Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A mixture of ethyl 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.20 g, 0.48 mmol) and 1 N aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) in ethanol (2 mL) was stirred at reflux for 1 h, cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH ˜2. The mixture was diluted with water (25 mL), and the aqueous layer was extracted with dichloromethane (2×50 mL). The aqueous layer was concentrated to dryness in vacuo to afford the crude title compound as an off-white foamy solid (0.18 g): MS (ES+) m/z 393.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)[CH3:4].[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[C:26]=3[C:34]([C:36]3[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=3)=[O:35])=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C.[Cl-].[Na+].O>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[C:26]=3[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:10][CH:7]4[CH2:8][CH2:9][N:5]([CH2:3][CH3:4])[CH2:6]4)=[CH:38][CH:37]=3)=[O:35])=[CH:23][CH:24]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reactant: CCN1CCC(O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OCCN5CCCC5)cc4)sc4ccccc34)cc2)C1
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Sodium hydride (60% oil dispersion, 38 mg) was suspended in DMF (1 mL) and stirred at ambient temperature for 15 min under argon before 1-ethyl-3-pyrrolidinol (92 μL) was added. After stirring for 15 min, 4-fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (223 mg) in 1 mL of DMF was introduced and the resulting solution was stirred at ambient temperature for 4 h. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product as a colorless oil (171 mg, 63%).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[NH2:11]
Reactant: Nc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)ccc2ccccc12

Procedure:
To a solution of naphthalen-1-amine (10 g, 69.8 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added N-bromosuccinimide (12.4 g, 69.8 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture stirred for 1 hour before the addition of water (400 mL). The product was extracted with ethyl acetate (3×200 mL), and the combined ethyl acetate washes were extracted with brine (3×50 mL). The ethyl acetate was concentrated, and the crude material was purified by flash chromatography (0-20% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15-8.24 (m, 1H) 7.73-7.82 (m, 1H) 7.40-7.52 (m, 3H) 7.07 (d, J=8.82 Hz, 1H) 5.87 (s, 2H); MS (APCI+) m/z 222.0 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.O.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:11][CH:2]([F:1])[C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(C(F)F)ccc[n+]1[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)F)c([N+](=O)[O-])cc[n+]1[O-]
Temperature: 95 °C

Procedure:
31.38 g of 3-difluoromethyl-2-methylpyridine N-oxide (XVII) was dissolved in 64 ml of concentrated sulfuric acid, to which a mixed solution of 93 ml of concentrated sulfuric acid and 107 ml of 65% nitric acid were added, and the resulting mixture was heated at 95° C. for 20 hours. The reaction solution was poured into iced water and the precipitated crystal was separated by filtering to obtain 17.79 g of 3-difluoromethyl-2-methyl-4-nitropyridine N-oxide (XVIII).
Reaction SMILES: [OH:1][CH:2](CC)[CH2:3]N.[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1[CH:29]=[CH:28][N:27]=C1>CN(C=O)C>[Si:7]([O:1][CH:2]([CH3:3])[CH2:29][CH2:28][NH2:27])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(O)CN
Solvent: CN(C)C=O
Product: CC(CCN)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 181.5 %

Procedure:
To a solution of 2-hydroxybutylamine (4.00 g, 44.87 mmol) in anhydrous DMF (25 mL) was added tert-butyldiphenylsilylchloride (16.9 mL, 66.19 mmol) and imidazole (9.16 g, 13.46 mmol). The reaction mixture was stirred at room temperature for 2 days, then concentrated under reduced pressure, and diluted with CH2Cl2 (150 mL). The organics were washed with 5% aqueous NaHCO3 solution (50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. The crude material was purified by column chromatography (0 to 100% EtOAc in hexane) to give 3-(tert-butyldiphenylsilyloxy)butan-1-amine (8.00 g, 54%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:31])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1.[H][H]>[Pt].CO>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:33][CH:32]=2)[CH2:12][CH2:13]1)=[O:31]
Reactant: O=C(NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: CO
Product: Nc1ccccc1C(=O)NCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 45 %

Procedure:
To 1 part of a solution of 2 parts of thophene in 40 parts of ethanol are added 18 parts of N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-2-nitrobenzamide and 200 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 7.5 parts (45%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide; mp. 113.2° C. The mother liquor is evaporated, yielding a second fraction of 6 parts (36%) of 2-amino-N-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]benzamide as an oily residue.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[C:19]([CH2:33][NH2:34])=[CH:20][C:21]2[N:25]=[CH:24][N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:22]=2[CH:32]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][C:19]4[C:18]([F:17])=[CH:32][C:22]5[N:23]([CH:26]6[CH2:31][CH2:30][CH2:29][CH2:28][O:27]6)[CH:24]=[N:25][C:21]=5[CH:20]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: NCc1cc2ncn(C3CCCCO3)c2cc1F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2c(cc1CNc1nccc(Nc3cc(C4CC4)[nH]n3)n1)ncn2C1CCCCO1
Temperature: 120 °C
Yield: 39.9 %

Procedure:
A tube was charged with 53 (235 mg, 1.0 mmol), 106 (237 mg, 0.95 mmol), DIPEA (1.0 mL) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated in vacuo to afford 170 mg (39%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (108) as white solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].O>C(O)(=O)C>[CH3:6][C:5]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([F:8])[CH:10]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(F)c1

Procedure:
A solution of acetic anhydride (30.30 g, 0.297 mol) in glacial acetic acid (30 ml) is added to stirred 3-fluoroaniline (30.0 g, 0.27 mol). The resulting stirred mixture is heated under reflux for 20 minutes and poured into cold water (500 ml). the product is extracted into ether (×2) and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is recrystallized from aqueous acetic acid to yield colourless crystals with a yield of 28.90 g (70%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[S:10]1[C:11]2[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=[N:9]1
Reactant: OCc1cccc2nnsc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc2nnsc12
Yield: 91.5 %

Procedure:
To a solution of 16.6 g of 7-hydroxymethylbenzo-1,2,3-thiadiazole in 100 ml of chloroform there are introduced with stirring at room temperature 35 g of manganese dioxide, during which process the internal temperature rises briefly to 31 ° C. When the temperature has dropped again to 25° C., the mixture is heated and refluxed overnight. Another 5 g of manganese dioxide are subsequently added, and heating of the mixture is continued until the reaction is complete. The hot mixture is filtered over Hyflo and the filtrate is then evaporated. The residue is digested in a little hexane and then filtered, which gives 15 g (91.4%) of the title compound of m.p. 134°-136° C.
Reaction SMILES: C([N:8]([CH2:45][CH2:46][O:47][CH3:48])[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[CH3:48][O:47][CH2:46][CH2:45][NH:8][C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:29][CH2:30]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1
Reactant: COCCN(Cc1ccccc1)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COCCNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A mixture of 2-(1-((2-(2-(benzyl(methoxyethyl)amino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.22 g, 0.34 mmol) and palladium on carbon (10 wt %, 0.2 g) and acetic acid (0.15 mL) in ethanol (10 mL) was stirred under a hydrogen atmosphere at 70° C. for 18 hours. The reaction mixture was then filtered though celite and concentrated. The crude product was purified by RP-HPLC to give 358 (54 mg, 28%). LCMS m/z: 564.4 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(=O)(O)[O-:11].[Na+].[CH3:15][CH2:16][O:17][CH2:18]C>ClCC(OC)=O>[CH3:18][O:17][C:16](=[O:11])[CH2:15][NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1
Reactant: CCOCC
Reactant: O=C([O-])O
Reactant: Nc1ccc(F)c(F)c1
Agent: COC(=O)CCl
Agent: [Na+]
Product: COC(=O)CNc1ccc(F)c(F)c1
Reaction time: 16 h

Procedure:
A suspension of 3,4-difluoroaniline (15.0 g) and sodium bicarbonate (19.5 g) in methyl chloroacetate (15.2 ml) was stirred at 80°-90° under nitrogen for 16 h. The cooled reaction mixture was poured into ether (100 ml) and filtered. The filtrate was washed with 2N aqueous hydrochloric acid (100 ml), dried and concentrated to give a solid (16.5 g) which was recrystallised from dichloromethane (20 ml) and n-hexane (40 ml) to give the title compound (9.21 g), m.p. 71°-73°.
Reaction SMILES: [CH2:1](/[C:3](/[CH:10]([OH:12])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2].N1C=CC=CC=1.C1COCC1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH2:1](/[C:3](/[CH:10]([O:12][C:26](=[O:27])[CH2:25][Cl:24])[CH3:11])=[C:4](/[CH2:8][CH3:9])\[C:5]([NH2:7])=[O:6])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC/C(C(N)=O)=C(/CC)C(C)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC/C(C(N)=O)=C(/CC)C(C)OC(=O)CCl
Reaction time: 0.25 h
Yield: 98 %

Procedure:
27 (rac-Diethyl (2E)-4-hydroxypent-2-enamide) (1.05 g, 6.0 mmol), pyridine (969 μl, 12 mmol) and DMAP (147 mg, 0.60 mmol) are dissolved in toluene (30 ml) and THF (10 mL) and cooled to 0° C. Chloroacetylchloride (954 μl, 12 mol) in toluene (4 ml) is added dropwise under stirring at ≦2° C. over 15 min. The reaction mixture is stirred 2.5 h at 0° C. The resulting suspension is then poured onto H2O (50 ml) and extracted with tBuOMe (150 and 75 ml). The organic phases are washed with 1 M HCl (50 ml), H2O (50 ml), saturated NaHCO3 (50 ml) and brine (50 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. The residue is filtered with tBuOMe (50 ml) and tBuOMe:AcOEt 50:50 (300 ml) over SiO2 (15 g) and yields 34 (rac-Diethyl (2E)-4-(chloroacetoxy)pent-2-enamide) (1.46 g, 98%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:43]=[CH:42][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[OH:41][CH:38]1[CH2:39][CH2:40][N:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:22]3[CH:21]=[C:20]([O:19][C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[S:13])=[CH:43][CH:42]=4)[CH:25]=[CH:24][N:23]=3)=[O:28])[CH2:30][CH2:31]2)[CH2:36][CH2:37]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reaction time: 4 h
Yield: 19 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (214 mg) and (+)-10-camphorsulfonic acid (105 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=100:0 to 97:3) to provide the title compound (58.6 mg, 19%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=O)C>C(O)C>[OH:20][CH2:19][C:18]1[N:7]2[C:2]([CH2:3][O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=32)=[N:1][C:15](=[O:14])[CH:17]=1
Reactant: NC1=Nc2ccccc2OC1
Reactant: CCOC(=O)C#CCO
Solvent: CCO
Product: O=c1cc(CO)n2c(n1)COc1ccccc1-2
Yield: 72.5 %

Procedure:
A solution of the compound of formula II, 3-amino-2H-1,4-benzoxazine (10.7 g, 72.1 mmol, described in Example 3) and hydroxymethylacetylenecarboxylate ethyl ester (9.7 g, 75.7 mmol) in ethanol (100 ml) was allowed to stand at room temperature (20° to 24° C.) for 6 days. The resulting precipitate was collected giving 12.03 g of the title compound as tan crystals with mp 235°-237° L C., the mp remaining unchanged or recrystallization from ethanol. The title compound had IR(nujol)3130, 1640 cm-1 ; NMR(Trifluoroacetic acid)δ5.2 (s,2H); 5.3(s,2H); 7.6(m,5H); Anal. Calc'd: C, 62.60%; H, 4.38%; N, 12.17%; Found: C, 62.32%; H, 4.24%; N, 12.17%.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][CH2:9][C:10]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:11]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[N:12]1[C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[C:14]([CH3:15])[C:10]([CH2:9][O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])=[N:11]1
Reactant: CCOC(=O)C(C)(C)OCc1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1 g of 2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 6 ml THF was added a solution of 232 mg of LiOH in 1 ml water at room temperature. After 16 h the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a yellow solid. Yield: 634 mg.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.5 %

Procedure:
A mechanically stirred mixture of 4-iodo-2-methylphenol (1.62 moles; 391 g), cesium carbonate (1.99 moles; 650 g), and 1.75 L of acetone is treated with benzyl bromide (1.70 moles; 203 mL; 291 g) over 15 m. The reaction mixture was stirred for 21 h at RT and filtered. The filter cake is washed with 1 L of acetone, and the combined filtrates are concentrated. The crude semi-solid is recrystallized from pentane to give 475 grams (90%) of the desired product as a white solid. 1H NMR (CDCl3) δ: 7.40 (m, 7H), 6.64 (d, J=8.6 Hz, 1H), 5.06 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([O:4][CH:2]([CH3:3])[CH3:1])[N:9]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
To a solution of IPA (50.0 g, 0.369 mol) in 500 mL of THF slowly was added 60% NaH (27.0 g, 0.671 mol) at RT under N2 atmosphere and stirred at RT for 20 min. Then the reaction mixture was slowly treated with 2,6-dichloropyrazine (50 g, 0.336 mol) at RT and stirred at RT for 1 h. The resulting mixture was poured into ice water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to afford crude 2-chloro-6-isopropoxypyrazine (53 g) as pale brown liquid. This material was used further step without purification. MS (ESI, m/z): 173 (M+1).
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C1C=CC=CC=1.[NH2:31][C:32]([NH2:34])=[S:33]>C(O)C>[NH2:34][C:32]1[S:33][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][CH2:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:31]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(=O)CBr
Solvent: CN(C)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(2,6-dichlorobenzyloxyimino)-3-oxobutyrate (7.2 g) was dissolved in ethanol (20 ml) and N,N-dimethylaniline (2.33 ml) and thiourea (1.4 g) added with stirring. After 18 h the title compound was filtered off, washed with ethanol and dried (4.9 g), m.p. 171°-2° C., νmax (KBr) 3423, 1722, 1619, 1529, 1284, 1188, 1021, and 995 cm-1, δH [(CD3)2SO]1.22 (3H, t), 4.33 (2H, q), 5.51 (2H, s), 6.96 (1H, s), 7.24 (2H, br s), and 7.54 (3H, m), [Mass spectrum: M+ (373/375)].
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O.O>O1CCCC1>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OC)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added 60% sodium hydride (1.54 g, 38.5 mmol) and the mixture was stirred for 15 min. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hr and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (7.07 g, yield 97%) as a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH2:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][C:20]([CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:21][CH:22]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CC(C)Cc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-isobutylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as a yellow foam (25.5 mg, 19%). HPLC, Rt: 4.39 min. (purity 93.6%). LC/MS, M+(ESI): 361.1, M−(ESI): 359.1.