Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1.Cl.[CH3:24][O:25][C:26](=[O:42])[C@@H:27]([NH2:41])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:24][O:25][C:26](=[O:42])[C@@H:27]([NH:41][C:15]([C:12]1[CH:11]=[N:10][C:9]([CH2:8][O:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([O:3][C:2]([F:1])([F:22])[F:21])[CH:5]=2)=[CH:14][N:13]=1)=[O:17])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Yield: 53.2 %

Procedure:
A solution of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid (0.182 g, 0.579 mmol) was treated with 2(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride (0.162 g, 0.637 mmol), HBTU (0.440 g, 1.158 mmol), and DIEA (0.310 g, 1.737 mmol) by the general procedure A. The crude crude product was purified by flash column chromatography on silica gel to give 0.170 g of 3-biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester. LCMS: 553 (M+2)+
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([O:21][CH3:22])[N:14]=2)[CH:9]=[CH:8][C:7]=1[B:30]1OC(C)(C)C(C)(C)[O:31]1)(=O)C.[OH-].[Na+].Cl>CO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]([C:10]2[CH:9]=[CH:8][C:7]3[B:30]([OH:31])[O:4][CH2:5][C:6]=3[CH:11]=2)[C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[N:14][C:15]=1[O:21][CH3:22])#[N:20]
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(B3OC(C)(C)C(C)(C)O3)c(COC(C)=O)c2)ccc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of 5-(tert-butoxycarbonyl(5-cyano-6-methoxypyridin-2-yl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (2.20 g, 3.82 mmol) in methanol (38 mL) was added 1 mol/L sodium hydroxide (11.5 mL, 11.5 mmol). The reaction was stirred at room temperature for three hours and was then neutralized with 1 mol/L hydrochloric acid until pH=6 to 7. The solvent was removed under reduced pressure and the mixture was extracted with ethyl acetate and the organic layer was washed with an aqueous boric acid solution (0.5 M) five times. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by column using Combiflash to give tert-butyl 5-cyano-6-methoxypyridin-2-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (1.302 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 3.50 (s, 2H), 4.94 (s, 2H), 7.14 (dd, J=1.8, 7.8 Hz, 1H), 7.22 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 9.19 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Yield: 92.8 %

Procedure:
A solution of 5.9 g (38.7 mmol) of 4-nitrobenzyl alcohol, 17.6 ml(193.5 mmol) of 3,4-dihydro-2H-pyran and 500 mg (2.6 mmol) of p-toluene sulfonic acid monohydrate in 200 ml of dichloromethane was stirred at room temperature for 4 hours. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, using 1:4 ethyl acetate/hexane as eluent. Product containing fractions were combined and evaporated to give 8.52 g (93%) of 2-(4-nitrobenzyloxy)-tetrahydropyran as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]2=[O:17])=[C:5]1[C:27]([O:29]C)=[O:28])[CH:2]=[CH2:3].[OH2:31]>CC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13](=[O:14])[N:4]3[CH2:1][CH:2]([CH2:3][OH:31])[O:29][C:27](=[O:28])[C:5]3=2)[C:10]1=[O:17]
Reactant: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.20 g, 0.46 mmol), N-methylmoroholine N-oxide (67 mg, 0.58 mmol), water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) in acetone (1 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:40](=[O:41])[CH2:39][Cl:38])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(NC(=O)CCl)cc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 9.26 g (20 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 45 mL of THF and 10 mL of DMF was added 3.90 mL (28 mmol) of triethylamine followed by 1.99 mL (25 mmol) of chloroacetyl chloride over 5 min. The solution was stirred 30 min. at 0° C. and quenched by addition of 150 mL of 0.1 N aq. HCl. The resulting solid was collected by filtration, washed with water then 1:1 ether-hexanes, and air-dried to afford 10.2 g (95%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. 1H NMR (300 MHz, DMSO) δ 12.49(s, 1H); 9.74(s, 1H); 7.97(s, 2H); 7.46(d, 2H, J=8.0 Hz); 7.20(d, 2H, J=8.8 Hz); 4.19(s, 2H); 3.80(s, 2H); 3.20-3.33(m, 1H); 1.28(d, 6H, J=6.9 Hz).
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
Morpholin-4-ylamine (0.1 mL, 1.16 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.250 g, 0.59 mmol) in dry DMF (4 mL). The reaction mixture was then stirred at 120° C. for 5.5 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution and refluxed at 70° C. for 3 h. The solution was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.105 g, (36.45%). 1H NMR (DMSO-d6): δ 2.50-2.60 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.80 (t, 2H, CH2), 2.80 (t, 2H, CH2), 3.62-3.70 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.20 (t, 1H, NH), 6.85 (s, 2H, 2Ar), 8.15 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (CI+) 496 (M+).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][C@H:10]1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O>>[CH3:27][S:28]([O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][C@H:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:10]([O:18][CH3:19])[CH2:11]1)(=[O:30])=[O:29]
Reactant: CO[C@@H]1CN(CCO)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(CCOS(C)(=O)=O)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1

Procedure:
Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethanol (Intermediate 170, 740 mg, 2.1 mmol) was reacted with methanesulfonyl chloride (0.20 mL, 2.5 mmol) in the presence of triethylamine (0.41 mL, 2.9 mmol) as described for Intermediate 6. The crude product was presumed to be unstable and was used without further purification directly for the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)S1

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-(4-{3-(4-phenyl-benzyl)imidazo[5,4-b]pyridin-2-ylmethoxy}benzyl)-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 55) and 36 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 450 mg of the title compound, melting at 189°-191° C.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:12][CH3:13])=[C:9]([CH3:11])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>>[C:1]([C:6]1[NH:7][C:8]([CH2:12][CH3:13])=[C:9]([CH3:11])[C:10]=1[CH2:14][CH:15]([CH3:17])[CH3:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1cc(C)c(CC)[nH]1
Product: CCOC(=O)c1[nH]c(CC)c(C)c1CC(C)C

Procedure:
The crude product, obtained in Example 68 but using 2-carbethoxy-4-methyl-5-ethylpyrrole and isobutyraldehyde, solidified at 0° C. after distillation (70° C. 1 × 10-4 mm). It was recrystallized twice from methanol, m.p. 53°-55° C. (12%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Yield: 106.4 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 111.10 mmol) in AcN (200 mL) were added K2CO3 (145.9 g, 333.30 mmol) and 2-(chloromethyl)quinoline (28.50 g, 133.32 mmol) at RT. The reaction mixture was heated at 90° C. for 12 h and then cooled to RT and filtered. The filtrate was concentrated in vacuo. The residue was then diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, a saturated NH4Cl solution, and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (38.0 g, 89%) as a solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([CH2:27][CH:28]=[CH2:29])[C:24](O)=[C:23]([CH2:31][CH:32]=[CH2:33])[CH:22]=1>N1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH2:31][CH:32]=[CH2:33])[C:24]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[C:25]([CH2:27][CH:28]=[CH2:29])[CH:26]=1
Reactant: C=CCc1cc(CCC(=O)OC)cc(CC=C)c1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: C=CCc1cc(CCC(=O)OC)cc(CC=C)c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 149.8 %

Procedure:
Trifluoromethane sulphonic anhydride (1.68 g) was added dropwise at 0-5° C. to a stirred solution of methyl-3(3,5-diallyl-4-hydroxyphenyl)propionate (2.5 g) in dry pyridine (20 ml). The mixture was then stirred at ambient temperature for a further 16 hours. The pyridine was removed by evaporation. The residue was treated with water (30 ml) and the mixture was extracted with ether (3×30 ml). The ethereal extracts were combined, washed with water (30 ml), dried (MgSO4) and evaporated. The residue was purified by filtration through a short pad of silica gel (Merck Art 7736) using a mixture of 50% ether in n-pentane as eluent to give methyl-3-[3,5-diallyl-4-(trifluoromethylsulphonyloxy)phenyl]propionate (3.5 g) as a pale yellow oil; NMR: 2.52(2H,t), 2.75(2H,t), 3.34(4H,d), 3.48(3H,s), 4.87-5.03(4H,m), 5.68-5.9(2H,m) and 7.03(2H,s).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][C:9]1([Cl:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:15][C:9]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:8]1[C:6]([OH:7])=[O:5]
Reactant: COC(=O)C1(Cl)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(Cl)CC1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
158 g of methyl 2-tert-butoxycarbonyl-1-chloro-1-cyclopropanecarboxylate was dissolved in 350 ml of dichloromethane. Then 160 ml of trifluoroacetic acid was added thereto and the obtained mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and n-hexane was added to the residue. The crystals thus formed were collected by filtration and washed with n-hexane. Thus 116 g (yield 97%) of 2-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:25]=2)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1n[nH]c2ccccc12
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2n[nH]c3ccccc23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1H-Indazole-3-carboxylic acid. LC-MS (basic): tR=0.77 min; [M+H]+=477.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>O1CCCC1>[CH3:11][C:10]1[N:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([C:19]([F:20])([F:22])[F:21])=[CH:14][N:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2cc(C)c(C(F)(F)F)cn2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-n2ncc(C(=O)O)c2C)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
5-Methyl-1-[4-methyl-5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (270 mg) was dissolved in tetrahydrofuran (5 ml), 1 N aqueous solution of sodium hydroxide (5 ml) was added thereto, and stirred at 80° C. for 4 hours. After completion of the reaction, the solvent was evaporated, to the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (204 mg) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:21][C:17]1([CH3:22])[CH2:18][CH2:19][CH2:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:16]1
Reactant: CC1(C)C=C(c2ccc(OCc3ccccc3)cc2)CCC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CCCC(c2ccc(O)cc2)C1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To 1-benzyloxy-4-(3,3-dimethyl-cyclohex-1-enyl)-benzene (4.3 g, 16.4 mmol) in MeOH (50 mL) and EtOAc (50 mL) was added 10% Pd/C (0.67 g) under N2. This mixture was stirred under H2 (1 atm) overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the title compound as a white solid (3.43 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]2[O:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([C:34](O)=[O:35])[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:34]([C:32]3[N:33]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:30][C:31]=3[C:37]([F:39])([F:40])[F:38])=[O:35])=[CH:15][N:14]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COC1CN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1
Yield: 48 %

Procedure:
[1-(5-Nitro-pyridin-2-yl)-azetidin-3-yloxy]-acetic acid tert-butyl ester (210 mg, 0.679 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (183 mg, 0.71 mmol), DIPEA (355 uL, 2.03 mmol) and BOP (315 mg. 0.74 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield (1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-acetic acid tert-butyl ester as a light brown solid (169 mg). ES-MS calcd for C25H25F3N4O5 (m/e) 518.50, obsd 519.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.O.[NH4+:21]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[C:15]([C:16]([NH2:21])=[O:18])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2nc(-c3ccncc3)oc12
Reactant: [NH4+]
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccncc3)oc12
Yield: 33 %

Procedure:
Methyl 2-(pyridin-4-yl)benzo[d]oxazole-7-carboxylate (130 mg, 0.51 mmol) in ammonium water (15 mL) was stirred at 25° C. overnight. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(pyridin-4-yl)benzo[d]oxazole-7-carboxamide as a solid (41 mg, yield 33%). 1H-NMR (400 MHz, DMSO-d6) δ 7.56-7.60 (t, J=8 Hz, 3H), 7.66-7.69 (q, 3H), 7.99-8.05 (q, 3H), 8.45 (s, 1H), 8.65-8.67 (d, J=8 Hz, 1H), 8.83-8.84 (d, J=4 Hz, 1H), 9.47 (s, 1H); LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(4-methyl-1-piperazinyl)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 23) (312 mg, 0.70 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a white foam (320 mg).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([S:6][CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)CCS
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(SCCN(C)C)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 2-(dimethylamino)ethanethiol hydrochloride was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-{[2-(dimethylamino)ethyl]thio}-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 2.20 (s, 6H), 2.30 (s, 3H), 2.57 (m, 2H), 2.83 (m, 1H), 3.28 (m, 2H), 7.31 (d, 1H), 7.59 (m, 3H), 7.93 (s, 1H), 8.08 (d, 1H), 8.38 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 443.