Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:40])=[C:10]([CH2:12][O:13][C:14]3[CH:39]=[CH:38][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]1([C:7]2[O:8][C:9]([CH3:40])=[C:10]([CH2:12][O:13][C:14]3[CH:39]=[CH:38][C:17]([CH2:18][O:19][C:20]4[C:24](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:21]=4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)cc1
Yield: 86.6 %

Procedure:
To a mixture of ethyl (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoate (0.39 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 2 hrs. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (2E)-3-[3-({4-[(2-phenyl-5-methyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]-2-propenoic acid as colorless crystals (0.32 g, yield 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 186-187° C.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:47])[NH:12][C:13]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]4[CH:30]=[CH:29][C:28](B5OC(C)(C)C(C)(C)O5)=[CH:27][N:26]4[C:40]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].[CH2:48]([O:55][C:56]1[C:61](Br)=[CH:60][CH:59]=[CH:58][N:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:6]([O:10][C:11](=[O:47])[NH:12][C:13]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]4[CH:30]=[CH:29][C:28]([C:61]5[C:56]([O:55][CH2:48][C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:57][CH:58]=[CH:59][CH:60]=5)=[CH:27][N:26]4[C:40]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH2:16]1)([CH3:8])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(B5OC(C)(C)C(C)(C)O5)cn4c3-c3ccccc3)cc2)CCC1
Reactant: Brc1cccnc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(-c5cccnc5OCc5ccccc5)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 110 °C

Procedure:
To the crude DMF solution of the boronate from Step 1 was added 2-benzyloxy-3-bromopyridine (0.25 g), aqueous sodium carbonate solution (2M, 2.8 mL) and dioxane (4 mL) and the mixture placed under argon. [1,1-bis-(diphenylphosphino)-ferrocene]-dichloropalladium-dichlormethane-complex (0.070 mg) was added and the mixture heated at 110° C. under microwave irradiation for 30 minutes. On cooling the mixture was partitioned between DCM and water and extracted. The organic portion was washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound (138 mg).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].CN1CCN(C)C1=O>O>[F:25][C:24]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Nc1ccccc1C(F)(F)F
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=[N+]([O-])N=C1NCCN1C=Nc1ccccc1C(F)(F)F
Yield: 52.9 %

Procedure:
0.05 g of boron trifluoride ether complex was added under ice-cooling conditions to a mixture of 5.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 3.47 g of o-aminobenzotrifluoride and 5 ml of 1,3-dimethyl-2-imidazolidinone. Immediately, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and concentrated. Ether was added to the resultant oily residue and the resultant crystals were removed by filtration, followed by washing with hot ethyl acetate to give 3.43 g of 1-(2-trifluoromethylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[N:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][N:6]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a solution of rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester prepared in Example 138 (0.2 g, 0.33 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 20 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid as a white foam (0.12 g). In a manner similar to the method described in Examples 1e, rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid (0.12 g, 0.2 mmol) was reacted with 2-amino-2-methyl-1-propanol (Aldrich) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-N-(2-hydroxy-1,1-dimethyl-ethyl)-nicotinamide as a white solid (30 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34]>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H20FN3O3S, 425.12; m/z found, 426.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.57 (s, 1H), 8.29-8.22 (m, 2H), 7.95-7.85 (m, 1H), 7.69-7.61 (m, 1H), 7.61-7.53 (m, 1H), 7.42-7.33 (m, 4H), 7.29 (d, J=7.8, 1H), 6.54-6.49 (m, 1H), 5.92 (d, J=6.7, 1H), 3.64-3.51 (m, 1H), 3.47-3.34 (m, 2H), 2.34 (s, 1H), 1.03 (d, J=6.5, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[BH4-].[Na+].[OH-].[K+].ClC[CH:20]1[CH2:22][CH2:21]1>C(O)C.C(Cl)(Cl)Cl.O>[CH:20]1([CH2:12][S:11][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[CH2:22][CH2:21]1
Reactant: ClCC1CC1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(SCC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
To a stirred mixture of 11.7 g (0.06 mole) of 2-nitro-4-thiocyanoaniline in 500 ml of absolute ethanol under nitrogen there is added 2.5 g (0.06 mole) of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3.9 g (0.06 mole) of KOH in 25 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 4.8 g (0.06 mole) of (chloromethyl) cyclopropane in 10 ml of absolute ethanol is added and the mixture is stirred at room temperature for 15 minutes then refluxed for 2 hours. Equal amounts of water and CHCl3 are added until 2 layers are formed. The organic layer is separated, dried (MgSO4), and the solvent removed in vacuo to give 9.1 g of an orange-red solid, m.p. 45°-47°.
Reaction SMILES: OC1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH:12]C(C)=O.[OH:16][CH:17]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]1O>>[CH2:3]([NH2:12])[CH:4]([OH:5])[CH:6]([OH:7])[CH:8]([OH:9])[CH:10]([OH:11])[CH2:17][OH:16]
Reactant: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: NCC(O)C(O)C(O)C(O)CO

Procedure:
1H NMR of IV, Na-salt (500 MHz, D2O, 2 mM NaHCO2, 30° C.): δ=5.473 (m, 2 —CH═CH— of DOPE), 5.328 (m, OCH2CHCH2O of DOPE), 4.574 and 4.473 (m, HA: H−1 of GlcNAc, H−1 of GlcA; CO—OCHCHCH2 of DOPE), 4.246 (dd, J=12.3 Hz, J=6.8 Hz, CO—OCHCHCH2 of DOPE), 4.027 (t, J=5.7 Hz, POCH2CH2N of DOPE), 3.95-3.34 (HA: H−2÷H-6 of GlcNAc, H−2÷H−5 of GlcA; POCH2CHCH2 of DOPE), 2.413 (m, 2 CH2COO of DOPE), 2.302 (m, 2 CH2CON), 2.049 (m, 2 CH2CH═CHCH2 of DOPE), 2.039 (m, NCOCH2 of GlcNAc), 1.630 (m, 2 CH2CH2CON and 2 CH2CH2COO of DOPE), 1.306 (m, —CH2— of DOPE), 0.892 (˜t, 2 CH2 of DOPE) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C@@H:17]2[O:46][C@H:45]([CH2:47][O:48]CC3C=CC=CC=3)[C@@H:36]([O:37]CC3C=CC=CC=3)[C@H:27]([O:28]CC3C=CC=CC=3)[C@H:18]2[O:19]CC2C=CC=CC=2)[N:3]=1>C(O)C.O1CCCC1.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C@@H:17]2[O:46][C@H:45]([CH2:47][OH:48])[C@@H:36]([OH:37])[C@H:27]([OH:28])[C@H:18]2[OH:19])[N:3]=1
Reactant: CCc1ccc(Cc2c(C)nn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Cc2c(C)nn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
3-(4-ethylphenylmethyl)-2,4-pentanedione 28 (700 mg) and 2,3,4,6-tetra-O-benzyl-α,β-D-glucosehydrazone 29 (1.70 g) (See Schmidt, R. R. et al., Liebigs Ann. Chem. 1981, 2309) were dissolved in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 18 hours under argon atmosphere. The solvent was evaporated under reduced pressure, and the residue was dissolved in toluene (20 ml), and the mixture was heated with stirring under reflux for 2 hours. The mixture was left alone until it was cooled, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-65:35) to give 3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)pyrazole 30 (299 mg) as a pale yellow semisolid. APCI-Mass m/Z 737 (M+H). (2) The above tetrabenzyl compound 30 (294 mg) was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (4 ml), and added thereto was palladium hydroxide (100 mg), and the mixture was stirred at room temperature for 16 hours under hydrogen atmosphere under normal pressure. Insoluble materials were filtered off, and the solvent was evaporated under reduced pressure. The residue was crystallized from diethyl ether to give the desired 3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 31 (118 mg) as colorless powder. APCI-Mass m/Z 377 (M+H).
Reaction SMILES: N[C:2]1[C:3]2[C:27]3(CCOC3)[C:26](=[O:32])[NH:25][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:7]=1.[Se](=O)=[O:34]>O1CCOCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[CH:2][C:3]3[C:27](=[O:34])[C:26](=[O:32])[NH:25][C:4]=3[N:5]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C1(CCOC1)C(=O)N2
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2C1=O

Procedure:
2.00 g (5.550 mmol) of Example 4 were initially charged in dioxane (200 ml), 3.079 g (27.751 mmol) of selenium dioxide were added and the mixture was heated at reflux for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated and purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 1:1). This gave 890 mg of the title compound (42% of theory).
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([C:18]2[CH:19]=[N:20][C:21]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=2[C:24]#[N:25])=[CH:13][C:12]=1[S:30]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][C:35]2[CH:40]=[CH:41][CH:42]=[CH:43][C:34]1=2)(=[O:32])=[O:31])(C)(C)C>Cl.O1CCOCC1>[Cl:17][C:15]1[C:14]([C:18]2[CH:19]=[N:20][C:21]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:23]=2[C:24]#[N:25])=[CH:13][C:12]([S:30]([N:33]2[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]2=3)(=[O:31])=[O:32])=[C:11]([CH:16]=1)[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:44])=[O:5]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1S(=O)(=O)N1CCCCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(C(F)(F)F)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCCC(=O)O)cc1Cl

Procedure:
4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid tert-butyl ester 6-1 (30 mg, 0.046 mmol) was stirred in 4M HCl in dioxane (1 mL) at 40° C. for 2 hrs and concentrated. The resulting oil residue was purified by TLC plates eluting with 4% methanol in DCM to afford 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid 7-1. MS: 593.8 (M+H)+; tR=8.94 min (method 2).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[NH2:5].[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31](N2C=CN=C2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([NH:5][CH:4]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[C:3]([O:2][CH3:1])([O:19][CH3:20])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NCCCc1ccccc1)n1ccnc1
Reactant: COC(OC)(c1ccncc1)C(N)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(OC)(c1ccncc1)C(NC(=O)NCCCc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethoxy-2-(4-pyridyl)-1-(4-fluorophenyl)ethanamine (51.12 g, 0.185 mol) and N-(3-phenylpropyl)-1H-imidazole-1-carboxamide (42.42 g, 0.185 mol) in toluene (300 mL) under N2, was stirred and heated to reflux temperature for 3 h. The solution was cooled to room temperature and the dark brown solution was diluted with ethyl acetate (200 mL). The mixture was washed with water (2×200 mL), brine (200 mL), and dried with Na2SO4. The solvents were removed in vacuo to yield a brown solid which was recrystallized from a solvent mixture of ethyl acetate/hexane (1:1) to yield an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=O)[C:5]=1[OH:12])[CH3:2].[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([NH:19][S:20]([CH2:23][C:24](O)=[O:25])(=[O:22])=[O:21])=[CH:17][CH:16]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]2[C:5]=1[O:12][C:24](=[O:25])[C:23]([S:20]([NH:19][C:18]1[CH:27]=[CH:28][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)(=[O:22])=[O:21])=[CH:7]2)[CH3:2]
Reactant: CCOc1cccc(C=O)c1O
Reactant: COc1ccc(NS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(OC)cc3)c(=O)oc12

Procedure:
A solution of 3-ethoxysalicylaldehyde (1 mmol) and 4-methoxyanilinosulfonyl acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 1, Method A to yield the title compound; m.p. 196-198° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.ClCCl>[CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 4.22 g (17.8 mmol) of 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoic acid and 85 ml of dichloromethane, added 1.7 ml (19.5 mmol) of oxalyl chloride. After the bubbling subsided, five drops of DMF were added and the solution was stirred at room temperature for 21 hours. The solution was evaporated to 4.8 g of an oil which was used in the next step without purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=4)[CH:16]=[C:11]3[C:10]([CH3:28])=[N:9]2)=CC=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)(Cl)Cl.CCCCCC>[CH3:28][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(c2)c(C)nn3Cc2ccc(OC)cc2)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a stirred solution of Compound 3 (70 mg, 0.175 mmol) in chloroform (15 mL) was added trifluoroacetic acid (3 mL) and heated to 50° C. overnight. The reaction was evaporated and diluted with water; pH was adjusted to 8-10 with sodium carbonate solution. The aqueous phase was extracted with dichloromethane twice (2×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude, which was passed through 100-200 mesh silica gel eluting the EXAMPLE 1 at 60% ethyl acetate in hexane as pale yellow colour solid. MS-ES+ 277.9, 1H NMR (400 MHz, DMSO-D6-D6) 4: 13.29 (s, 1H), 10.29 (s, 1H), 8.74 (d, 1H), 8.40 (d, 1H), 8.03 (s, 1H), 7.69 (m, 1H), 7.43 (m, 2H), 6.44 (m, 1H), 6.26 (dd, 1H), 5.78 (dd, 1H), 2.55 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8](O)[CH2:9][CH2:10][CH3:11].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd]>[CH2:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14](=[O:16])[CH3:15])=[CH:3][C:2]=1[OH:1])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(O)c1ccc(NC(C)=O)cc1O
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Product: CCCCc1ccc(NC(C)=O)cc1O
Yield: 70 %

Procedure:
N-(3-Hydroxy-4-(1-hydroxybutyl)phenyl)acetamide (184 g) was reduced in 20 g batches by dissolving it in de-oxygenated acetic acid (210 mL) in the presence of 10% Pd/C (7 g) at 60 Psi in a Parr hydrogenator for eleven hrs. Upon completion the reaction was filtered over celite and diluted. The acetic acid was removed in vacuo. The resulting oil was diluted with ethyl acetate and was washed three times with water and once with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude compound was purified via flash chromatography with 100% ethyl acetate to obtain the title compound in 70% yield (120 g) as a waxy tan solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[C:6](=S)[O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3.O1CCOCC1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH:6]([CH:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[NH:28])[O:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3
Reactant: Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C1C(CO)COC(=S)N1CC2
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C1C(CO)COC(C3C=CC=CC3=N)N1CC2
Yield: 45 %

Procedure:
To a solution of 3.09 g (0.01 mole) of 1-(hydroxymethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H-[1,3]oxazino[4,3-a]isoquinoline-4-thione in 200 ml of dioxane 0.015 mole of HgO are added, and the mixture is reacted with 9.3 g (0.1 mole) of aniline. The reaction mixture is allowed to stand at room temperature for 24 hours, whereupon the HgS is filtered off, and the solvent and the excess of aniline are distilled off. The aimed compound is obtained in a yield of 45%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.CC([O-])(C)C.[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1nccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc3ccccc23)C1
Temperature: 110 °C

Procedure:
To a solution of 1-chloroisoquinoline (5.00 g, 30.6 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (7.34 g, 36.6 mmol) in anhydrous toluene (150 mL) was added t-BuOK (10.27 g, 91.7 mmol), BINAP (951 mg, 1.53 mmol), and Pd(OAc)2 (343 mg, 1.53 mmol). The reaction mixture was purged with nitrogen three times, and heated at 110° C. overnight. The reaction mixture was cooled to room temperature and poured into water. The mixture was then extracted with EtOAc (4×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting dark solid was purified by silica gel column chromatography eluting with a gradient of (10-15%) EtOAc/petroleum ether to deliver the title compound (4.89 g, 49%) as a yellow solid.