Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[C:37]([C:38]#[N:39])=[CH:36][N:35]=[CH:34][CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:38]#[N:39])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccncc2C#N)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4C#N)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile following a procedure analogous to that described in Example 28. LC (method 10): tR=1.64 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:33]1([O:39][C:40](=[O:44])[CH:41]([CH3:43])[NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.O>[C:33]1([O:39][C:40](=[O:44])[CH:41]([CH3:43])[NH:42][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CC(N)C(=O)Oc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: CC(NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C)C(=O)Oc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
0.24 g of N-methylpiperidine was added to a solution containing 0.57 g of N-phenoxycarbonyl-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.33 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 0.5 g of DL-alanine phenyl ester was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.2 g of the desired product in the form of white powder (yield: 20%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(OC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)(C)(C)C>>[CH2:13]([O:11][C:10](=[O:12])[C@H:3]([CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)[NH:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CN[C@@H](Cc1c[nH]cn1)C(=O)OCc1ccccc1

Procedure:
N-Methyl-L-histidine was converted with benzyl alcohol in the presence of hydrochloric acid at room temperature into the corresponding benzyl ester and this was reacted according to the procedure described by D. H. Rich et al. in Proc. 9thAmerican Pept. Symp.. Toronto 1985. page 217, with t-butoxycarbonyl-L-phenylalanine in the usual manner. Thereafter, the N-[N-t-butoxycarbonyl)-3-phenyl L-alanyl]-N-methyl-L-histidine benzyl ester obtained was hydrogenated for one hour in the presence of 5% palladium on carbon, to obtain N-[N-(t-butoxy-carbonyl)-3-phenyl L-alanyl]-N-methyl-L-histidine, Rf: 0.2 in a 80:20:3:3 mixture of chloroform, methanol, water and acetic acid. This compound was then reacted in the usual manner with (αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. The crude product obtained was then chromatographed on silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia, upon which the two epimeric compounds were separated. Recrystallization of the crude product obtained from the first fraction from ether/ methylene chloride/hexane yielded t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl] carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoyl]-phenylethyl] carbamate as white crystals of melting point 95°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH3:14])=[CH:8][C:4]=1[C:5]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:7]
Reactant: COc1ccc(CSC)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CSC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(methylthiomethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([O:36][C:37](=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44])[CH3:35]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:46])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCCCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.26 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 6-(chloroformyl)hexanoic acid ethyl ester (0.46 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 1:1) to give ethyl 6-(N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}carbamoyl)hexanoate (0.43 g, 50%) as a white solid: mp 82-84° C.; 1H NMR (DMSO-d6) δ d 11.11 (s, 1H), 8.41 (t, J=5.6 Hz, 1H), 7.86-7.65 (m, 3H), 5.18-5.11 (dd, J=5.4 and 12.4 Hz, 1H), 4.72 (d, J=5.7 Hz, 2H), 4.05 (q, J=7.1 Ha, 2H), 2.97-2.83 (m, 1H), 2.64-2.48 (m, 2H), 2.30-2.15 (m, 4H), 2.08-2.04 (m, 1H), 1.56-1.47 (m, 4H), 1.32-1.23 (m, 2H), 1.17 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ d 172.80, 172.71, 172.52, 169.77, 167.45, 166.92, 139.49, 134.67, 133.13, 131.49, 127.04, 121.78, 59.60, 48.84, 37.57, 35.02, 33.38, 30.91, 28.08, 24.83, 24.16, 21.96, 14.09; Anal. Calcd. For C23H27N3O7: C, 60.39; H, 5.95; N, 9.18. Found: C, 60.10; H, 5.82; N, 8.82.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].Cl[CH:8]([CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:9]([F:13])=C(F)F.[CH3:24]O>>[F:13][C:9](=[CH:8][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:17])[C:1]([O:2][CH3:24])=[O:4]
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(CC(Cl)C(F)=C(F)F)c1ccccc1
Agent: [K+]
Product: COC(=O)C(F)=CCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
Potassium carbonate (6.0 g, 43.5 mmol) was added to a solution of 3.0 g (10.5 mmol) 3-chloro-4-phenylsulfonyl-1,1,2-trifluoro-1-butene in 30 mL methanol at room temperature in a 100 mL round-bottom flask. The resulting mixture was stirred for 12 hours at room temperature. After removal of solvent in vacuo, the residue was partitioned between 50 mL diethyl ether and 50 mL 10% aqueous hydrochloric acid. The whole mixture was stirred for one hour at room temperature. The ether layer was washed once with brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent gave a crystalline product, which was purified by recrystallization from 30% ethyl acetate in hexanes to give 2.50 g (93.9%) methyl 2-fluoro-4-phenylsulfonyl-2butenoate as pale yellow crystals, mp 104.0°-105.0° C. 1H-NMR (300 MHz, CDCl3): δ 3.82(3H, s), 4.05(2H, dd, J=28 Hz), 6.17(1H, dt, J=8, 30 Hz), 7.55-7.9(phenyl protons 5H). Mass spectrum: m/e=258 (M+). 19F-NMR (CDCl3): φ 121.4(d, J=31.0 ). Anal.: Calcd. for C11H11FO4S: C, 51.16; H, 4.26. Found: C, 51.02; H, 4.37.
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]2=[N:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:20])[N:6]2[CH2:5]1)[CH:2]=[CH2:3]>CC1C=CC(C(C)C)=CC=1.[Pd].C(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]3[C:19](=[O:20])[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=[C:7]32)=[CH:12][CH:11]=1
Reactant: C=CCC1Cn2c(ncc(C(=O)OCC)c2=O)-c2cc(OC)ccc21
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: ClCCl
Product: CCCc1cn2c(=O)c(C(=O)OCC)cnc2c2cc(OC)ccc12
Yield: 62.6 %

Procedure:
A mixture of ethyl (±)-7-allyl-6,7-dihydro-10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (190 mgs.) in p-cymene (5 ml.) containing 10% palladium on carbon (50 mgs.) was refluxed for 4 hours. The mixture was cooled, diluted with methylene chloride and filtered to remove the catalyst. The filtrate was evaporated to dryness in vacuo and the residue recrystallized from ethanol, with charcoal treatment, to give yellow needles of title product (119 mgs., 63%), m.p. 187°-188°.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=[O:15].[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20]>>[C:14]([CH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[S:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[C:17]([OH:26])=[O:25])([OH:16])=[O:15]
Reactant: O=C(O)c1ccccc1S
Reactant: CC(C(=O)O)c1ccc(N)c(CC(=O)O)c1
Product: CC(C(=O)O)c1ccc(Sc2ccccc2C(=O)O)c(CC(=O)O)c1

Procedure:
2-(4-Amino-3-carboxymethylphenyl)propionic acid or its salt is diazotized in the same manner as in Preparation-I, and the resulting compound (i.e., diazo compound) is reacted with thiosalicylic acid at 0 to 100° C., preferably under basic conditions, to give the 2-[3-carboxymethyl-4-(2-carboxyphenylthio)phenyl]propionic acid or its salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1N=C(N)C(C2C=CC([N+:32]([O-:34])=[O:33])=CC=2C2C=CC=C(Cl)C=2Cl)=CN=1.NC1N=C(N)C(C2C=C([N+]([O-])=O)C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Nc1ncc(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)c(N)n1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Agent: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:26])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])=[O:15])[CH2:6][CH2:5]2.[O:28]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:28][C:7]([CH3:26])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:27])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCN1CCCC1=O)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCN2CCCC2=O)=C(C)C1=O
Yield: 100.1 %

Procedure:
Oxidation as described in protocol B, using 113.2 mg (0.302 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)chroman-2-carboxamide and 364.6 mg CAN (0.665 mmol) yielded 118 mg of 2-hydroxy-2-methyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(O)ccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 4-fluoro-3-methylphenol (3.0 g, 23 mmol) and methylene chloride (96 mL) was cooled to 0° C. in an ice bath. Triethylamine (4.9 mL, 35 mmol) was introduced to the solution followed by dropwise addition of acetyl chloride (2.3 mL, 33 mmol). The ice bath was removed and the mixture was stirred for 1 hour. The mixture was then extracted with methylene chloride and washed with 0.5 N HCl, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and evaporated to give 4-fluoro-3-methylphenyl acetate (3.9 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.00 (m, 1H), 6.87 (m, 2H), 2.29 (m, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:36]=[CH:35][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:24](O)=[O:25])=[C:18]([F:37])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.[CH3:38][N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1>CN(C=O)C>[N:10]1([C:14]([C:16]2[CH:36]=[CH:35][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:34])[CH2:32][OH:33])[CH:29]=3)[C:24]([NH:44][C:41]3[CH:42]=[CH:43][N:39]([CH3:38])[N:40]=3)=[O:25])=[C:18]([F:37])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: Cn1ccc(N)n1
Reactant: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
DIPEA (93 mg, 0.72 mmol; 4.0 equivalents) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoic acid (70 mg), HATU-(144 mmol; 2.1 equivalents) and 1-methyl-1-H-pyrazole-3-amine (26 mg, 0.27 mmol, 1.5 equivalents) in DMF (2 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The DMF was removed in vacuo, water was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed, eluting with 0-100% ethyl acetate in isohexane, to give desired compound (45 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:4]=[CH:5][N:6]=1.CC1N=CN(C2C=C(N)C=C(C(F)(F)F)C=2)C=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:47][C:48]3[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=3)[N:42]=2)[CH:36]=1>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:17][C:52](=[O:53])[C:51]3[CH:50]=[CH:49][C:48]([NH:47][C:43]4[N:42]=[C:41]([C:37]5[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=5)[CH:46]=[CH:45][N:44]=4)=[CH:56][CH:55]=3)[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Product: Cc1nccn1-c1cc(NC(=O)c2ccc(Nc3nccc(-c4cccnc4)n3)cc2)cc(C(F)(F)F)c1

Procedure:
3-(2-methyl-imidazol-1-yl)-5 -trifluoromethyl-phenylamine prepared in Preparation 31 was used instead of 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine and 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid prepared in Preparation 19 according to the similar procedure to Example 1 to give the titled compound as pale white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])[N:17]=3)[N:14]=2)[CH:3]=1)=[O:33])([CH3:28])[CH3:27])#[N:25]
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 50.6 %

Procedure:
Using N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (140 mg, 0.430 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (97 mg, 0.516 mmol), oxalyl chloride (75 μL, 0.860 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (108 mg, 51%) was obtained as a white powder.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:14])=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCC(=O)O)cc1
Yield: 75 %

Procedure:
Toluene 10b (99.9%, 5.5 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 24 h according to the general procedure. Yellow crystals of 11b were obtained in 75% yield. 1H-NMR: 7.88 (d, 2H, J=8.2 Hz, Ar--H); 7.26 (d, 2H, J=4.8 Hz, Ar--H); 3.29 (t, 2H, J=6.6 Hz, CH2CH2COOH); 2.80 (t, 2H, J=6.6 Hz, CH2CH2COOH); 2.41 (s, 3H, CH3). 13C-NMR: 192.44; 178.70; 144.13; 133.91; 129.29; 128.14; 33.02; 28.06; 21.63.
Reaction SMILES: C(O[C:9](=O)[N:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][C:13]=1[CH3:26])C)C1C=CC=CC=1>[Pd].CO>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:10][CH3:9])=[C:13]([CH3:26])[CH:14]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
The mixture of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-carbamic acid benzyl ester (14.0 g, 36.0 mmol) and palladium on carbon (10 wt %, 0.5 g) in methanol (100.0 mL) is stirred under a hydrogen atmosphere (balloon) at room temperature overnight. After filtration the filtrate is concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give the title compound as oil (7.4 g, 81%). LC-ES/MS: 252.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].FC(F)(F)C(O[I:25](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:19])[C:7](=[O:8])[C:6]([I:25])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(I)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 135 %

Procedure:
To 8.88 g of 2-ethyl-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone in 50 ml carbon tetrachloride and 50 ml chloroform, were added [bis(trifluoroacetoxy)iodo]benzene (6.82 g) and iodine (4 g). The reaction solution was stirred at room temperature for 4 hours. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The solution was extracted with 50 ml water and dichloromethane (100 ml×3). The organic layer was concentrated in vacuo and the resulting residue was purified by lo column chromatographic separation (hexane/ethylacetate=1:1) to yield 8.7 g of 2-ethyl-4-iodo-2-methyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.5 Hz, 3H), 1.51 (s, 3H), 1.93 (q, J=7.5 Hz, 2H), 3.11 (s, 3H), 8.11 (d, J=8.7 Hz, 2H), 8.34 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1701, 1552, 1314, 1148, 747, 551.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9]CC=C)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13]1(C)[CH:18]=C(C)C=C(C)[CH:14]=1>>[CH3:8][C:6]1[C:5]([CH2:18][CH:13]=[CH2:14])=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: C=CCOc1cc(C)cc(C)c1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1c(C)cc(C)cc1O
Yield: 74 %

Procedure:
837 g of allyl 3,5-dimethylphenyl ether (B) were dissolved in 1 500 ml of mesitylene, and the solution was refluxed for two days. The solvent was removed in vacuo and the residue was taken up in tert-butyl methyl ether. The mixture was extracted repeatedly using sodium hydroxide solution, and the aqueous phases were combined and acidified with hydrochloric acid. The product which separates out was taken up in tert-butyl methyl ether, and the mixture was dried over magnesium sulphate, concentrated and distilled. A total of 619 g (74% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)-phenol of a boiling point of 145° C. at 30 mbar and a melting point of 51° C. were obtained.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][CH:8]1[CH2:13][NH:12][CH:11]([CH3:14])[CH2:10][NH:9]1.[OH2:15]>C(#N)C>[Cl:1][CH:2]([Cl:6])[C:3]([N:9]1[CH2:10][CH:11]([CH3:14])[N:12]([C:3](=[O:15])[CH:2]([Cl:6])[Cl:1])[CH2:13][CH:8]1[CH3:7])=[O:4]
Reactant: CC1CNC(C)CN1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O
Solvent: CC#N
Product: CC1CN(C(=O)C(Cl)Cl)C(C)CN1C(=O)C(Cl)Cl
Yield: 36 %

Procedure:
29.4 g (0.2 mol) of dichloroacetyl chloride were added dropwise to a solution of 22.8 g (0.2 mol) of 2,5-dimethyl-piperazine in 150 ml of acetonitrile at 20° C., while stirring. The reaction mixture was allowed to react subsequently at 20° C. for 5 hours and was then poured into 300 ml of water and the precipitate obtained was filtered off and recrystallized from toluene. 12 g (36% of theory) of N,N'-bis-(dichloroacetyl)-2,5-dimethylpiperazine were obtained in this manner in the form of colorless crystals of melting point 214° C.