Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=O)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=C1NCCC1Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Clc1ccc(CC2CCNC2)cc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
To a solution of 3-(4-chlorobenzyl)-2-pyrrolidinone (420 mg, 2 mmol) in dry THF (25 mL) and under N2 LAH (190 mg, 5 mmol) was added in portions with stirring over a period of a couple of minutes. The temperature was increased to 60° C. and the stirring continued for 2.5 h. The mixture was quenched with 200 μL water, 200 μL 5M NaOH and 600 μL water. The solid Li- and Al-salts were filtered off and the filtrate was evaporated to give a colourless oil (387 mg, 99%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]=[C:44]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:45][NH:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=[O:48]>CN(C=O)C.O>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([N:64]1[CH2:63][CH2:62][N:61]([C:44](=[O:43])[CH2:45][NH:46][C:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:51][CH:50]=2)=[O:48])[CH2:66][CH2:65]1)=[O:16]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
DIPEA (149.8 mg, 1.16 mmol) was added at room temperature to a stirred solution of 2-methoxy-benzoic acid (39.2 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123 mg, 0.64 mmol). After 2 minutes biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 60 mg (93.0% yield) of biphenyl-4-carboxylicacid {2-[4-(2-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LC-MS purity: 92.98%, HPLC Purity: 98.70%. 1H NMR: (CDCl3) δ 7.94 (d, 2H), 7.7-7.6 (q, 4H), 7.52-7.44 (t, 2H), 7.44-7.4 (m, 1H), 7.4-7.3 (m, 2H), 7.1-7.0 (t, 1H), 7.0-6.92 (dd, 1H), 4.4-4.24 (dd, 2H), 4.0 (s, 1H), 3.88 (d, 3H), 3.8 (s, 2H), 3.7-3.58 (m, 2H), 3.5-3.24 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[C:10]([CH3:24])([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[C:29]([CH3:32])=[N:30][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:26]2[CH:31]=[N:30][C:29]([CH3:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=2)[C:10]([CH3:23])([CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)C(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2(C)C)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
To a solution of tert-butyl-3,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.12 g, 6.28 mmol) in 1,4-dioxane (90 mL) were added 5-bromo-2-methyl-3-nitropyridine (1.64 g, 7.54 mmol), tetrakis(triphenylphosphine)palladium (642 mg, 0.556 mmol), potassium phosphate (4.96 g, 23.4 mmol) and water (22 mL). The reaction mixture was flushed with nitrogen gas and allowed to stir for 24 h at 80° C. The reaction mixture was filtered through a Celite® pad and washed with DCM. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl-3′,3′,6-trimethyl-5-nitro-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate (1.3 g, 60%) as a white solid. LCMS (FA): Rt=2.16 min, m/z=348.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1>>[C:19]([O-:20])(=[O:25])[CH3:14].[CH3:23][O:22][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[CH2:13][N:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:3][CH:4]=2)[N:9]=[C:8]1[NH3+:12]
Reactant: COc1cccc(OC)c1CN1Cc2ccc(Br)cc2N=C1N
Reactant: COc1ccc(OB(O)O)cc1
Product: CC(=O)[O-]
Product: COc1ccc(-c2ccc3c(c2)N=C([NH3+])N(Cc2c(OC)cccc2OC)C3)cc1

Procedure:
Synthesis was performed according to EXAMPLE 82 from 7-bromo-3-(2,6-dimethoxybenzyl)-3,4-dihydroquinazolin-2-amine and 4-methoxyphenylboric acid in a CEM microwave at 100° C. (120 watt) for 120 minutes.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:36]1([CH:42]2[CH2:46][CH2:45][CH2:44][NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[O:20]=[C:19]([N:43]1[CH2:44][CH2:45][CH2:46][CH:42]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:22])([F:23])[F:1])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: c1ccc(C2CCCN2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1c1ccccc1
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated with 1,1′-carbonyldiimidazole (32.5 mg, 0.2 mmol) in one portion at room temperature. Stirring was continued at room temperature for 15 minutes. Then 2-phenylpyrrolidine (29 mg, 0.2 mmol) was added and stirring continued for 1 hour. Most of the solvent was removed under reduced pressure and the crude product was further purified by MDAP to give the title compound (55 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:11]([CH3:22])[C:12]4[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=4[N:14]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)[N:11]([CH3:22])[C:12]=2[CH:18]=1)=[O:20]
Reactant: NCCOCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2ccc(C(=O)NCCOCCO)cc21
Yield: 46 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (40 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid (70 mg), 2-(2-amino-ethoxy)-ethanol (23 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 445.6.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[N+:17]([O-])=[O:18])[N:5]=1)([CH3:3])[CH3:2].C>C(OCC)(=O)C.[Pd]>[CH:1]([C:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[NH:17][OH:18])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(Cl)cc2[N+](=O)[O-])c(=O)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1nn(-c2ccc(Cl)cc2NO)c(=O)o1
Yield: 47.3 %

Procedure:
A solution of 5-isopropyl-3-(2-nitro-4-chlorophenyl)-1,3,4-oxadiazolin-2-one (16 g.) in ethyl acetate (130 cc.) containing 3% w/w palladium of charcoal (1 g.) is hydrogenated at atmospheric pressure and at approximately 20° C. After the absorption of hydrogen (1.9 liters) (70% of the theoretical amount), the reaction is stopped and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure and the residue taken up in benzene (50 cc.); the crystals obtained are filtered off and washed with benzene (15 cc.). 5-Isopropyl-3-(2-hydroxylamino-4-chlorophenyl)-1,3,4-oxadiazolin-2-one (7.2 g.) which melts at 138°-140° C., is obtained. The benzene filtrate is recycled and is subjected to an operation identical to that described above. 5-Isopropyl-3-(2-hydroxylamino-4-chlorophenyl)-1,3,4-oxadiazolin-2-one (2.9 g.), which melts at 138°-140° C., is obtained.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@@H:53](C)[C:54]([NH:56][CH:57]2[CH2:60]N[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C.O1CCCC1>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:60])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CNC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (924 mg) in anhydrous acetonitrile (15 ml), N,N'-carbonyldiimidazole (352 mg) was added and the mixture was stirred at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (343 μl) and a solution of the compound (1.76 g), which had been obtained in (2), in anhydrous tetrahydrofuran (15 ml) were added. The resulting mixture was treated in a similar maimer to that described in Referential Example 16-(3), whereby the title compound (1.64 g) was obtained as an amorphous substance.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C:8]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:13]2[CH:14]=[CH:15][CH:16]=[C:12]2[C:11](=[O:17])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[F:26])[C:9]1=[O:27])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]2[C:9](=[O:27])[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:7][C:6]([OH:33])=[O:5])[N:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[C:11]2=[O:17])=[C:20]([F:26])[CH:21]=1
Reactant: CCOC(=O)C1(CC(=O)OC(C)(C)C)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CC(=O)O)C(=O)N(Cc2ccc(Br)cc2F)C(=O)c2cccn21
Yield: 83.5 %

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-4-ethoxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid tert-butyl ester (28.7 g) and trifluoroacetic acid (125.1 g, 84.5 ml) in dichloromethane (100 ml) was refluxed for 3 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel using chloroform as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (21.4 g, 3.6%) as colorless crystals, mp 142°-144° C.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([OH:19])=O)[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH2:27][S:28][CH3:29])[NH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>ClCCl.O>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH2:27][S:28][CH3:29])[NH:25][C:17](=[O:19])[C@@H:12]([C@@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][S:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])=[O:10]
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
To a solution of N-(benzylsulfonyl)-D-isoleucine (6.3 g, 22.2 mmol) and L-methionine methyl ester hydrochloride (6.7 g, 33.3 mmol) in dichloromethane (100 ml), HOBt (4.1 g, 26.6 mmol), EDC HCl (5.1 g, 1.2 mmol) and N-methylmorpholine (3.4 g, 33.3 mmol) were added and stirred at room temperature under a nitrogen stream. After 12 hours, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure and the residue was applied to flash column chromatography (Merck Silicagel 60; mobile phase: dichloromethane) to give N-(benzylsulfonyl)-D-isoleucyl-L-methionine methyl ester (6.4 g, 14.9 mmol; yield 67%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC([O-])(C)C.[K+].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-amino-3-nitrophenol (0.8 g, 5.34 mmol, 1.2 eq) in DMSO (3.8 mL, 5×) was treated with KOt-Bu (0.6 g, 5.34 mmol, 1.2 eq), and the mixture was stirred at RT for 2 h. The contents were treated with 4-chloro-6,7-dimethoxyquinazoline (1.0 g, 4.45 mmol, 1.0 eq) and K2CO3 (0.33 g, 2.4 mmol, 0.53 eq) then heated at 110° C. for 16 h. The mixture was cooled to RT, diluted with EtOAc and washed with NaHCO3 (sat). To remove the emulsion, the mixture was filtered through Celite, then the organic layer was washed with brine, 1N NaOH, then brine again. The organic portion was dried with Na2SO4, filtered and evaporated to give the title compound as a brown solid. MS(MH+)=343.1; Calc'd 342.31 for C16H14N4O5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4](Br)[CH:3]=1.[CH3:13][O-:14].[Na+].O>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 1,3-dibromo-5-tert-butylbenzene (289 mg, 1 mmol) in DMF (20 mL) were added NaOMe (2 eq) and CuI (0.03 eq). The mixture was stirred at 80° C. for 3 h and then was poured into water and extracted with EA. The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated to give compound 14a as solid (200 mg, 82%).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:12])=O>>[ClH:12].[Cl:12][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1CO
Reactant: O=S(Cl)Cl
Product: Cc1cccnc1CCl
Product: Cl

Procedure:
The title compound was prepared in accordance with the general method of example E from 2-(hydroxymethyl)-3-methylpyridine and thionylchloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([Cl:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>CCOC(C)=O>[Cl:40][C:34]1[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=[C:32]([NH:31][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([CH3:29])=[N:11][N:12]([C:19]3[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:33]=1
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1cnc(OC)nc1OC

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 52.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.89 min (HPLC 1); tR: 1.12 min (LC-MS 2); ESI-MS: 573/575 [M+H]+ (LC-MS 2); Rf=0.21 (EtOAc).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=2)[N:5]=[C:4]2[CH2:18][N:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=3)[C:20](=[O:21])[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:38](OB(OCC)OCC)[CH3:39].C1COCC1>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:18][N:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=4)[C:20](=[O:21])[C:3]3=[C:2]([CH2:38][CH3:39])[CH:7]=2)[CH:9]=[N:10][C:11]=1[O:16][CH3:17]
Reactant: CCOB(OCC)OCC
Reactant: COc1cc(-c2cc(Cl)c3c(n2)CN(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2cnc(OC)c(OC)c2)nc2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C2
Temperature: 80 °C

Procedure:
As shown in step 10-iii Scheme 10, 4-Chloro-2-(5,6-dimethoxypyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 82, 75 mg, 0.165 mmol and a degassed solution of 2M aqueous sodium carbonate (826 uL, 1.65 mmol] were suspended in 10 mL of toluene. The reaction mixture was purged with nitrogen for 5 minutes and tetrakistriphenylphosphine palladium(0) (38 mg, 0.033 mmol] was added, followed by the addition of 2 M triethylborate solution in THF (992 μL, 1.0 mmol). The reaction vessel was sealed and heated for 14 hours at 80° C. The reaction mixture was cooled and the volatiles removed under reduced pressure. The residue was dissolved in EtOAc/DCM 1:1 and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography produced 2-(5,6-dimethoxypyridin-3-yl)-4-ethyl-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 182, 1.1 mg): ESMS (M+1) 448.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](O)=[O:24]>>[NH:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc[nH]4)cc23)CC1
Yield: 88.8 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 21.1 mg (0.131 mmol) pyrrole-2-carboxylic acid, 12.6 mg (78%) of the title compound were recovered.
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]1[C:30]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO>[CH:1]1([C@@H:7]2[CH2:12][N:11]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[C:30]=3[N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc(F)c1N1CCOCC1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNC[C@H]1C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(Cc2cccc(F)c2N2CCOCC2)C[C@H]1C1CCCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of 3-((R)-2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (50.0 mg, 0.13 mmol, 1.0 equiv) and 3-fluoro-2-morpholinobenzaldehyde (108.8 mg, 0.52 mmol, 4.0 equiv) in acetic acid (0.2 mL) and methanol (0.5 mL) was stirred at room temperature for 60 minutes. Then sodium triacetoxyborohydride (110.2 mg, 0.52 mmol, 4.0 equiv) was added to the mixture and the resulting mixture was stirred at 75° C. for 3 hours. The solvent was removed by Genevac and the residue was dissolved in EtOAc (6 mL). The organic phase was washed by brine (3 mL), dried over Na2SO4 and concentrated. The residue was purified by HPLC (0.1% NH4OH) to afford the product (9 mg, 12%). MS: 577.2 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[C:23](O)(=[O:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: CC(=O)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and acetic acid; MS: m/e=334.4 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-:27].[Na+]>C(Cl)Cl.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:18][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:27])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2nc3cc(C(=O)Cl)ccc3o2)cc1
Reactant: Oc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nc3cc(C(=O)Oc4ccccc4)ccc3o2)cc1
Reaction time: 20 h

Procedure:
A solution containing 4.43 g. (0.016 mole) of 2-(4-methylphenyl)-5-benzoxazolecarbonyl chloride in 50 ml. of methylene chloride was added dropwise to a solution containing 1.88 g. (0.02 mole) of phenol and 0.80 g. (0.02 mole) of sodium hydroxide in 25 ml. of water. After stirring at 50° for 20 hours, the layers were separated and the organic layer was dried (MgSO4) and concentrated to give 2.9 g. (54%) of ld: UV (CH2Cl2) λmax 306 nm (18,200), ε325 =3500.