Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+].C([N:55](C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:55])=[O:17])=[CH:11][C:10]=2[CH3:18])=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=1[CH2:29][N:30]1[C@@H:34]([CH3:35])[C@@H:33]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[O:32][C:31]1=[O:43]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(N)=O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (15 mg, 0.025 mmol) in CH2Cl2 (2 mL), was added 2M oxalyl chloride in CH2Cl2 (0.038 mL, 0.076 mmol) and 2 drops of DMF. The mixture was stirred at room temperature under N2 for 30 min. The reaction mixture was concentrated in vacuo. The residue was re-dissolved in THF (2 mL), then ammonium hydroxide (0.035 mL, 0.254 mmol) and diisopropylethylamine (0.013 mL, 0.076 mmol) were added. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxamide as a white powder. LCMS calc.=590.2; found=590.0 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture o atropisomers) δ 8.49 (t, J=4.3 Hz, 1 H); 7.77 (br s, 1 H); 7.72 (s, 0.5 H); 7.66 (br s, 1.5 H); 7.46-7.38 (m, 3 H); 7.33-7.29 (m, 1 H); 7.14 (dd, J=2.2, 7.7 Hz, 1 H); 7.09 (dd, J=6.2, 8.5 Hz, 1 H); 7.06 (s, 0.5 H); 7.01 (s, 0.5 H); 6.95 (d, J=4.3 Hz, 0.5 H); 6.90 (d, J=4.4 Hz, 0.5 H); 6.17 (br s, 1 H); 5.79 (br s, 1 H); 5.43 (d, J=8.1 Hz, 0.5 H); 5.20 (d, J=8.0 Hz, 0.5 H); 4.92 (d, J=15.9 Hz, 0.5 H); 4.86 (d, J=15.8 Hz, 0.5 H); 4.22 (d, J=15.8 Hz, 0.5 H); 4.00 (d, J=15.8 Hz, 0.5 H); 3.88 (s, 1.5 H); 3.87 (s, 1.5 H); 3.80-3.75 (m, 1 H); 2.57 (s, 1.5 H); 2.56 (s, 1.5 H); 2.39 (s, 1.5 H); 2.35 (s, 1.5 H); 0.58 (d, J=6.5 Hz, 1.5 H); 0.47 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[I:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([C:20](=[CH:23]NC1C=CC=CC=1)[C:21]#[N:22])=[O:19]>C(O)C.CO>[NH2:22][C:21]1[N:2]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[CH3:13])[C:7]([OH:9])=[O:8])[N:3]=[CH:23][C:20]=1[C:18](=[O:19])[C:17]1[CH:31]=[CH:32][CH:33]=[C:15]([I:14])[CH:16]=1
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Temperature: 75 °C
Yield: 22 %

Procedure:
To a stirred solution of 3-hydrazino-4-methyl-benzoic acid hydrochloride 1 (Example 3A, 314 mg, 1.54 mmol, 1.0 eq) in 50 mL of ethanol and 5 mL of methanol was added 2-(3-iodo-benzoyl)-3-phenylamino-acrylonitrile 2 (579 mg, 1.54 mmol, preparation: International Patent Application Publication No. WO 02/57101 A1, pg. 84). The mixture was heated to 75° C. for 18 h. The precipitated solids were collected on a flitted filter and were washed with ethanol to provide 3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-4-methyl-benzoic acid 3 (153 mg, 22%) as a white solid. MS m/z 448 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.05 (bs, 2H), 7.34 (dd, J1=J2=7.7 Hz), 7.58 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.81 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.03 (m, 1H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C>[OH:30][C:24]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:25][CH2:26][N:27]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)=[O:4])[CH2:28][CH2:29]1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: COc1cccc(C2(O)CCNCC2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(C2(O)CCN(CC(=O)c3ccc4c(c3)CCC(=O)N4)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a stirred solution of 6-(Chloroacetyl)-3,4-dihydroquinolin-2(1H)-one (7.30 g, 32.7 mmol) in DMF (32 ml) were added 4-(3-methoxyphenyl)-4-piperidinol (J. Labelled Compd. Radiopharm., 41, p464, 1998). (8.12 g, 39.2 mmol) and triethylamine (13.7 ml, 98.0 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 4 hours at room temperature and poured into water (80 ml). The precipitate was collected by filtration and washed with dichloromethane (20 ml). The solid was stirred in 0.5N NaOH (65 ml) for 1 hour at room temperature and the suspension was filtered to afford the title compound (5.98 g, 46%) as a yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH:18]=[C:17]2[O:26][Si](C)(C)C)=[CH:12][CH:11]=1>C1COCC1.O.CCOC(C)=O>[Br:1][CH:18]1[C:17](=[O:26])[CH:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19]1
Reactant: C[Si](C)(C)OC1=CCC2(CC1c1ccc(F)cc1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C(Br)CC2(CC1c1ccc(F)cc1)OCCO2
Reaction time: 2 h
Yield: 240.9 %

Procedure:
Step AAC (2): Followed a method described by A. de Meijer et. al Chem. Eur. J. 2007, 13, 3739. N-bromosuccinimide (52 mg, 0.29 mmol) was added to a solution of (9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-8-yloxy)trimethylsilane (89 mg, 276 mmol) in THF/water (1:1, 1.4 mL). The resulting mixture was allowed to stir for 2 hr. The crude reaction was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo to afford 7-bromo-9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-on (230 mg, 253%) yield). The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].COC1C=CC([O:22][CH3:23])=CC=1C=O.[O:24]1C=CCCC1.C([Li])CCC>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([C:23]([OH:22])=[O:24])[C:4]=1[OH:11]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: COc1ccc(OC)c(O)c1
Reactant: C1=COCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(C(=O)O)c1O

Procedure:
Treatment of 2,5-dimethoxybenzaldehyde with m-chloroperbenzoic acid provides, after workup, 2,5-dimethoxyphenol. Protection of the phenol can be accomplished by formation of a THP ether using dihydropyran and acid. Formylation of the resultant compound can be carried out using butyllithium and DMF. Subsequent acidification liberates the phenol to yield 3,6-dimethoxysalicylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C@@H:8]12[C:17](=[O:18])[O:16][C:14](=[O:15])[C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:17]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:18])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Solvent: C1COCCO1
Product: CN1CCN(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)CC1
Reaction time: 1.25 h

Procedure:
0.37 cm3 of N-methylpiperazine in solution in 5 cm3 of dioxane is added, under an argon atmosphere, to 0.50 g of (−)-trans-1,2-cyclohexanedicarboxylic anhydride in solution at −15° C. in 20 cm3 of dioxane. After 1.25 hours at 20° C., the reaction mixture is filtered, the solid is washed with 20 cm3 of diethyl ether, drained, and then dried under reduced pressure (2,7 kPa) at 20° C., to give 0.65 g of (1R, 2R)-2-[(4-methylpiperazin-1-yl)carbonyl]-1-cyclohexanecarboxylic acid in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[N:30]=[C:31]=[O:32]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH:18][C:31]([NH:30][C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[O:21][CH3:20])=[O:32])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: COc1ccc(N=C=O)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCC2OCCc3c2sc(N)c3C(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.9 %

Procedure:
To a solution of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (64 mg, 0.22 mmol) in dichloromethane (1 ml) was added 2,4-dimethoxyphenylisocyanate (40 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (30 ml), washed with saturated sodium carbonate (3×25 ml), brine (3×25 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to preparative thin layer chromatography (100% dichloromethane). Rf=0.8 was isolated and the solvent evaporated in vacuo which afforded 55 mg (53%) of 2-amino-7-(3-(2,4-dimethoxy-phenyl)ureidomethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:22])[CH2:15][O:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][CH2:11]1>C(Cl)(Cl)(Cl)Cl>[C:13]([O:12][CH2:11][C:10]([CH3:9])([CH3:22])[CH2:15][Br:1])(=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)COC(c2ccccc2)OC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CBr)COC(=O)c1ccccc1
Temperature: 24 °C
Yield: 91.6 %

Procedure:
N-Bromosuccinimide (20.7 g) was added to a stirred solution of 5,5-dimethyl-2-phenyl-1,3-dioxane (19.2 g) in 200 mL of CCl4 containing 8.5 g of BaCO3 in suspension. The mixture was heated to reflux under Ar for 2.2 h, then cooled to 24° C. over 15 h, filtered and concentrated. The residue was partitioned between ether and water, and the ethereal solution was washed with brine, dried (MgSO4), filtered and concentrated to give 24.8 g of a yellow oil which was stored in the dark at 0° C. under Ar.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Br:22])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:23])[S:18]([CH3:21])(=[O:19])=[O:20])[C:14]([Br:22])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a solution of 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.38 mmol) in DMF (3 mL) was added K2CO3 (160 mg, 1.16 mmol) and MeI (164 mg, 1.16 mmol). The mixture was heated at 60° C. for 1 hour, concentrated in vacuo to remove DMF and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude product. The crude product was purified by column chromatography to give 2-acetyl-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, yield: 45%). 1H-NMR (CDCl3, 400 MHz) δ 9.73 (s, 1H), 9.01 (s, 1H), 7.78 (s, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 403/405.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)=[O:9])[CH:3]=1.[CH2:26]([NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH3:28]>>[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([N:29]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:26][CH2:27][CH3:28])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:25][CH:24]=1
Reactant: CCCNCC1CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)c2cc(Cl)ncn2)cc1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN)cc2)ncn1

Procedure:
Following the general method as outlined in Example 72 (Steps 1 and 2), starting from tert-butyl (4-{[(6-chloropyrimidin-4-yl)carbonyl]amino}benzyl)carbamate (Intermediate 22) and N-propylcyclopropanemethylamine (Aldrich), the title compound was obtained as a beige solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([Br:25])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27]>>[Br:25][C:19]1[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:7]2[N:6]3[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1cc(Br)cc2c1-n1c(Br)nnc1CN=C2c1ccccn1
Product: CCN1CCN(c2nnc3n2-c2c(cc(Br)cc2[N+](=O)[O-])C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-10-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-ethylpiperazine to give 8-bromo-10-nitro-1-(4-ethylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CN1CCCC1=O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[N:11]=[C:4]2[CH:3]=[C:2]([O:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: COc1ccc(O)cc1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2cc(N)n3nc(-c4ccco4)nc3c2)cc1

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. p-methoxy-phenol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 322 M+H+ (100%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>C(#N)C>[C:32]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[S:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCOC(=S)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCOC(=S)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OC(C)=O)C(=O)OC2
Reaction time: 2 h

Procedure:
To a solution of 1.6 g of ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate in 120 ml of acetonitrile at 0° C. was added 0.74 ml of pyridine followed by 1.0 ml of acetyl chloride. After stirring for 2 hours the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and evaporated to an oil, which was triturated with ether to give ethyl (E)-6-(1,3-dihydro-4-acetoxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-thiohexenoate, m.p. 81°-84° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-benzyloxycarbonyl-3-hydroxymethyl-piperidine (1.29 g, 5.24 mmol, 1 eq) in CH2Cl2 (50 mL) at 0° C. was added diisopropylethylamine (2.7 mL, 15.72 mmol, 3 eq) followed by methanesulfonylchloride (0.61 mL, 7.86 mmol, 1.5 eq) via syringe. Let stir 10 minutes and removed the cooling bath. After 30 minutes the reaction was complete by thin layer chromatography analysis. Removed the CH2Cl2 under reduced pressure and used material crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.CN.[CH:13]([N:16](C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:13])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNc1cc(Cl)nc(Cl)n1
Reaction time: 72 h

Procedure:
2,4,6-Trichloropyrimidine (I, 30 g) is added to a suspension of methylamine hydrochloride (II, 10 g) in THF (250 ml). The mixture is cooled to -6° and diisopropylethylamine (55 ml) is added slowly. The mixture is stirred for 3 days at 20°-25° and then is concentrated under reduced pressure. The residue is absorbed on silica gel (75 g) with ethyl acetate/methylene chloride (1/1) and applied to a silica gel (1 kg) column packed in ethyl acetate/hexane (1/1). Elution is performed with ethyl acetate/hexane (1/1) collecting 500 ml fractions. The appropriate fractions (8-14) are pooled and concentrated to give the title compound, NMR (CDCl3) 6.29, 6.2 and 2.9δ.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[NH:28][C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=5)[C:13]=4[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C)C1C=CC(C(Cl)=O)=CC=1.[C:41]([C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>>[C:41]([C:45]1[CH:46]=[CH:47][C:48]([C:49]([NH:26][C:21]2[CH:22]=[C:23]([F:25])[CH:24]=[C:19]([C:18]3[C:13]4[CH:12]=[C:11]([C:8]5[CH2:9][CH2:10][C:5]6([O:1][CH2:2][CH2:3][O:4]6)[CH2:6][CH:7]=5)[NH:28][C:14]=4[N:15]=[CH:16][N:17]=3)[C:20]=2[CH3:27])=[O:50])=[CH:52][CH:53]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccc(C(=O)Cl)cc1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12

Procedure:
Example 27 was prepared analogue to Example 15 by replacing Intermediate 6 with Intermediate 18 and 4-dimethyaminobenzoyl chloride with 4-tert-butylbenzoyl chloride.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31][C:32]([F:43])([F:42])[O:33]C1C=C(C=CC=1)C=O>>[F:31][C:32]([F:43])([F:42])[O:33][C:30]1[CH:29]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1cccc(OC(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-(trifluoromethoxy)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 476 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.29 (1H, s) 8.04 (1H, t, J=5.56 Hz) 8.01 (1H, d, J=5.42 Hz) 7.77 (1H, dd, J=5.42, 0.15 Hz) 7.47 (1H, d, J=5.37 Hz) 7.39 (1H, d, J=7.76 Hz) 7.26-7.35 (3H, m) 7.18 (1H, d, J=7.96 Hz) 6.80 (1H, d, J=5.42 Hz) 6.42 (1H, dd, J=3.47, 1.90 Hz) 3.74 (2H, s) 3.35 (2H, q, J=6.35 Hz) 2.63 (2H, t, J=6.49 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:24]5[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=5)[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: N#Cc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-cyanophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 331.0 (M+H)+, retention time 1.26 minutes.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:13]([C:12]1[CH:17]=[CH:18][C:19]([CH2:21][Br:1])=[CH:20][C:11]=1[O:10][CH3:9])([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC

Procedure:
N-Bromosuccinimide (45.3 g) was added to methyl 2-methoxy-4-methylbenzoate (45.8 g) in carbon tetrachloride (~11) containing a trace of dibenzoyl peroxide. The suspension was heated under reflux until no orange colour persisted, then cooled, filtered and the filtrate evaporated to give the title compound, bp 136°-144°/7 mm. τ (CDCl3) 6.17 (3H, s), 6.13 (3H, s), 5.59 (2H, s), 2.9-3.15 (2H, m), 2.3 (1H, J=8 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[C:17]([F:28])[CH:16]=3)=[CH:11][C:10]=2[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:35]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[C:17]([F:28])[CH:16]=3)=[CH:11][C:10]=2[CH2:31][CH:32]([CH3:33])[CH3:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(OC(c3ccccc3)c3ccccc3)c(CC(C)C)c2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cc1cc(CNc2ccc(CCC(=O)O)c(F)c2)ccc1OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of ethyl 3-(4-{[4-(diphenylmethoxy)-3-isobutylbenzyl]amino}-2-fluorophenyl)propanoate (0.50 g, 0.93 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added an aqueous solution (4 mL) of 85% potassium hydroxide (0.20 g, 3.03 mmol), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diethyl ether to give the title compound (354 mg, yield 75%) as colorless prism crystals.