Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[NH:17][C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>C(O)C.[Pd]>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[NH:17][C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1[nH]c2ccc(/C=C/c3ccccc3)cc2c1CCCOc1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: O=C(O)c1[nH]c2ccc(CCc3ccccc3)cc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 14 (0.005 g), cyclohexene (0.5 mL), Pd/C (catalytic) in ethanol (4 mL) was heated at 130° C. (270 W) in a microwave (CEM Discover) for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated. The concentrate was purified by preparative reverse phase HPLC (Zorbax SB, C-18, 20% to 100% acetonitrile/water/0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.88 (brs, 1H), 11.32 (s, 1H), 8.34 (m, 1H), 7.84 (m, 1H), 7.53 (m, 2H), 7.42 (d, 1H), 7.34 (m, 2H), 7.23 (m, 3H), 7.13 (m, 1H), 7.01 (m, 3H), 6.84 (d, 1H), 4.08 (t, 2H), 2.56 (s, 4H), 2.19 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)O1.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:10]([CH2:9][O:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)[CH:7]=[N:6][CH:5]=1)#[N:11]
Reactant: N#CCOc1cncc(Br)c1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(-c3cncc(OCC#N)c3)cc2s1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A dry 15 mL, one neck round bottom flask was charged with 2-(5-bromopyridin-3-yloxy)acetonitrile (0.162 g, 0.762 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.2021 g, 0.635 mmol), 5 mL THF and a stirbar. The flask was flushed with Ar for 2 minutes, and fitted with an inert atmosphere inlet. To the stirring solution was added tetrakis(triphenylphosphine)palladium (0.147 g, 0.127 mmol) followed by 2 M sodium carbonate (0.953 ml, 1.91 mmol). The slurry was refluxed overnight, and cooled to room temperature. The mixture was poured onto 15 mL water and extracted with DCM (3×20 mL). The DCM extracts were Loaded onto an unbuffered Varian Chem elute CE1010 (100 mL, PN 12198010). The tube was extracted with DCM (4×20 mL). The combined extracts were concentrated in vacuo, and the residue was taken up in 1 mL DCM. A precipitate formed, which was collected using a course glass filter fitted with a 0.22 μm syringe filter. The solid was dried at 60° C. at <1 mmHg for 1 h to afford N-(6-(5-(Cyanomethoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (15 mg, 7.3%). 1H NMR (300 MHz, Pyr) δ ppm 2.36 (s, 3H) 4.98 (br. s., 1H) 5.56 (s, 2H) 7.75 (dd, J=8.40, 1.90 Hz, 1H) 7.93 (dd, J=2.81, 1.86 Hz, 1H) 8.02 (dd, J=8.44, 0.48 Hz, 1H) 8.27 (dd, J=1.90, 0.44 Hz, 1H) 8.77 (d, J=2.85 Hz, 1H) 8.93 (d, J=1.83 Hz, 1H). 13C NMR (75 MHz, Pyr) δ ppm 23.71 (s, 1 C) 55.20 (s, 1 C) 116.92 (s, 1 C) 120.84 (s, 1 C) 121.15 (s, 1 C) 122.27 (s, 1 C) 126.25 (s, 1 C) 133.18 (s, 1 C) 134.41 (s, 1 C) 137.61 (s, 1 C) 138.12 (s, 1 C) 143.50 (s, 1 C) 150.53 (s, 1 C) 154.29 (s, 1 C) 160.70 (s, 1 C) 170.19 (s, 1 C). HPLC-MS: retention time=1.34 min (93.6%@215 nm; 96.7% @254 nm; m/z=325.6, calculated for C16H12N2O4S+H+=325.1).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:7]([C@@H:23]([OH:52])[C@@H:24]([NH:34][C:35](=[O:51])[C:36]2[CH:50]=[CH:49][CH:48]=[C:38]([C:39]([N:41]([CH2:45][CH2:46][CH3:47])[CH2:42][CH2:43][CH3:44])=[O:40])[CH:37]=2)[CH2:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)C1)C=C.C(N1CCOC[C@@H]1[C@@H](O)[C@@H](NC(=O)C1C=CC=C(C(N(CCC)CCC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CCC)C(C1C=C(C=CC=1)C(O)=O)=O)CC.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1COCCN1C(C1C=CC=CC=1)C1C=CC=CC=1)O>ClCCl>[F:33][C:28]1[CH:27]=[C:26]([CH2:25][C@H:24]([NH:34][C:35](=[O:51])[C:36]2[CH:50]=[CH:49][CH:48]=[C:38]([C:39]([N:41]([CH2:45][CH2:46][CH3:47])[CH2:42][CH2:43][CH3:44])=[O:40])[CH:37]=2)[C@H:23]([OH:52])[C@H:7]2[CH2:1][O:4][CH2:5][CH2:9][NH:8]2)[CH:31]=[C:30]([F:32])[CH:29]=1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)N(C(c2ccccc2)c2ccccc2)C1
Agent: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2COCCN2C(c2ccccc2)c2ccccc2)c1
Agent: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2COCCN2)c1
Reaction time: 0.33 h

Procedure:
Step 5 (A): N1-((1S,2S)-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide. To a solution of 3-(dipropylcarbamoyl)benzoic acid (Preparation E, 14 mg, 0.055 mmol) in dichloromethane (1 mL) was added Hunig's base (18 mg, 0.14 mmol) to make a clear solution and HATU (25 mg, 0.064 mmol) was then added. After stirring for 20 min, the reaction mixture was added (1S,2S)-2-amino-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)propan-1-ol (Preparation D, (20 mg, 0.046 mmol) and the reaction mixture was stirred at rt overnight. Dichloromethane (100 mL) was added and washed with H2O (50 mL) twice, dried over Na2SO4, and concentrated to give the title compound as a crude product ready for next step without purification: 1H NMR (CD3OD, 500 MHz) δ 0.71 (3H, m), 1.01 (3H, m), 1.52 (2H, m), 1.74 (2H, m), 2.52 (1H, d, J=5 Hz), 2.63 (2H, dd, J=5, 15 Hz), 2.71 (1H, m), 3.12-3.19 (3H, m), 3.44-3.49 (3H, m), 3.94-3.99 (2H, m),4.04 (1H, m), 4.58 (1H, m), 5.06 (1H, m), 5.50 (1H, s), 6.76 (1H, m), 6.92-6.95 (2H, m), 7.14-7.19 (3H, m), 7.25-7.32 (3H, m), 7.44 (2H, m), 7.49-7.55 (2H, m), 7.58 (2H, d, J=10 Hz), 7.63 (1H, s), 7.73-7.76 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: Oc1ccccc1F
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccccc2F)=C(c2ccccc2)S1(=O)=O
Yield: 62 %

Procedure:
The title compound was prepared as described for Example 12 from 2-fluorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent then dissolved in EtOAc. The product containing fractions were evaporated and the residue was washed with aqueous K2CO3 (2M) and evaporated to give the title compound (0.063 g, 62%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.45-7.40 (m, 3H), 7.11-7.03 (m, 2H), 6.94-6.85 (m, 2H), 5.57 (t, 1H), 3.91 (t, 2H), 3.15-3.10 (m, 2H), 1.90-1.82 (m, 2H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 153.9, 152.0, 146.8, 146.7, 135.3, 131.8, 129.8, 128.8, 125.2, 124.6, 124.5, 121.9, 121.8, 116.6, 116.5, 115.5, 107.4, 67.2, 61.7, 41.7, 29.2, 27.8. Mass Spectrum M+H+ 433.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:23])([CH3:22])[NH:16]2)=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[OH:8][CH2:9][C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][O:32][CH3:33])=[CH:26][C:25]=2[O:34][CH3:35])=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:22])([CH3:23])[NH:16]2
Reactant: COCOc1ccc(-c2ccc3c(c2C(=O)OC)NC(=O)C(C)(C)N3)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccc3c(c2CO)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 40.9 %

Procedure:
Lithium aluminium hydride (753 mg, 19.8 mmol) was suspended in anhydrous tetrahydrofuran (60 mL) under nitrogen atmosphere. An anhydrous tetrahydrofuran solution (20 mL) of 8-methoxycarbonyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-6, 4.87 g, 12.2 mmol) was added dropwise thereto at −10° C., and stirred for 40 minutes at the same temperature. After ethyl acetate (10 mL), water (10 mL), and 2N aqueous HCl solution (15 mL) were added to the reaction mixture successively, ethyl acetate (300 mL) were added thereto. Water (300 mL) was added and the whole was partitioned. The organic layer was washed with saturated brine (400 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.86 g) as a yellow solid. (Yield 41%)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[C:15]([N+:20]([O-])=O)[CH:16]=[CH:17][CH:18]=2)[C:13](=[O:23])[C:12]([CH3:24])=[CH:11]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[ClH:25].[H][H]>CO.CCOCC.[Pd]>[ClH:25].[CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=2)[C:13](=[O:23])[C:12]([CH3:24])=[CH:11]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(Cn1cc(C)c(=O)c2c([N+](=O)[O-])cccc21)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCOP(=O)(Cn1cc(C)c(=O)c2c(N)cccc21)OCC
Yield: 99 %

Procedure:
A solution of (3-Methyl-5-nitro-4-oxo-4H-quinolin-1-ylmethyl)-phosphonic acid diethyl ester (Compound 303B, 20 mg; 0.05 mmol) in methanol (5 mL) was charged with Pd/C (5 mg) and 1M HCl in ether (1 mL) under nitrogen and stirred under 1 atmosphere of hydrogen overnight at RT. The solution was filtered the filtrate concentrated to get the final compound (yield 20 mg; 99%; tlc 1:9 MeOH:DCM); 1H NMR (300 MHz, CDCl3), δ ppm, 8.12 (s, 1H), 8.01 (d, 6 Hz, 1H,) 7.88-7.83 (m, 1H) 7.40 (d, J=9 Hz, 1H) 4.12-4.13 (m, 4H,) 3.31-3.29 (m, 2H), 2.14 (s, 3H), 1.27-1.25 (m, 6H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:18])[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>N1C=CC=CC=1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([O:8][C:4]1[CH:3]=[C:2]([O:1][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:7]=[CH:6][N:5]=1)=[O:18]
Reactant: COc1ccccc1C(=O)Cl
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)Oc1ccnc(OC(=O)c2ccccc2OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 2 %

Procedure:
A 2.00 g quantity of 4-hydroxy-2-pyridone was suspended in 60 ml of pyridine, and 5.52 g of 2-anisoyl chloride was added to the suspension. The mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated and the concentrate was washed with benzene and extracted with ethyl acetate. The extract was concentrated and the concentrate was subjected to a silica gel column chromatography using chloroform-acetone (30:1) as an eluent, giving 120 mg of the title compound in a yield of 2%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=O)[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:22][N:23](C)[CH:24]=O.S(Cl)(Cl)=O.CNC>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([N:23]([CH3:24])[CH3:22])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2nc3ccc(Cl)nc3n2CC(=O)O)cc1
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3ccc(Cl)nc3n2CC(=O)N(C)C)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
A slurry of 5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.8 g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68 g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionyl chloride (1.22 g, 0.0102 mole) was added dropwise to the stirred suspension. After stirring at room temperature for twenty minutes, the solution was cooled again in an ice bath and a solution of dimethylamine in tetrahydrofuran (18.9 ml of a 2.95M solution, 0.056 mole) was added dropwise. The suspension was stirred at room temperature under nitrogen for one hour and then the solvents were removed under reduced pressure. The residue was triturated in water (100 ml) and the resulting solid was collected by filtration and rinsed three times with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and brought to the cloud point with water. Upon cooling, a solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 70° C. to give 2.17 g (71% yield) of title compound, mp 182°-185° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[C:26]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[Cl:35])=[CH:18][C:17]([C:37](OCC)=[O:38])=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[NH3:42].B(Cl)(Cl)Cl>CO>[Cl:35][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:27][C:22]=1[C:21]([NH:20][C:19]1[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[N:16]=[C:17]([C:37]([NH2:42])=[O:38])[CH:18]=1)=[O:36]
Reactant: N
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1
Agent: ClB(Cl)Cl
Solvent: CO
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(O)c2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To a solution of ethyl 1-(3-(benzyloxy)phenyl)-5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1H-pyrazole-3-carboxylate (Example 128, 220 mg, 0.385 mmol) in methanol (3 mL) was added 880 ammonia (7 mL) and the reaction was heated at 60° C. for 18 hours in a Reactivial™. The reaction was cooled, concentrated in vacuo and dissolved in DCM (5 mL). The solution was cooled to 0° C. and boron trichloride (1M in DCM, 3.41 mL, 3.41 mmol) was added dropwise. The reaction was stirred at room temperature for 30 minutes before being quenched by the addition of methanol (20 mL) and stirred for 18 hours. The reaction was concentrated in vacuo azeotroping with MeOH. The residue was purified using preparative HPLC followed by trituration with TBME to afford the title compound (12 mg, 6%).
Reaction SMILES: [C:1]([N:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:22][CH:21]=1>>[C:1]([N:4]([CH:13]([CH3:17])[C:14]([N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)=[O:16])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(C(C)=O)C(C)C(=O)O)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(C)=O)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously toExample 1, by using equivalent quantities, reacting N-acetyl-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-acetyl-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (M.P. 111° to 113°), saponification of which and processing of the reaction produce yields N-[N-acetyl-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 155° to 157°).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[S:28][C:27]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=4[C:25]=3[CH3:34])(=[O:23])=[O:22])=[C:16]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39].C(OCC)(=O)C.CCOCC>C(OCC)(=O)C>[ClH:39].[CH3:38][S:35]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][C:17]=1[NH:20][S:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=2[C:25]=1[CH3:34])(=[O:22])=[O:23])(=[O:36])=[O:37]
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1c(S(=O)(=O)Nc2ccc(C3CCNCC3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[4-(5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.025 g) in ethyl acetate (1 ml) was treated with 2.5 N HCl/ethyl acetate (2 ml). The reaction mixture was stirred at rt for 2 h. Ether (20 ml) was added, the precipitate was filtered off, washed with ether and dried under high vacuum over P2O5 to obtain the title compound (0.020 g) as a yellowish powder. MS (ISP): 483.3 (M+H)+
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=O)(=O)C.C([N:32](CC)CC)C.ClCCOC=O.N>CN(C)C=O.O1CCCC1>[SH:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)[C:6]([NH2:32])=[O:8]
Reactant: CCN(CC)CC
Reactant: COc1ccc2nc(COc3ccc(CC(SC(C)=O)C(=O)O)cc3)n(C)c2c1
Agent: N
Agent: O=COCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2nc(COc3ccc(CC(S)C(N)=O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 2-acetylthio-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid (1.53 g), anhydrous triethylamine (0.4 g), chloroethylformate (0.65 g), anhydrous tetrahydrofuran (10 ml) and anhydrous N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hour. An aqueous solution of ammonia (20 ml, 28%) was added to the reaction mixture and this mixture was stirred for 2 hours and then allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by liquid chromatography (LiChroprepNH2 (Merck)) using ethanol:ethyl acetate=1:12 as the eluant to afford the title compound (0.21 g, mp 204-208° C.) as a pale yellow powder.
Reaction SMILES: Cl[N:2]1[CH2:5][CH:4]([N:6](Cl)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C:3]1=[O:18].CO.C[O-].[Li+].[CH3:24][O:25]P(OC)OC>O1CCCC1.C(OCC)(=O)C.C1C=CC=CC=1.C(OCC)(=O)C.C(O)(=O)C>[CH3:24][O:25][C:4]1([NH:6][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][NH:2][C:3]1=[O:18]
Reactant: COP(OC)OC
Reactant: O=C1C(N(Cl)C(=O)OCc2ccccc2)CN1Cl
Agent: C[O-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC1(NC(=O)OCc2ccccc2)CNC1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 730 mg (0.0025 mole) of 1-chloro-3-[N-chloro-N-[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 5 ml of tetrahydrofuran is cooled to -78° C. and 4 ml of methanol containing 285 mg of lithium methoxide is added. After 20 minutes at -78° C., 0.6 ml of acetic acid and 0.6 ml of trimethylphosphite are added. The solution is stirred for 5 minutes at -78° C., allowed to warm to ambient temperature and stirred for 30 minutes. The resulting solution is diluted with ethyl acetate, washed with 5% sodium bicarbonate, water, 5% potassium bisulfate, water, saturated salt solution, and dried. Solvent removal gives an oil that is applied to four 20×20 cm×1 mm silica gel plates. Development with benzene-ethyl acetate (1:1) and isolation of the major UV-active band of Rf=0.25 gives 91 mg of oil that crystallizes from ether to give a solid. Recrystallization from ether gives the title compound, melting point 112°-114° C.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[CH2:5][CH2:4]1)=O.[OH-].[Na+]>Cl>[F:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([CH:6]2[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)[CH:14]=1
Reactant: COc1ccc(F)cc1C1CCN(C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)cc1C1CCNCC1
Temperature: 25 °C

Procedure:
The crude product of 1-formyl-4-(5-fluoro-2-methoxy-phenyl)-piperidine (0.80 g, 3.4 mmole) was dissolved in HCl (16 mL, 0.5 N) and McOH (5 mL), and the mixture was brought to reflux for 16 hours. The mixture was cooled to room temperature and basified with NaOH (2.5 N), and extracted with EtOAc (3×25 mL) to give 4-(5-fluoro-2-methoxy-phenyl)-piperidine which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14])(=O)=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH:16]1[C:12]2[C:13](=[O:14])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:11]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccccc2Sc2ccccc21
Temperature: 25 °C
Yield: 91.2 %

Procedure:
2-(2-aminophenylsulfuryl)benzoic acid (30 g, 0.122 mol) obtained in Example 5, sulfuric acid (0.15 g), and xylene (100 ml) were placed into a 0.5 L reactor, and then refluxed at 145–150° C. for six hours. The resultants were cooled to room temperature, after which the produced solid was filtered and washed with methanol. The solid was dried under reduced pressure, to give 10H-dibenzo[b,f][1,4]thiazepin-11-one (25.3 g), as the yield of 91%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:5]=[N:4][C:3]=1[N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:3]3[N:4]=[N:5][C:6]([CH2:9][C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(Cc2ccncc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccncc4)c(C)c3C)C[C@H]2C)cn1
Yield: 55.6 %

Procedure:
According to the protocol described below for example 46, 4,5-dimethyl-3-((R)-3-methyl-piperazin-1-yl)-6-pyridin-4-ylmethyl-pyridazine (155 mg, 0.51 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (99 mg, 0.56 mmol) afforded the title compound as an orange oil (123 mg, 56%).