Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9]N.[C:13]([OH:23])(=O)[C:14]1[C:15]([O:20][CH3:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.Cl.C[N:26](CCCN=C=NCC)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH:7]([NH:26][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8](=[O:11])[CH3:9]
Reactant: COc1ccccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)CCCCC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCCC(NC(=O)c1ccccc1OC)C(C)=O
Reaction time: 36 h

Procedure:
Combine a mixture of 7-amino-6-oxo-heptanoic acid methyl ester and 5-amino-6-oxo-heptanoic acid methyl ester hydrochlorides (2.36 g, 11.3 mmol) with o-anisic acid (1.71 g, 11.3 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.16 g, 11.3 mmol), 1-hydroxybenzotriazole hydrate (11.3 mmol), N,N-diisopropylethylamine (5.88 mL, 33.8 mmol) in DMF and stir for 24-48 hours. Dilute the mixture with water and extract with EtOAc. Wash the combined extracts with brine and dry over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for isolation of a mixture of 7-(2-methoxy-benzoylamino)-6-oxo-heptanoic acid methyl ester and 5-(2-methoxy-benzoylamino)-6-oxo-heptanoic acid methyl ester (3.45 g, 99%). MS (ES): (M+1)+ 308.1 m/z.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:25]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:22]1[CH2:23][CH2:24][C:25]2[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:18][C:19](=[O:26])[C:20]=2[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2=C1CNCC2
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
The title compound was synthesized in a manner analogous to R06039-222 except 3-diisopropylamidopyridine was coupled to benzophenone to provide intermediate 1,1-diphenylfuro[3,4-c]pyridin-3-one. 1,1-diphenylfuro[3,4-c]pyridin-3-one was reduced in a manner analogous to 3,3-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (compound 2) to afford 1,1-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-3-one. Benzyl isocyanate (0.023 g, 0.17 mmol) was then added to a solution of 1,1-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-3-one (0.05 g, 0.17 mmol) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.038 g, 50%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.66-3.70 (dd, 2H, J=6 Hz), 4.10-4.15 (m, 2H), 4.34-4.42 (dd, 2H, J=6 Hz), 5.09 (t, 1H, J=6 Hz), 7.20-7.38 (m, 15H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:18][N:17]=[N:16][C:15]=1[NH:27][NH2:28].ClC1N=NC=C(C2C=CC(C)=CC=2)C=1NN>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[N:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2cnnc(NN)c2Cl)cc1
Agent: Cc1ccc(-c2cnnc(Cl)c2NN)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnn3c(=O)[nH]nc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirring solution of triphosgene (19.0 g, 64.0 mmol) in THF (200 mL) was cooled to 0° C. under argon and the mixture of 1-(4-chloro-5-p-tolylpyridazin-3-yl)hydrazine and 1-(3-chloro-5-p-tolylpyridazin-4-yl)hydrazine (3.0 g gross), prepared as described in Example 362C, was added over 3 min. The reaction mixture was allowed to warm to RT gradually and then stirred for 16 h. Solvent was removed under vacuum to reduce the reaction mixture to half its original volume, and the resulting suspension was cooled to an ice bath. Ice water (300 mL) was added, followed by stirring for 1 h. The product was collected by filtration and washed with 0.1 M aqueous HCl (50 mL×2), then H2O (50 mL×2). After drying under vacuum at 50° C. for 2 d, the title compound, 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (2.2 g) was obtained as a yellow solid. MS [M+H]+ 261; HPLC retention time=2.75 min; 1HNMR (400 MHz, THF-d8) δ 11.69 (s, 1H), 8.10 (s, 1H), 7.49-7.51 (m, 2H), 7.34-7.35 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:10])=[O:5])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]O)[CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)=[O:15])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Reactant: OCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1cccnc1

Procedure:
The solution of 2.37 g of N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, 0.61 g of 3-pyridylcarbinol and 1.15 g of dicyclohexylcarbodiimide in 25 ml of methylene chloride is stirred at room temperature for two days. The solid is removed, and the filtrate is diluted with 150 ml of ether and extracted with 0.5N hydrochloric acid. The acidic aqueous layer is separated, basified and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, filtered, concentrated and flash chromatographed on silica gel eluting with ethyl acetate:ethanol (9:1) to yield 3-pyridylmethyl N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl)-3-aminopropionate as an oil; NMR (CDCl3) δ8.70 (m, 2H), 7.77 (m, 1H), 7.28 (m, 11H), 5.56 (t, 1H, J=7 Hz), 5.12 (s, 2H), 4.03 (q, 2H, J=8 Hz), 1.08 (t, 3H, J=8 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCOC(=O)c1ccc(I)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of butyl 4-iodobenzoate (3.5 g, 11 mmol), 4-trifluoromethylbenzene boronic acid (2.30 g, 12 mmol), potassium carbonate (4.77 g, 35 mmol), toluene (40 mL), and water (20 mL) was deaerated by sparging with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.23 mmol) was added, and the mixture was heated at reflux for 3 h and then cooled to ambient. The organic layer was separated, washed with brine, dried (MgSO4), passed through short column of silica gel, and concentrated to deposit a gold solid. The product was purified by recrystallization from aqueous isopropanol to provide 1.03 g (28% of theory) of a white powder. 1H NMR (CDCl3): δ 1.00 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 4.36 (t, 2H), 7.66 (d, 2H), 7.72 (s, 4H), 8.14 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl[S:21]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[S:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CNCc2ccc(F)c(F)c2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CN(Cc2ccc(F)c(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from N-(3,4-difluorobenzyl)(4-methoxyphenyl)-methanamine (example 5-36a) and methyl 4-(chlorosulfonyl)benzoate (example 5-10c). MS (M−H, 446); 1H NMR (400 MHz, DMSO-d6): δ ppm: 3.69 (s, 3H), 4.20 (s, 4H), 6.73 (d, J=8.8 Hz, 2H), 6.93 (m, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.22 (m, 1H), 7.74(d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]=2[CH3:20])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:20][C:19]1[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][C:15]=1[C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(C2(O)CCN(Cc3ccccc3)CC2)oc2ccccc12
Agent: [Pd]
Solvent: CO
Product: Cc1c(C2(O)CCNCC2)oc2ccccc12
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3b (260 mg, 0.81 mmol) in methanol (5 ml) was added 10% Pd/C (130 mg). The mixture was degassed with nitrogen for 10 minutes and continued stirring at 20-35° C. under H2 gas atmosphere for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered on celite bed, celite bed washed with methanol and resultant filtrate concentrated to get the desired product as a yellow waxy solid (180 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J=6.8, 2.0 Hz, 1H), 7.47-7.44 (m, 1H), 7.26-7.18 (m, 2H), 5.20 (bs, 1H), 2.92 (s, 1H), 2.73 (d, J=10.7 Hz, 2H), 2.44 (t, J=10.5 Hz, 2H), 2.34 (s, 3H), 2.15-2.07 (m, 2H), 1.84 (d, J=12.7 Hz, 2H); MS (ES) m/e 232.1 (M+H)+.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH2:26]([NH2:29])[CH2:27][CH3:28]>C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:29]2[CH2:26][CH2:27][CH3:28])=[CH:13][CH:14]=1
Reactant: CCCN
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCN1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Distilled THF (20 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (535.4 mg, 1.91 mmol) followed by triethylamine (398.9 mg, 0.549 mL, 3.94 mmol) and n-propylamine (159.8 mg, 0.22 mL, 1.792 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrysallisation from a minimum amount of boiling ethyl acetate and an excess of petrol yielded the title product as a white crystalline solid (425 mg, 1.409 mmol, 77%). 1H NMR: (300 Hz, CDCl3) δ ppm 0.76 (t, 3H, H11), 1.45 (m, 2H, H10), 2.86 (m, 1H, H9), 3.36 (m, 1H, H9′), 7.16 (d, 1H, H5), 7.38 (dd, 4H, H1-H4), 7.45 (m, 2H, H6-H7), 7.70 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 11.87 (N—CH2—CH2—CH3), 21.96 (N—CH2—CH2), 40.69 (N—CH2), 90.50 (O—C—N), 122.75, 122.99, 128.24, 128.76, 129.58, 131.04, 131.24, 132.73, 133.13, 139.94, 149.59 (Ar), 166.96 (C═O). Mp: 201.5-201.7° C. IR: 1466, 1608, 1664, 2968, 3157 cm−1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]1=[O:23].[CH2:24](Br)[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][C:6]1[C:7]2[O:8][CH2:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:1][C:2]=2[C:3]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[C:4]([F:10])[CH:5]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3c2N=C(c2ccccc2)CO3)c1=O
Reaction time: 1 h
Yield: 18.7 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.5 g), phenacyl bromide (0.29 g) and potassium carbonate (0.2 g) in acetone (30 ml) was stirred under reflux conditions for 1 hour. Then insoluble salt was removed through Celite and the filtrate concentrated under reduced pressure. The oily substance was purified by column chromatography on silica gel using ethyl acetate-hexane(1:4) as eluent to give the title compound (0.12 g).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[SH:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[OH-].[K+]>CC(O)C>[NH:8]1[CH:9]=[C:5]([CH2:4][CH2:3][S:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[N:6]=[CH:7]1
Reactant: Sc1ncc[nH]1
Reactant: ClCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1c[nH]c(SCCc2c[nH]cn2)n1

Procedure:
183 mg (1.1 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride, 110 mg (1 mmol) of 2-mercapto-1H-imidazole and 200 mg (3.26 mmol) of solid potassium hydroxide are brought to reflux in 10ml of 2-propanol for 4 h. The mixture is then evaporated and the semi-solid residue is chromatographed through silica gel, using a chloroform/methanol (5/1) mixture. The resulting product is treated with oxalic acid in ethanol to provide the title compound in the form of an oxalate salt, M.p.: 224°-226° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17](C)=[CH:16][CH:15]=[CH:14][N:13]=1.[C:19]([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[CH3:19][C:14]1[N:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccnc1N
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(Nc2ccc([N+](=O)[O-])cc2)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.46 g of 2-amino-3-methylpyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.239 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.108 g of 6-methyl-N-(4-nitrophenyl)pyrid-2-amine (9) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:51])[CH:5]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C@H:28]([NH:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:23][CH:22]=1)[C:6]1[N:7]=[N:8][N:9]([C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:10]=1)C.[OH-].[Na+]>CCO.CCOC(C)=O.O.Cl>[C:43]([NH:42][C@H:28]([C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH:5]([C:6]2[N:7]=[N:8][N:9]([C:11]([CH3:19])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:12])[N:10]=2)[C:4]([OH:51])=[O:3])=[CH:26][CH:25]=1)(=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CCOC(=O)C(Oc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1)c1nnn(C(C)(C)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(c1ccccc1)n1nnc(C(Oc2ccc(C[C@H](NC(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)cc2)C(=O)O)n1
Reaction time: 1.5 h

Procedure:
A solution of {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-phenoxy}-[2-(1methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-acetic acid ethyl ester of Step C (0.070 g, 0.10 mmol) in EtOH (2 mL) is treated with 2 N NaOH (1 mL). After 1.5 h, the reaction is diluted with EtOAc, water and 10% HCl and the layers separated. The organic layer is washed with water and brine, dried (MgSO4) and concentrated to provide {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-phenoxy}-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-acetic acid which is used without further purification.
Reaction SMILES: C([O-])(=O)C.[K+].[Br:6]Br.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[C:16]=2[F:23])[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[CH:10]=1>C(O)(=O)C>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[C:16]=2[F:23])[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[Br:6]
Reactant: BrBr
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(F)c2F)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2F)nc(N)c1Br
Temperature: 23 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Potassium acetate (750 mg, 7.6 mmol, 3.0 equiv) and bromine (150 μL, 2.8 mmol, 1.1 equiv) were sequentially added to a stirred suspension of methyl 6-amino-2-(4-chloro-2,3-difluorophenyl)pyrimidine-4-carboxylate (760 mg, 2.5 mmol, 1.0 equiv) in glacial acetic acid (10 mL) at 23° C. The resulting thick orange mixture was stirred at 23° C. for 2 h. The reaction mixture was quenched with saturated sodium thiosulfate solution (˜50 mL) and adjusted to pH=7 using 50% sodium hydroxide solution. The resulting white mixture was diluted with water (150 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by flash chromatography (SiO2, 33% ethyl acetate in hexane) to afford the title compound as a white powder (760 mg, 79% yield): mp 175-178° C.; 1H NMR (300 MHz, CDCl3) δ 7.76 (ddd, 1H, J=9, 7, 2 Hz), 7.23 (ddd, 1H, J=9, 7, 2 Hz), 5.70 (br s, 2H), 4.01 (s, 3H); IR (neat film) 3473 (s), 3317 (s), 3179 (s), 2963 (w), 1740 (s), 1651 (s); ESIMS m/z 378 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]4[O:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]=4[C:24]=3[CH3:25])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](OB([O-])[O-])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]5[O:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]=5[C:24]=4[CH3:25])[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=1
Reactant: Cc1c(C)c(N2CCN(c3ccnc(Cl)n3)CC2)c(C)c2c1OC(C)(C)C2
Reactant: COc1ccc(OB([O-])[O-])cc1
Product: COc1ccc(-c2nccc(N3CCN(c4c(C)c(C)c5c(c4C)CC(C)(C)O5)CC3)n2)cc1
Yield: 23.2 %

Procedure:
By using 2-chloro-4-[4-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]pyrimidine (200 mg, 0.517 mmol) synthesized in Example 82 and (4-methoxyphenyl)borate (157 mg, 1.03 mmol), the reaction was carried out in the same manner as Reference example 22 to synthesis the title compound 54.9 mg (yield 12%). Melting point was 240 to 242° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:25][CH2:26]2)[CH:6]=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 10.6 %

Procedure:
To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.096 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added 2,5-dichlorobenzenesulfonyl chloride (86 mg, 0.352 mmol) and DIEA (62 μL, 0.352 mmol). Reaction was stirred at room temperature for 6 h. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 6.6 mg the title compound (11%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+]>CN(C)C=O.CO>[C:1]1([CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:17])=[S:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC(=S)c1cccnc1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=S)c1cccnc1Cc1ccccc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 18.3 g (75 mmol) of 2-phenylmethylthionicotinic acid and 16.2 g (100 mmol) of carbonyldiimidazole in 250 mL of dry dimethylformamide was stirred at room temperature for 2 hours. The solution was cooled to 0° and 25 mL of 4M sodium methoxide in methanol was added. After warming to room temperature the solution was partitioned between ether and water and the aqueous layer was washed with two portions of ether. The ether extracts were washed with brine, dried over MgSO4, and concentrated. The residue was crystallized from ether-hexane to afford 17.4 g (89%) of fine white needles, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[OH:16])[CH2:3][CH2:2]1>[Pd].C(O)C.[H][H]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:8]([OH:16])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(O)c1
Reaction time: 12 h
Yield: 105 %

Procedure:
10% Palladium on carbon (10 mg, 0.892 mmol) was added to 2-morpholino-5-nitrophenol (prepared as described herein above; 200 mg, 0.892 mmol) in ethanol (20 mL), hydrogen gas was added (40 psi), and the reaction allowed to proceed for 12 h at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture filtered through Celite®, and the solvent removed in vacuo. The residue was purified by flash column chromatography (2% CH3OH/CH2Cl2) to provide the title compound 5-amino-2-morpholinophenol (200 mg, 0.937 mmol, 105% yield) as a solid.