Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([Br:46])=[C:40]([O:47][CH3:48])[CH:39]=3)=[C:14]([C:34]([O:36][CH3:37])=[O:35])[N:15]([C:20]3[CH:25]=[CH:24][C:23]([NH:26]C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:49][CH3:50])C1C=CC=CC=1.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.CO>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([N:15]2[C:14]([C:34]([O:36][CH3:37])=[O:35])=[C:13]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([Br:46])=[C:40]([O:47][CH3:48])[CH:39]=3)[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:49][CH3:50])[CH:11]=3)[C:16]2=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(Br)c(OC)c2)c2cc(OC)c(OCc3ccccc3)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2cc(OC)c(Br)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(N)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
The compound obtained in Example 317 (3.66 g) is dissolved in 1,4-dioxane (45 ml), and thereto are added conc. hydrochloric acid (50 ml) and methanol (5 ml). The mixture is heated with stirring at 90° C. for 1.5 hour. To the mixture is added gradually a 2M aqueous sodium hydroxide solution (200 ml) under ice-cooling, and the mixture is neutralized with a saturated aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 2-(4-aminophenyl)-4-(4-bromo-3,5-dimethoxyphenyl)-7-hydroxy-6-methoxy-3-methoxycarbonyl-1(2H)-isoquinolinone (2.54 g) as listed in Table 27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)=[C:18]([C:32]([F:35])([F:34])[F:33])[CH:17]=1.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)=[C:18]([C:32]([F:33])([F:35])[F:34])[CH:17]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: COC(=O)C1CCN(c2ccc(Nc3c([N+](=O)[O-])cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C1CCN(c2ccc(Nc3c(N)cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 73.2 %

Procedure:
To a solution of compound 8.2 methyl 1-(4-(6-bromo-3-nitroquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.26 g, 0.47 mmol, 1 equiv.) in dioxane (3 mL) at room temperature was added Tin(II) chloride dihydrate (0.53 g, 2.35 mmol, 5 equiv.). The resulting mixture was heated to 80° C. under argon for 5 hours. Upon cooling to room temperature, the mixture was neutralized with aqueous NaHCO3 and filtered. The flitrate was extrated with EtOAc (30 mL×2) and the combined organic layer was washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (hexanes:EtOAc 1:1) to afford desired product 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (0.18 g; 73%). LC-MS (M+H): 523.10
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.O[C@H]1O[C@@H]([C@@H](CO)O)[C@H](O)[C@H]1O.O[C@@H]1O[C@@H]([C@@H](CO)O)[C@H](O)[C@H]1O.O=C[C@H]([C@@H]([C@@H]([C@H](CO)O)O)O)O.O[C@@H]1O[C@@H](CO)[C@@H](O)[C@@H](O)[C@@H]1O.O[C@H]1O[C@@H](CO)[C@@H](O)[C@@H](O)[C@@H]1O.O[C@@H]1O[C@H]([C@H](CO)O)[C@@H](O)[C@@H]1O.O[C@H]1O[C@H]([C@H](CO)O)[C@@H](O)[C@@H]1O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)[C@@H]1O[C@@H](O)[C@H](O)[C@H]1O
Agent: OC[C@@H](O)[C@@H]1O[C@H](O)[C@H](O)[C@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
α-D-galactopyranose; β-D-galactopyranose; α-D-galactofuranose; β-D-galactofuranose; L-galactose; α-L-galactopyranose; β-L-galactopyranose; α-L-galactofuranose; β-L-galactofuranose
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])(=O)[CH3:2].Cl.[NH2:36][OH:37]>C(O)C.C(OC(C)C)(C)C>[OH:37][N:36]=[C:1]([CH3:2])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34]
Reactant: NO
Reactant: CC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CC(CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)=NO
Temperature: 25 °C
Reaction time: 40 h
Yield: 42.3 %

Procedure:
A mixture of (3RS)-1-acetylmethyl-1,3-dihydro-3-(2- indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one (0.42 g), hydroxylamine hydrochloride (62.5 mg) in ethanol (20 ml) was stirred at room temperature for 40 hours. The mixture was evaporated to dryness and the residue was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (40:1). The fractions containing the objective product were combined and evaporated to give a pale green oil, which was pulverized in diisopropyl ether to afford (3RS)-1-(2-hydroxyiminopropyl)-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one (177 mg).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10]([C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N+:13]=1[O-:20])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[C:5]([O:9][C:10]([C:12]1([C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[NH+:13]1[O-:20])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)[n+]1[O-]
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1=CC=C(N)C(C(=O)OC(C)(C)C)(C(=O)c2ccccc2)[NH+]1[O-]
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 96.9 %

Procedure:
4 mL of a chloroform solution containing 0.45 g (2 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide and 0.26 g (2 mmol) of diisopropylethylamine was prepared, and was adjusted to 10° C. 0.29 g (2 mmol) of benzoyl chloride was added dropwise to the solution over 10 minutes at 10° C. After stirring further for 40 minutes at 10° C., 5 mL of water was added thereto, followed by liquid separation. The chloroform layer obtained by liquid separation was washed twice with 5 mL of water, and then dried with magnesium sulfate, followed by filtration. The resulting solution was concentrated under reduced pressure and dried to obtain 0.64 g of 2-t-butoxycarbonyl-2-benzoyl amino-6-methylpyridine-N-oxide (yield: 97%) in the form of yellow-brown amorphous which was the target product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([Br:20])[CH:7]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Br:20])[CH:7]=1
Reactant: Brc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Oc1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Aluminium chloride (11.7 g, 87.6 mmol) was added in portions to a solution of 1,3-dibromo-5-benzyloxybenzene (10.0 g, 29.2 mmol; see step (i) above) and N,N-dimethylaniline (35.4 g, 292 mmol) in CH2Cl2 (100 mL) at room temperature under a nitrogen atmosphere. After 30 min, the mixture was partitioned with 1N HCl (300 mL) and EtOAc (5× 150 mL). The combined organic extracts were washed with saturated NaHCO3 (150 mL) and brine (150 mL) then, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex:EtOAc (9:1) afforded the sub-title compound (6.1 g, 82%) as a white solid.
Reaction SMILES: C(=O)=O.CC(C)=O.N.[K].[CH3:10][C:11]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].[C:20]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21]>C1COCC1.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:19][C:17]1[CH:18]=[C:11]2[C:12](=[CH:15][CH:16]=1)[C:13]([NH2:14])=[N:21][C:20]([C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)=[CH:10]2
Reactant: Cc1ccc(C#N)c(C)c1
Reactant: N#Cc1cccc2ccccc12
Agent: [Fe+3]
Agent: N
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2c(N)nc(-c3cccc4ccccc34)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
A 250-mL, three-necked, round-bottomed flask equipped with a dry ice-acetone cooled reflux condenser, addition funnel, and a gas inlet was charged with liquid ammonia (175 mL). Iron (III) nitrate nonahydrate (0.23 g, 0.57 mmol) was added to the liquid NH3 in one portion as a solid, and then potassium metal (4.2 g, 107.4 mmol) was added cautiously in small portions. A solution of 2,4-dimethylbenzonitrile (7.0 g, 53.4 mmol) in THF (20 mL) was added to the reaction mixture dropwise over a period of 5 minutes, the reaction was stirred for 15 minutes, a solution of 1-cyanonaphthalene (12.6 g, 79.8 mmol) in THF (30 mL) was then added dropwise over a period of 10 minutes, and the reaction mixture was allowed to stir overnight as the liquid ammonia gradually evaporated. The crude reaction mixture was cautiously poured into excess ice water. The layers were separated, and the aqueous phase was extracted with methylene chloride. The combined organic extracts were dried and concentrated. The residue was purified by flash chromatography with 2:1 hexane-ethyl acetate, and the crude product was recrystallized from 2:1 hexane-ethyl acetate to afford the title compound (3.82 g, 13.4 mmol, 24% yield) as a solid: mp 170°; IR(CHCl3) 3512, 3409 cm-1 ; MS m/e 285(M+ +H); 1H NMR(CDCl3) δ 8.13-8.23(m,1H), 7.80-7.97(m,2H), 7.62-7.78(m,2H), 7.37-7.61(m,1H), 7.27-7.36(m,1H), 7.17-7.26(m,1H), 5.28(s,2H), 2.51(s,3H); HRMS m/e calcd for C20H16N2 (M+) 284.1315, Found 284.1305. Anal. Calcd for C20H16N2 : C,84.48; H,5.67; N,9.85. Found: C,84.39; H,5.63; N,9.57.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:15])[CH2:12][C:13]#[CH:14].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH3:10][N:11]([CH3:15])[CH2:12][C:13]#[C:14][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1F
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cnc(F)c(N)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 45.4 %

Procedure:
A mixture of 5-bromo-2-fluoropyridin-3-amine (1.00 g, 5.24 mmol), N,N-dimethylprop-2-yn-1-amine (0.68 mL, 6.28 mmol), and cesium carbonate (3.41 g, 10.5 mmol) in DMF (25 mL) was degassed with argon for 15 min. To this slurry were added bis(acetonitrile)palladium(II) chloride (0.068 g, 0.26 mmol) and Xphos (0.324 g, 0.68 mmol). The suspension was allowed to stir at 50° C. for 4 h under an atmosphere of nitrogen and was then concentrated. The residue was purified by column chromatography to give 5-[3-(dimethylamino)prop-1-yn-1-yl]-2-fluoropyridin-3-amine (0.46 g, 45%).
Reaction SMILES: [BH4-].[Na+].CO.[N:5]1[CH:10]=[C:9]([CH:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[N:7][CH:6]=1.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.O>[N:7]1[CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[N:5][CH:6]=1
Reactant: C(=Nc1ccccn1)c1cncnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(NCc2cncnc2)nc1
Reaction time: 0.08 h
Yield: 63.4 %

Procedure:
Powdered 98% sodium borohydride (2.868 g, 75.5 mmole) was added to solution of methanol (80 mL) and tetrahydrofuran (400 mL), and the mixture was stirred vigorously for 5 minutes. The product of Step A (13.9 g, 75.5 mmole) was dissolved in tetrahydrofuran (400 mL), and the resulting solution was added dropwise to the sodium borohydride suspension at a constant rate of approximately 33 mL/minute. The appearance of the reaction mixture changed from a light yellow slightly cloudy suspension to a clear red solution. Reaction progress was monitored by thin layer chromatography eluting with a 10% methanol: 40% dichloromethane: 50% toluene solvent. Upon reaction completion, acetic acid (3 mL) was added dropwise, and the reaction mixture was stirred for 5 minutes. Acetic acid (2 mL) and water (30 mL) were added, the reaction mixture was briefly stirred, and then ethyl acetate was added (500 mL). The reaction mixture was washed with 1N aqueous sodium hydroxide solution (300 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure at 50° C. The resulting crude oil was dissolved in dichloromethane (50 mL), and the solution was eluted through a plug of silica gel (100 g) with ethyl acetate (3 L). The eluant was concentrated to a yellow-orange oil which slowly crystallized to provide 8.909 g (63.4%) of the title product as a pale yellow solid. 1H NMR (CDCl3) δ 9.12 (s, 1H), 8.76 (s, 2H), 8.10 (d, 1H), 7.42 (t, 1H), 6.64 (t, 1H), 6.42 (d, 1H), 4.99 (br s, NH), 4.61 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=3)[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.CN1C2C=CC(C3NN=C(N)C=3)=CC=2N=C1.[O:33]1[CH2:35][CH:34]1[CH2:36][N:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1.CCN(C(C)C)C(C)C>CCO>[CH2:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:45][CH2:46][N:37]1[CH2:36][CH:34]([OH:33])[CH2:35][NH:16][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)[NH:15][N:14]=1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: Cn1cnc2ccc(-c3cc(N)n[nH]3)cc21
Agent: Cn1cnc2cc(-c3cc(N)n[nH]3)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1cnc2ccc(-c3cc(NCC(O)CN4CCc5ccccc5C4)n[nH]3)cc21
Yield: 4.1 %

Procedure:
A solution of 5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-3-amine and 5-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-3-amine (60 mg, 0.27 mmol), 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (54 mg, 0.27 mmol) and DIPEA (72 mg, 0.54 mmol) in EtOH (5 mL) was stirred overnight at 120° C. The mixture was concentrated and then purified by prep-HPLC and prep-TLC to give the desired 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-3-yl)amino)propan-2-ol (4.5 mg, Yield 4.1%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][NH2:13].[OH-].[Na+]>[Cu].Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: CC(=O)c1cc(F)ccc1F
Reactant: CN
Agent: [Cu]
Agent: Cl
Agent: [Na+]
Product: CNc1ccc(F)cc1C(C)=O
Temperature: 25 °C

Procedure:
A mixture of 2',5'-difluoroacetophenone (20 g), methylamine (33% w/w solution in industrial methylated spirit, 31ml), industrial methylated spirit (30 ml) and copper powder (0.2 g) was heated at 80° in a sealed pressure vessel for 24 hours. The reaction mixture was allowed to cool to ambient temperature and the mixture washed out of the vessel with industrial methylated spirit (2×30 ml). A solution of sodium sulphide nonahydrate (1 g) in water (10 ml) was added to the combined reaction mixture and washings and the mixture heated to 50° for 15 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE) and the filter bed washed with industrial methylated spirit (50 ml). The combined filtrate and washings were evaporated to give an oil which was stirred with hydrochloric acid (5M, 80 ml) overnight. The mixture was adjusted to pH 8-9 using aqueous sodium hydroxide (specific gravity 1.5) and then extracted with dichloromethane (3×100 ml). The combined extracts were dried over magnesium sulphate and the solvent removed by distillation. The residue was extracted with diethyl ether (100 ml), the extract treated with activated charcoal (5 g) and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:petroleum ether (1:1) to give the novel compound 5'-fluoro-2'-(methylamino)acetophenone, m.p. 43°-45°.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[C:16]([F:33])=[C:17]([C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=2[Cl:21])=[O:14])=[CH:9][C:8]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>ClCCl>[CH2:35]([O:34][C:8]1[CH:9]=[C:10]([C:13]([C:15]2[C:16]([F:33])=[C:17]([C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=2[Cl:21])=[O:14])[CH:11]=[CH:12][C:7]=1[NH:6][C:3](=[O:4])[CH2:2][Cl:1])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Cl)CCl
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)c(OCc3ccccc3)c2)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NC(=O)CCl)c(OCc3ccccc3)c2)c1F
Yield: 95.4 %

Procedure:
Step 4 Chloroacetyl chloride (0.323 ml, 4.05 mmol) was added to a mixture of tert-butyl N-[(1R)-1-(3-{[4-amino-3-(benzyloxy)phenyl]carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate (1.6 g, 3.12 mmol), triethylamine (0.651 ml, 4.68 mmol) and dichloromethane (30 ml) at room temperature. After 30 minutes a small additional portion of chloroacetyl chloride was added and in 60 minutes the reaction was complete. The reaction mixture was washed with dilute citric acid solution and dilute sodium bicarbonate and then concentrated. The residue was purified on silica eluting with 30-70% ethyl acetate/petrol to furnish tert-butyl N-[(1R)-1-(3-{[3-(benzyloxy)-4-(2-chloroacetamido)-phenyl]-carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate as a yellow oil (1.754 g). [M−H]−=587
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(S(N)(=O)=O)cnc1NCC1CCOCC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 364E (0.16 g) and 5% palladium on carbon (0.025 g) in ethanol (5 mL) was treated with a balloon of hydrogen. The reaction mixture was stirred overnight. The solid was filtered off. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[C:15](Cl)([Cl:17])=[O:16]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([Cl:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N(C(=O)Cl)c2ccccc2)c1
Yield: 99.7 %

Procedure:
According to the procedure of Example 15, Step A, 3.66 g (20 mmole) of 3-methyldiphenylamine, 20 mL (38.6 mmole) of 1.93M phosgene is toluene solution, and 20 mL of toluene gave 4.9 g (100%) of a dark solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([NH:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1)=[O:4]
Reactant: Nc1cc(-c2ccccc2)sn1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1cc(-c2ccccc2)sn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
N,N-Dimethylcarbamoyl chloride (1.29 g) and aluminum chloride (1.60 g) are dissolved in toluene (40 ml), and the mixture is stirred at room temperature for 30 minutes. To this mixture is added 3-amino-5-phenylisothiazole (1.76 g), and the resulting mixture is refluxed for 6 hours with stirring. After cooling, the reaction mixture is mixed with water and shaken with toluene. The organic layer is separated, washed with water, dried, and concentrated to dryness to give 1,1-dimethyl-3-(5-phenyl-3-isothiazolyl)urea (2.38 g). Yield is 96.4%. Melting point of the colorless crystals is 129 to 130.5° C. (after recrystallization from benzene/petroleum benzin).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:3]2[C:2]([NH2:1])=[N:6][N:5]=[N:4]2)=[CH:17][CH:16]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnnc2N)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-amino-1H-tetrazole (1.50 g, 17.6 mmol) in DMF (30 mL) were added Cs2CO3 (8.62 g, 26.4 mmol) and PMBCl (2.90 g, 18.5 mmol). After stirred at 60° C. for 3 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was diluted with DCM and the resulted precipitate was collected by filtration to give 1-(4-methoxy-benzyl)-1H-tetrazol-5-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 5.27 (s, 2H), 6.78 (s, 2H), 6.92 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.8 Hz).
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:23]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4c(c3)OCCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCCO3)c1
Yield: 102.2 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-ethoxy-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (70 mg, 0.1 mmol) and 1.0 N aqueous sodium hydroxide (1 mL) to afford 4-[2-(2-carboxy-ethyl)-3-{6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-ethoxy-phenoxy]-hexyl}-phenoxy]-butyric acid (62 mg, 99%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C35H42O9 (M+Na)+ 629.2721. found 629.2721.