60%, by weight, of a crude polyphenyl-polymethylene-polyisocyanate (viscosity about 200 cP at 25° C.). The polyphenyl-polymethylene-polyisocyanate had been obtained by aniline-formaldehyde condensation followed by phosgenation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:18]1[CH2:19][CH2:20][C:15]([CH3:24])([CH3:14])[CH2:16][CH:17]=1
Reactant: N#CC1(c2ccc(N)c(Br)c2)CC1
Reactant: CC1(C)CC=C(B(O)O)CC1
Product: CC1(C)CC=C(c2cc(C3(C#N)CC3)ccc2N)CC1

Procedure:
The title compound was prepared from 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile (as prepared in this step) and 4,4-dimethylcyclohexen-1-yl boronic acid using the conditions described in Example 1, step (e). 1H NMR (CD3OD; 400 MHz): δ 6.95 (dd, 1H, J=8.2, 2.3 Hz), 6.88 (d, 1H, J=2.3 Hz), 6.71 (d, 1H, J=8.2 Hz), 5.62 (m, 1H), 2.52-2.23 (m, 2H), 1.98-1.97 (m, 2H), 1.55-1.51 (m, 4H), 1.31-1.28 (m, 2H), 1.01 (s, 6H).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:31]3[CH2:34][CH2:33][CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1)c1ccccc1Cl
Reactant: C1CNC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CCC3)n2)cc1)c1ccccc1Cl
Temperature: 130 °C
Yield: 13 %

Procedure:
In the next step, a mixture of N-(4-(4-(1,2,4-thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)-2-chlorobenzamide (188 mg, 0.42 mmol), azetidine (67.5 mg, 1.18 mmol), DiPEA (0.17 mL, 1.0 mmol) in 1,4-dioxane (10 mL) was heated to 130° C. for 20 minutes. The crude product (940 mg) was purified by preparative HPLC to yield 27 mg of N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-(azetidin-1-yl)pyrimidin-2-ylthio)phenyl)-2-chlorobenzamide with 99+% purity (HPLC method B, Rf=7.183 minutes).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:15](=[O:17])[CH2:14][S:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: O=C(O)CSc1nc(-c2ccc(F)cc2)cs1
Product: CC(C)(C)NC(=O)CSc1nc(-c2ccc(F)cc2)cs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 54.3 mg (0.74 mmol) of tert-butylamine. Yield: 31 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:33]([C:34](=[O:45])[NH:35][C:36]3[CH:44]=[C:43]4[C:39]([CH:40]=[N:41][NH:42]4)=[CH:38][CH:37]=3)=[CH:32][C:17]3[N:18]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([NH:35][C:34]([C:33]3[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]([F:29])([F:30])[F:31])=[N:18][C:17]=4[CH:32]=3)=[O:45])[CH:44]=2)[CH:40]=[N:41]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(Nc4ccccc4C(F)(F)F)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1

Procedure:
The product from Example 87 was treated with 4M HCl in dioxane employing the procedure described for Example 80 to afford of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 521 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:14]([O:13][CH3:12])[CH:15]=3)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Product: COc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccc(OC)c(OC)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 3,4-dimethoxyaniline gave N2,N4-bis-(3,4-dimethoxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 28.30 min.; purity: 100%; MS (m/e): 428 (MH+); 1H NMR (CDCl3): δ 10.30 (1H, s), 9.14 (1H, s), 7.52 (1H, s), 7.08 (3H, m), 7.00 (1H, d, J=8.4 Hz), 6.84 (1H, d, J=8.4 Hz), 6.76 (1H, d, J=8.4 Hz), 3.90 (3H, s), 3.87 (3H, s), 3.68 (3H, s), 3.60 (3H, s).
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].NC(N)=O>O>[OH:13][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1
Reactant: COc1cnc(N)c(OC)n1
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cnc(O)c(OC)n1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-amino-3,5-dimethoxypyrazine (0.02 mole) in 300 ml. of 6M sulfuric acid at 0°-5° C. is treated with 0.022 mole sodium nitrite in 25 ml. of water at such a rate to insure that the temperature of the reaction mixture does not rise above 5° C. After standing 45 minutes at 0°-5° C., a little urea is added to destroy excess nitrous acid and the mixture then is treated with sodium hydroxide solution until strongly basic. The reaction mixture is warmed to 60° C. for one hour and then brought to pH 8.5. The mixture is concentrated to a third of the original volume and cooled in the refrigerator overnight. The product is separated by filtration and dried in vacuo, recrystallized from a suitable solvent to give 2-hydroxy-3,5-dimethoxypyrazine.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[S:21]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])(=[O:23])[NH2:22]>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:21]([NH2:22])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:13]([C:14]([F:17])([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2cccc(F)c2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3cccc(F)c3s2)cc1
Yield: 88 %

Procedure:
The procedure of Example 9 was repeated using 1-(7-fluorobenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(7-fluorobenzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 88%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@H:23]([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1C[C@@H](F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1C[C@@H](F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 48.5 %

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 25 mg, 87.9 μmol) was reacted with (2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN 796884-06-5, 17.8 mg, 106 μmol) to obtain the title compound (17 mg, 49%) as white solid; MS (EI): m/e=399.4 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][O:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][O:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:41](=[O:42])[C:38]1[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1noc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3onc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A solution of {3-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (method 47) (100 mg, 0.213 mmol) in DCM (4 ml) was added p-toluoyl chloride (66 mg, 0.426 mmol) followed by triethylamine (65 mg, 0.639 mmol). The mixture was stirred at 30-40° C. for 2 days. The mixture was then diluted with DCM, washed with saturated sodium bicarbonate aq. The organic phase was dried, filtered, and concentrated. The crude oil was purified by ISCO (solvent: EtOAc-hexane) to give {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6 -yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester as white solid (115 mg, 0.196 mmol). m/z: 588 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[C:12]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(F)(F)F
Solvent: O
Product: CC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Commercial 2-trifluoromethylaniline (13.5 g, 83.9 mmol) was dissolved in acetic anhydride (55 mL, 580.0 mmol) and stirred at room temperature for 1 h. Then the reaction mixture was poured into H2O, the whole was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with 5% aqueous NaHCO3, brine, dried (K2CO3), filtered and concentrated to provide the title compound as a white solid (15.7 g, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:20]([OH:28])[CH2:21][C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C@H:20]1[O:28][C:23](=[O:24])[C@H:22]([CH:25]([CH3:26])[CH3:27])[CH2:21]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CO)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OCc2ccccc2)OC1=O
Yield: 56.8 %

Procedure:
A solution of diol prepared in Example 19 (500 mg, 1.3 mmol) and Jones Reagent 2.7M (1.9 mL, 5.2 mmol) in 10 mL acetone was stirred vigorously at 10° C. for 3 hours. The reaction mixture was filtered through a plug of Celite® and the plug was washed repeatedly with diethyl ether. The ether layer was washed 2×5 mL with saturated brine, dried over MgSO4 and concentrated in vacuo to give a white solid. The solid was flash chromatographed on silica eluting with 20% EtOAc/80% hexanes to give 286 mg (57%) of the title compound which was identical to the lactone prepared in Example 24.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:18][C:19]1([CH3:27])[O:26][C:24](=[O:25])[CH2:23][C:21](=[O:22])[O:20]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][CH:23]2[C:24](=[O:25])[O:26][C:19]([CH3:27])([CH3:18])[O:20][C:21]2=[O:22])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.165 g, 1.42 mmol) was added to a solution of 4-chlorobenzaldehyde (1.00 g, 7.11 mmol) and Meldrum's acid (1.03 g, 7.11 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 1 hour and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.80 g, 7.11 mmol) was added. Stirring was continued for 3 hours and EtOH removed under reduced pressure. The residue was diluted with i-PrOH and filtered to provide the desired compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(OCC)C.C([Li])CCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:3][CH:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
4-bromobenzotrifluoride (4.8 g, 21.3 mmol) was placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out and the reaction flask was refilled with nitrogen gas in a rapid manner three times. To the reaction flask, 50 ml of anhydrous diethylether was added, and then 10 ml of n-butyllithium solution (25.6 mmol, 2.5 M in n-hexane) was slowly added at −78° C. to obtain a mixture. In the meanwhile, the color of the mixture changed from transparent to cloudy green. The mixture was kept at −78° C. and continuously stirred for 60 minutes. Next, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.2 ml, 25.6 mmol) was slowly added to the mixture at −78° C., and then the temperature was slowly raised to and kept at 20° C. for 12 hours for reaction. The color of the mixture in the reaction flask changed from cloudy green to cloudy white. Deionized water was slowly added to the mixture to terminate the reaction in the reaction flask. The solvents in the mixture were drawn out of the reaction flask, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride solution to collect an organic layer, followed by dehydration of the organic layer using sodium sulfate (Na2SO4) to thereby obtain a crude product. The crude product was recrystallized in a mixed solvent having dichloromethane and n-hexane (dichloromethane:n-hexane=1:1) at 20° C., thereby obtaining white crystals (4.27 g, 73% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](Br)[N:34]=1>>[NH2:32][C:33]1[N:34]=[C:35]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:31])[CH3:30])[C:8]=2[CH3:29])[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1cccc(Br)n1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)n1)OCC2c1ccc(C(C)C)cc1
Yield: 68 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-amino-6-bromopyridine, the title compound was obtained in the same manner as in Example 107. Yield: 68%. Melting point: 237-239° C. (ethyl acetate-hexane).