Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:15][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)Nc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and aniline to give N-phenyl-7-methoxybenzofuran-2-carboxamide (Compound 249a). Successively, it was formylated to give N-phenyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 249b), then compound 249b was reacted with methylamine hydrochloride to give compound 249 as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2C)cn1
Yield: 47 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 15) and pyrrolidine to give the title compound in 47% yield; NMR Spectrum: 1.67 (br s, 4H), 2.19 (s, 3H), 2.44 (s, 3H), 2.56 (br s, 4H), 2.89 (t, 2H), 4.44 (t, 2H), 6.95 (d, 1H), 7.18-7.25 (m, 2H), 7.60-7.64 (m, 2H), 8.16 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 446 (MH+).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17](=[O:64])[C@@H:18]([NH:44]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:19][C:20]2[N:21]=[CH:22][N:23]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=2)[C@@H:9]([OH:15])[C@H:10]([CH:12]2[CH2:14][CH2:13]2)[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.FC(F)(F)C(O)=O.C(=O)(O)[O-].[K+]>C(Cl)Cl>[NH2:44][C@@H:18]([CH2:19][C:20]1[N:21]=[CH:22][N:23]([C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=1)[C:17]([NH:16][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@@H:9]([OH:15])[C@H:10]([CH:12]1[CH2:13][CH2:14]1)[OH:11])=[O:64]
Reactant: O=C(N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
A solution of 1.52 g (1.79 mmol) of (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-trityl-α-(tritylamino)imidazole-4-propionamide in a mixture of 95.5 ml of methylene chloride, 3 ml of methanol and 1.5 ml of trifluoroacetic acid is stirred at room temperature for 5 minutes. Subsequently, 150 ml of 2N potassium bicarbonate solution and 150 ml of methylene chloride are added. The organic phase is separated, dried over sodium sulphate and evaporated. For purification, the residue is chromatographed on 100 g of silica gel using a 150:10:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained 1.03 g of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-tritylimidazole-4-propionamide as a colourless foam; MS: 607 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([CH3:20])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: Cc1cc2c(c(-c3ccccc3)c1)OC(CN=[N+]=[N-])C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc2c(c(-c3ccccc3)c1)OC(CN)C2
Yield: 61 %

Procedure:
Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[C:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].S([O-])(O)(=O)=O.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CCCCCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:26]2([OH:29])[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:28][CH2:27]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(Cl)cc1Br
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(Cl)cc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a stirred solution of 2-bromo-4-chloroanisole (164 g, 0.74 mol) in tetrahydrofuran (1 L), cooled at −70° C. and under an atmosphere of argon, was added butyl lithium (2.7 M in heptane, 280 ml) over a period of 1 hour. The mixture was stirred for 30 minutes, maintaining the temperature at −70° C., before the addition of N-boc-4-piperidone (145 g, 0.73 mol) in tetrahydrofuran (250 ml) over a period of 1 hour. The reaction temperature was warmed to −40° C. over 2 hours before the addition of sodium hydrogen sulphate (5M aqueous, 160 ml), sodium sulphate (300 g) and hexane (500 ml). The mixture was stirred for 10 hours. The organic layer was decanted, filtered through silica gel (300 g, 63/100 μm) washing with ethyl acetate:hexane (4:6, by volume, 2×400 ml). The filtrate was evaporated in vacuo and the residue recrystallized from ethyl acetate:hexane to afford the title compound as white crystals, 100 g, 39% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:7]([CH2:14][CH2:15]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[O:7]([CH2:14][CH2:15][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCOc1ccccc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc(OCCN2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 36 h
Yield: 64.7 %

Procedure:
Piperazine (2.15 g) and 2-phenoxyethyl bromide (1.00 g) were dissolved in tetrahydrofuran (30 ml), and the mixture was stirred at 40 to 60° C. for 36 hours. The reaction solution was evaporated, and aqueous saturated sodium bicarbonate and diethyl ether were added to the residue, and the aqueous layer was partitioned. Methylene chloride was added to the aqueous layer, and the organic layer was partitioned. The organic layer was dried over sodium sulfate anhydrous and evaporated, whereby the title compound (664 mg, 65%) was obtained.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:3]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([OH:1])[C:6]2([CH2:7][CH2:8]2)[CH2:5]1)(=[O:16])=[O:15]
Reactant: OCCCN1CC(O)C2(CC2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol (1.14 g, 6.67 mmol) and Et3N-(1.35 g, 13.34 mmol) in CH2Cl2 (20 mL) was added methanesulfonyl chloride (1.15 g, 10 mmol) dropwise at 0° C. The reaction was then stirred at 0° C. for 3 hrs. The reaction mixture was washed with cold water (10 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound as orange oil. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.FC(F)(F)S(O)(=O)=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:4]1(=[O:6])[O:12][C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2ccccc21
Yield: 95 %

Procedure:
As a method for producing a carboxylic anhydride, there have been known a reaction between a carboxylic acid and a carboxylic acid chloride and direct heating of a carboxylic acid. In the former case, since a large amount of hydrochloric acid is generated, a base in an amount in moles at least equivalent thereto must be used for neutralization, and hence the cost and time are increased. On the other hand, in the latter case, severe reaction conditions (300° C. or more) are required, and the yield is low. Besides those classical production methods, in Patent Document 1, a method for producing a phthalic anhydride derivative has been reported in which a dehydration reaction of a phthalic acid derivative is performed in an inert solvent in the presence of a catalytic amount of an acidic compound. As the acidic compound, for example, para-toluenesulfonic acid (p-TsOH), trifluoromethanesulfonic acid, polyphosphoric acid, and sulfuric acid are usable. For example, when phthalic acid was heated in toluene in the presence of a catalytic amount of p-TsOH under azeotropic reflux conditions with the removal of water, phthalic anhydride was obtained with a yield of 95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (270 mg, 0.70 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.61 ml, 3.51 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (361 mg, 0.77 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (232 mg, 0.32 mmol, 46% yield) as a clear oil: LCMS (ES) m/e 615, 617 (M+H)+.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[Cl:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([Cl:29])[CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.50 g, 0.135 mol) in CH2Cl2 (70 mL) was added drop wise, over a 30 minutes period, to a stirred solution of 1,2-dichloro-4-((E)-2-nitro-vinyl)-benzene (19.60 g, 0.09 mol) and trifluoroacetic acid (1.54 mL, 0.013 mol) in CH2Cl2 (160 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 25.0 g (79%) of the title compound as a yellow oil. ES-MS m/e: 351.0 (M+H+).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1-c1cc(-c2cccc(F)c2)ncc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 6.9 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.5 mg (0.1 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=[O:13])=[CH:2]1.C([N:24](CC)C(C)C)(C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:24])=[O:13])=[CH:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 264 mg (1 mmol.) of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid in 1.5 ml of THFd and 3 ml of DMFd was added 350 μl of N,N-diisopropylethylamine and 154 mg (1.4 mmol.) of N-hydroxybenzotriazole ammonium salt. The obtained mixture was cooled to −20° C. and 266 mg (1.4 mmol.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. The reaction mixture was stirred for 2 hours at −20° C. and then warmed to room temperature. After additional 12 hours, the organic layer was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with EtOAc to afford 76 mg of the title compound as a white solid (yield 29%) m.p. 222-224° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[N:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:16]=[CH:17]/[CH:18]([C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[C:25]([Cl:31])[CH:24]=3)[C:19]([F:22])([F:21])[F:20])[CH:12]=2)[C:7]1=[O:32])C>Cl.C(O)(=O)C>[Cl:31][C:25]1[CH:24]=[C:23]([CH:18]([C:19]([F:21])([F:22])[F:20])/[CH:17]=[CH:16]/[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:32])[N:6]([CH2:5][C:4]([OH:33])=[O:3])[N:15]=[CH:14]3)[CH:28]=[C:27]([Cl:29])[C:26]=1[F:30]
Reactant: CCOC(=O)Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O
Yield: 90.2 %

Procedure:
A solution of (E)-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetate (0.04 g, 0.07 mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) was heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the residue diluted with water. The aqueous layer was extracted with ethyl acetate and the separated ethyl acetate layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with diethyl ether-pentane mixture to afford the title compound as a brown solid (0.03 g): 1H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 8.43 (m, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, J=16.0, 8.0 Hz, 1H), 6.99 (d, J=16.0 Hz, 1H), 4.96 (m, 3H); ESIMS m/z 473.0 ([M−H]−); IR (thin film) 1629, 1168, 817 cm−1.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH3:7].[OH-].[Na+].C(=O)([O-])O.[Na+].[CH3:20][CH2:21]O>>[CH2:6]([NH:8][CH2:9][C:10]([O:12][CH2:20][CH3:21])=[O:11])[CH3:7]
Reactant: CCNCC(=O)O
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCNCC(=O)OCC

Procedure:
Sulfuric acid (3 mL) was added to a solution of N-ethylglycine (2.0 g) in EtOH (15 mL) and the mixture was stirred under reflux for 9 h. The mixture was cooled to RT and neutralized with 5M-sodium hydroxide, and saturated aqueous sodium hydrogen carbonate. The solution was extracted with EtOAc, the combined organic layer was washed with brine, dried and concentrated under reduced pressure. The sub-title compound (1.4 g) was obtained as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 4.17 (2H, q), 3.38 (2H, s), 2.63 (2H, q), 1.25 (3H, t), 1.10 (3H, t).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([O:17]C(C)C)[C:14]([Cl:21])=[CH:13][C:12]=2[Cl:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].[Na+]>C(OCC)C>[C:1]([C:5]1[S:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:21])=[CH:13][C:12]=2[Cl:22])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1cc(-n2nc(C(C)(C)C)sc2=O)c(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)c1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
11.7 g of 5-t-butyl-3-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-thiadiazol-2(3H)-one (compound Nr. 48; 32.4 mmoles) and 250 ml of methylene chloride are charged into a 500 ml flask in a nitrogen atmosphere. AlCl3 (12.9 g; 96.7 mmoles) is added to this solution in portions and the mixture is maintained under stirring at room temperature for 2 hours. The mixture is then carefully poured into 100 g of ice to which 100 ml of a saturated solution of sodium chloride have been added. 200 ml of ethyl ether are added and, after separation of the phases, the organic phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated with a rotavapor. 10 g of the desired product are obtained having m.p. 130°-132° C.
Reaction SMILES: C1COCC1.[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([NH:22][C@H:23]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=4[CH:31]=3)[C:24]([O:26]CC)=[O:25])=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:40]=[CH:41][CH:42]=[CH:43][C:9]=2[NH:8]1.O.[OH-].[Li+]>O>[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([NH:22][C@H:23]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=4[CH:31]=3)[C:24]([OH:26])=[O:25])=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:40]=[CH:41][CH:42]=[CH:43][C:9]=2[NH:8]1
Reactant: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 8 h

Procedure:
A mixture of 20 mL THF and 3.4 g (6.5 mmol) ethyl (R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate was combined with a solution of 0.58 g (13.5 mmol) lithium hydroxide hydrate in 5 mL water and stirred overnight. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in water and acidified by the addition of 1 M HCl. The precipitate was suction filtered and dried.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[Cl:24])=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added o-chlorobenzaldehyde (81.8 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (200 mg, 96% yield) as colorless crystals.