Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)CC1C=NC2C=CC=CC=2O1.[CH2:16]([C@H:20]1[N:25]([CH2:26][C:27]([F:30])([F:29])[F:28])[C:24]2[CH:31]=[CH:32][C:33]([N+:35]([O-])=O)=[CH:34][C:23]=2[O:22][CH2:21]1)[CH:17]([CH3:19])[CH3:18]>C(OCC)(=O)C.[Pd]>[NH2:35][C:33]1[CH:32]=[CH:31][C:24]2[N:25]([CH2:26][C:27]([F:30])([F:29])[F:28])[C@H:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:21][O:22][C:23]=2[CH:34]=1
Reactant: CC(C)C[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Agent: [Pd]
Agent: FC(F)(F)CC1C=Nc2ccccc2O1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H]1COc2cc(N)ccc2N1CC(F)(F)F
Yield: 65.3 %

Procedure:
(3R)-7-Amino-3,4-dihydro-3-isobutyl-4-(2,2,2-trifluoroethyl-2H-1,4-benzoxazine (Structure 16 of Scheme III, where R3, R4, R5, R7, R8=H, R=isobutyl, R13=CH2CF3) This compound was prepared by treatment of (3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (0.22 g, 0.69 mmol) and 10% Pd/C (0.075 g) in 5 mL ethyl acetate under an H2 atmosphere for 16 h. The mixture was filtered through Celite and concentrated to an oil. Flash chromatography (3:1 hexanes:ethyl acetate) afforded 0.13 g (65%) of (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine. Data for (3R)-7-amino-3,4-dihydro-3-isobutyl-4-trifluoroethyl-2H-1,4-benzoxazine: Rf0.3 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.63 (d, 1H, J=8.5), 6.27 (dd, 1H, J=8.5, 2.6), 6.23 (d, 1H, J=2.5), 4.10 (dd, 1H, ABx, J=10.6, 1.8), 3.97 (dd, 1H, ABx, J=10.6, 2.3), 3.70–3.51 (m, 2H), 3.38 (broad s, 2H), 3.19–3.13 (m, 1H), 1.75–1.63 (m, 1H), 1.47–1.25 (m, 2H), 0.93 (d, 3H, J=6.6), 0.89 (d, 3H, J=6.6).
Reaction SMILES: C[CH:2]1[CH:7](C)[CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:45])[C@H:11]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:33][CH:32]=2)[NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:3]1.O1CCCC1.C(N(CC)CC)C>CN(C)C=O>[CH:4]1([NH:9][C:10](=[O:45])[C@H:11]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:33][CH:32]=2)[NH:12][C:13](=[O:29])[C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:18][CH:19]=2)[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]1
Reactant: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)NC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
The above compound (III) was suspended in dimethylformamide (10 ml)--tetrahydrofuran (10 ml) solution, and triethylamine (0.4 ml) and trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid mixed acid anhydride were added under ice-cooling, followed by stirring for 30 minutes. Further, the reaction was carried out at room temperature for 3 hours. After a conventional post-treatment, N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-(3-cyanobenzyloxy)-L-phenylalanine 4-acetylanilide (IV) (1.31 g) was obtained. The above compound (IV) (1.31 g) was allowed to react with 4N-hydrogen chloride/dioxane solution (10 ml) for 1 hour, and the crystalline substance precipitated by addition of hexane was collected by filtration. The product was recrystallized from an ethanol-ether solution to obtain N-(trans-4-aminomethylcyclohexylcarbonyl)-4-(3-cyanobenzyloxy)-L-phenylalanine 4-acetylanilide hydrochloride (1.1 g).
Reaction SMILES: CO[C:3](=[O:42])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)=[CH:22][C:21]=1[F:39])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=C(C)O[N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:44]([C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([OH:50])=[O:49])[NH2:45].COC(=O)N=C(SC)C(C1C=C(OC)C=C(OCCF)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.N(C1N=CC=CN=1)N>>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C@@H:6]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:29][CH2:30][OH:31])=[CH:22][C:21]=2[F:39])[C:5]2[NH:4][C:3](=[O:42])[N:44]([C:46]3[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=3[C:48]([OH:50])=[O:49])[N:45]=2)=[CH:13][CH:12]=1)(=[NH:18])[NH2:15]
Reactant: NNc1ccccc1C(=O)O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OCCO[Si](C)(C)C(C)(C)C)cc1F
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Agent: Cl
Agent: NNc1ncccn1
Product: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c(F)cc1OCCO

Procedure:
The same procedure was carried out as in Examples (3f)-(3h), except that (2-{4-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester and 2-hydrazinobenzoic acid hydrochloride were used instead of respectively the {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in Example (3f) and 2-hydrazinopyrimidine in Example (3f), to give the title compound as a white solid.
Reaction SMILES: CC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C([O-])([O-])=O.[Cs+].[Cs+].I[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].[CH2:31]([OH:35])[CH2:32][CH2:33][CH3:34]>[Cu]I.C1(C)C=CC=CC=1>[CH2:31]([O:35][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])[CH2:32][CH2:33][CH3:34]
Reactant: N#Cc1cccc(I)c1
Reactant: CCCCO
Agent: [Cu]I
Agent: Cc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCOc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 28 h
Yield: 86.7 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 10 mol %), 5-methyl-1,10-phenanthroline (39 mg, 0.20 mmol, 20 mol %), Cs2CO3 (652 mg, 2.0 mmol), 3-iodobenzonitrile (229 mg, 1.0 mmol), n-butanol (366 μL, 4.0 mmol) and toluene (1 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 28 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate. The filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (2×20 cm; hexane/ethyl acetate 30:1) provided 152 mg (87% yield) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][C:10]2[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl.CC(C)=O.Cl>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][CH:41]=[C:32]([NH:31][C:16]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][O:8][C:7]3[CH:19]=[CH:20][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:24])[C:6]=3[CH2:21][CH2:22][CH3:23])[N:15]=2)=[O:18])[CH:33]=1
Reactant: CCCc1c(OCc2cccc(C(=O)O)n2)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cccc(N)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)OC)c3)n2)ccc(C(C)=O)c1O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Add one drop of dimethylformamide to a solution of 6-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridine-2-carboxylic acid (800 mg, 2.43 mmol) and oxalyl chloride (0.23 mL, 2.67 mmol) in dichloromethane (24 mL) (gas evolution), stir 1 hour. Add a solution of methyl 3-aminobenzoate (365 mg, 2.43 mmol) and potassium carbonate (671 mg, 4.86 mmol) in acetone (16 mL). Stir resultant mixture for 16 hours. Dilute with dichloromethane (100 mL) and 1N hydrochloric acid (100 mL). Extract aqueous phase with dichloromethane, wash combined organic phase with saturated sodium bicarbonate solution. Dry organic phase over sodium sulfate and condense under reduced pressure. Triturate the residue in 1:1 acetone/diethyl ether. Dissolve resultant solid in ethyl acetate and wash with saturated sodium bicarbonate (2×), Dry organic phase over sodium sulfate and condense under reduced pressure to afford the title compound as a white solid (856 mg, 1.85 mmol). MS (m/z): 463 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]3[CH:28]([F:30])[F:29])[N:16]=[C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:14]=2)[CH2:8][CH2:7]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.O>CN(C)C=O>[CH:43]1([NH:47][CH2:2][C:3]([NH:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([O:12][C:13]3[CH:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]4[CH:28]([F:30])[F:29])[N:16]=[C:15]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[N:14]=3)[CH2:8][CH2:7]2)=[O:4])[CH2:46][CH2:45][CH2:44]1
Reactant: O=C(CBr)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC1CCC1)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]acetamide (100 mg) was suspended in dimethylformamide (2 mL), and potassium carbonate (30 mg) and cyclobutylamine (60 μL) were added thereto, followed by stirring at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel chromatography (hexane:ethyl acetate=40:60-10:90) to obtain N2-cyclobutyl-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]glycinamide (79 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][C:7]=1[NH2:8].[CH2:19](C(CC)(CC)C([O-])([O-])[O-])[CH3:20].[OH-].[NH4+]>C(O)(=O)C>[CH3:19][C:20]1[N:8]=[C:7]2[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]2[N:1]=1
Reactant: CCOC(=O)c1cc(N)c(N)nc1C(=O)OCC
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2nc(C)nc-2[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Diethyl 5,6-diamino-2,3-pyridinedicarboxylate (10.38 g, 0.041 mol) is stirred under an N2 atmosphere in 100 mL glacial acetic acid, to give a clear orange solution. Triethylorthoacetate (TEOA), (0.19 mol) is then added and the mixture is heated to reflux for 15 hours. The cooled solution is poured into ice water and neutralized with ammonium hydroxide. The solution is extracted with ethyl acetate, the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated to an oil. The oil is taken up in ethyl acetate and the desired product is precipitated by the addition of hexanes in two crops of beige solid, totalling 8.11 g (71.3%), having a melting point of 164°-165° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]([F:40])([F:39])[C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc(C(F)(F)F)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 54 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.80 min, m/z=513.0 [M+H]+, m/z=511.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.79-1.91 (m, 1H) 2.85 (d, J=11.49 Hz, 1H) 3.16-3.27 (m, 2H) 3.40 (td, J=9.84, 7.21 Hz, 1H) 4.21 (br. s, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.81-7.89 (m, 2H) 8.01 (d, J=7.58 Hz, 1H) 8.08-8.13 (m, J=8.31, 2.45, 2.45, 2.45 Hz, 2H) 8.80 (d, J=2.20 Hz, 1H) 8.85 (d, J=1.96 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: CS([O:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[C:24]([CH3:25])=[CH:23][C:22](O)=[CH:21][C:20]=2[CH3:27])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:25][C:24]1[CH:23]=[C:22]([O:5][C@@H:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[CH:21]=[C:20]([CH3:27])[C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][OH:11])[CH:14]=1
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Reactant: CS(=O)(=O)O[C@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
The crude (S)-tetrahydrofuran-3-yl methanesulfonate 2b (522 mg, 3.14 mmol), 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (714 mg, 3.13 mmol, prepared by a method disclosed in Chinese patent application CN101616913) and cesium carbonate (3.10 g, 9.39 mmol) were dissolved in 30 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-(2′, 6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 2c (540 mg, yield 58.0%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13]C([C@@H]3CCCN3C(=O)[C@H](NC(=O)C)CC3C=CC(C4C=CC=CC=4)=CC=3)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:41]([O:43][C:44]([NH:46][C@H:47]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1)[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][C@H:51]1[C:55]([OH:57])=O)=[O:49])=[O:45])[CH3:42]>>[CH2:41]([O:43][C:44](=[O:45])[NH:46][C@H:47]([CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:65][CH3:66])=[CH:63][CH:64]=1)[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][C@H:51]1[C:55](=[O:57])[NH:13][CH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]2)=[O:49])[CH3:42]
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reactant: CCOC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Product: CCOC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 79 %

Procedure:
Using the procedure described in example 97f 0.115 g of 1-(2-(R)-ethoxycarbonylamino-3-(4-methoxyphenyl)-propionyl)-pyrrolidin-2-(S)-carboxylic acid was converted into 0.130 g (79%) of the title compound. (+)-APCI-MS: 520 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]CC)=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[K+].[OH-].[Na+]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[C:14]([Cl:33])[C:13]=3[Cl:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2Cl)C1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(Cl)c2Cl)C1

Procedure:
The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 137 with the ethyl ester from Example 327, and KOH with NaOH, providing a white solid. 1H NMR (CDCl3, 300 MHz) δ 1.70-2.0 (m, 2H), 2.0-2.20 (m, 1H), 2.54-2.68 (m, 1H), 3.03-3.46 (m, 2H), 3.80-4.11 (m, 2H), 4.27-4.40 (m, 4H), 4.50-4.70 (m, 1H), 6.60 (d, J=8.9 Hz, 1H), 6.79 (d, J=15.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 7.03 (dd, J=2.1, 8.5 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H), 7.93 (d, J=15.3 Hz, 1H). MS (ESI+) (M-2H)+ at m/z 492, 494, 496. Anal. Calcd for C23H21Cl2NO5S.0.73 H2O: C, 54.43; H, 4.46; N, 2.76. Found: C, 54.43; H, 4.39; N, 2.49.
Reaction SMILES: C=CC=C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13]CC=CC)[CH:10]=[CH:11][CH:12]=1>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1
Reactant: CC=CCCc1cccc(OC)c1
Agent: C=CC=C
Solvent: O
Product: COc1cccc(C)c1
Temperature: 110 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
After the flask was heated at a temperature of 110° C. during stirring in order to disperse the catalysts, 1,3-butadiene was fed for 6 hours at a flow rate of 0.3 mol/hour in order to promote the addition reaction. After the completion of the reaction, water was added to deactivate and separate the catalysts. The thus obtained reaction mixture was analyzed by gas chromatography. The results indicated that 5-(3-methoxyphenyl)-2-pentene was produced at 79% yield with respect to the consumed m-methoxytoluene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (i) using 4-bromo-2-fluorobenzenesulfonyl chloride and fluorobenzene.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:17]([O:14][CH2:13][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1coc(-c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: c1ccc(COCCc2coc(-c3ccccc3)n2)cc1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
To a solution of 2-(2-phenyloxazol-4-yl)-ethanol (Eli Lilly and Co. WO 9613264) (500 mg, 2.64 mmol) in THF (8 mL) was added NaH (215 mg, 5.28 mmol), followed by tetrabutylammonium iodide (96 mg, 0.26 mmol). After 10 min, benzyl bromide (677 mg, 3.96 mmol, 0.47 mL) was added via syringe. After 3 h, the reaction was partitioned between H2O (20 mL) and diethyl ether (20 mL). The organic phase was washed with brine and then the combined aqueous phases were back extracted with ether (50 mL). The organic phases were dried (MgSO4), filtered and concentrated. The product was purified by flash chromatography (80 mL SiO2, 25% EtOAc/hexanes) and obtained as a colorless oil (690 mg, 93%): Rf=0.46 in 25% EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) δ 8.03-8.01 (m, 2H), 7.52 (t, J=1.0 Hz, 1H), 7.45-7.41 (m, 3H), 7.34-7.33 (m, 3H), 7.29-7.26 (m, 1H), 4.57 (s, 2H), 3.80 (t, J=7.0 Hz, 2H), 2.93 (t, J=7.0 Hz, 2H); 13C (125 MHz, CDCl3) δ 161.3, 139.3, 138.2, 135.0, 130.1, 128.7, 128.4, 127.7, 127.6, 126.3, 73.0, 68.5, 27.3.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=O.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C([O-])(=O)C.[Na+]>CO>[OH:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:3]2[CH:2]=[N:24][C:17]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:23]=2)=[CH:6][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Reactant: Nc1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2cnc3ccccc3n2)cc([N+](=O)[O-])c1O

Procedure:
ada) A suspension of 14.5 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 5.41 g of 1,2-phenylenediamine in 350 ml of methanol is treated with 4.92 g of sodium acetate and the mixture is heated to boiling under reflux for 22 hours. The reaction mixture is then evaporated, the residue is dissolved in methylene chloride, this solution is washed four times with water, dried over sodium sulfate, filtered and evaporated. There is obtained 2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline of m.p. 195°-197° (from methylene chloride/methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10](I)=[CH:11][C:12]=1[C:13]#[N:14])([CH3:4])([CH3:3])[CH3:2].[N:17]1([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][N:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([C:26]2[CH:25]=[N:24][C:23]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:28][CH:27]=2)=[CH:11][C:12]=1[C:13]#[N:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1sc(I)cc1C#N
Reactant: CC1(C)OB(c2ccc(N3CCCCC3)nc2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccc(N3CCCCC3)nc2)cc1C#N

Procedure:
The title compound was prepared from tert-butyl(3-cyano-5-iodo-2-thienyl)carbamate (Example 581 Step 2) (500 g, 1.43 mmol) and 2-piperidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (658 mg, 2.29 mmol) as described in Example 581, Step 3.
Reaction SMILES: C(NN)(=O)C1C=CC=CC=1.[C:11]1([CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](O)=[O:35])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:11]1([CH2:17][C:18]([NH:20][NH:21][C:34]([C:33]2[CH:37]=[CH:38][N:39]=[C:31]([NH:30][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:32]=2)=[O:35])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: NNC(=O)c1ccccc1
Product: O=C(Cc1ccccc1)NNC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Yield: 65 %

Procedure:
Following the procedure as described in Preparation 13, making variations as required to replace benzohydrazide with 2-phenylacetohydrazide to react with 2-benzamidoisonicotinic acid, N-(4-(2-(2-phenylacetyl)hydrazinecarbonyl)pyridin-2-yl)benzamide was obtained in 65% yield: MS (ES+) m/z 374.9 (M+1).
Reaction SMILES: [Na:1].N1C(N)=C2C(N(C3(OC[C@H](OCP(O)(O)=O)[C@H]3O)O)C=N2)=NC=1.[N:25]1([C:33]2([O:51][CH2:50][C@H:37]([O:38][CH2:39][P:40]([O:46]C(C)C)([O:42]C(C)C)=[O:41])[C@H:35]2[OH:36])[OH:34])[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[Na:1].[N:25]1([C:33]2([O:51][CH2:50][C@H:37]([O:38][CH2:39][P:40]([OH:42])([OH:46])=[O:41])[C@H:35]2[OH:36])[OH:34])[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(=O)[nH]c2=O)[C@@H]1O)OC(C)C
Agent: Nc1ncnc2c1ncn2C1(O)OC[C@H](OCP(=O)(O)O)[C@H]1O
Agent: [Na]
Product: O=c1ccn(C2(O)OC[C@H](OCP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Yield: 49 %

Procedure:
This compound was prepared as described for 3a using 17 (200 mg, 0.53 mmol) as a starting material and TBMSBr (200 mL, 2.1 mmol). Compound 3c (93 mg, 0.26 mmol) was obtained as a colorless solid, in 49% yield, which was characterized as follows: