Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[S:21][CH:22]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:28]([F:31])([F:30])[F:29].C[OH:33]>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH:22]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]2)=[O:33])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:28]([F:30])([F:29])[F:31]
Reactant: O=C1CCC(Sc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)C1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: O=S(c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CCC(O)C1

Procedure:
Following General Procedure D, followed by treatment of the crude product with NaBH4 in MeOH, the title compound was prepared from 4-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (Intermediate 35).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([F:12])[C:7]([CH2:8][OH:9])=[C:6]([F:13])[CH:5]=1)[CH3:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[C@H:23]([CH2:30][CH3:31])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:13])[C:7]([CH2:8][O:9][C:27]([N:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:20])[CH2:22][C@H:23]2[CH2:30][CH3:31])=[O:28])=[C:10]([F:12])[CH:11]=1)[CH3:2]
Reactant: CCOc1cc(F)c(CO)c(F)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 81 %

Procedure:
This compound was prepared from 4-ethoxy-2,6-difluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (478 mg; 81%); MS (ISP): 429.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11]C=[CH:9][C:8]=2OC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[S:17]1CCC(NN)CC1>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][S:17][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Reactant: NNC1CCSCC1
Product: N#Cc1cnn(C2CCSCC2)c1N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-(tetrahydro-2H-thiopyran-4-yl)hydrazine provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.44 (s, 1H), 4.71 (s, 2H), 3.84-3.76 (m, 1H), 2.80-2.63 (m, 4H), 2.24-2.10 (m, 4H). MS: (M+H m/z 209.1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][N:9]=[C:10]2[NH:13][CH2:14][C:15]([NH:17][CH:18]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH:20]1[CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:30])[F:29])[CH:12]=3)[CH:7]=[N:8][N:9]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nncc3ccc(C(F)(F)F)cc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1nncc2ccc(C(F)(F)F)cc12)NC1CNC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 25 mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(7-(trifluoromethyl)phthalazin-1-ylamino)acetamido)azetidine-1-carboxylate (prepared as described in the previous step, 160 mg, 0.38 mmol, 1.00 equiv) in dichloromethane (1 mL). This was followed by the addition of trifluoroacetic acid (0.8 mL). The reaction mixture was stirred for 2 h at 0° C. The resulting mixture was concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: C[OH:2].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21]([OH:22])=[C:20]([O:23][CH3:24])[C:19]([O:25][CH3:26])=[CH:18][C:17]=1[CH3:27])(=[O:5])[CH3:4].N1C=CC=CC=1>O=O.C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:2])[C:17]=1[CH3:27])(=[O:5])[CH3:4]
Reactant: CO
Reactant: COc1cc(C)c(CCCCCCCCCOC(C)=O)c(O)c1OC
Agent: [Co+2]
Agent: O=O
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCOC(C)=O)=C(C)C1=O

Procedure:
To a methanol solution (30 ml) of 6-(9-acetoxynonyl)-2,3-dimethoxy-5-methylphenol (1.1 g) are added pyridine (0.3 ml) and bis(salicylidene)ethylenediiminocobalt(II) (14 mg), followed by stirring in oxygen streams at atmospheric temperature and pressure for 72 hours. The reaction product is isolated as in Example 7 and recrystallized from hexane. The above procedure yields 6-(9-acetoxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as orange-yellow needles melting at 30° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)=[CH:3][CH:2]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>CC#N.FC(F)(F)C(O)=O>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:11]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=2)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)[nH]n1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2ccc(C)cc2)n(C2CCCCO2)n1
Yield: 117.3 %

Procedure:
A mixture of methyl 5-p-tolyl-1H-pyrazole-3-carboxylate (224 mg, 1.03 mmol), 3,4-dihydro-2H-pyran (190 μL, 2.07 mmol) and trifluoroacetic acid (2 μL, 0.02 mmol) in anhydrous MeCN (3 mL) was refluxed for 2 hrs. The solvent was evaporated. The residue was resuspended in CH2Cl2 (50 mL) and was washed with H2O and brine. After drying with Na2SO4, solvent evaporation and silica gel column chromatography (PE-EtOAc, 6:4) methyl 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylate (363 mg, 68%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:26])[N:11]([CH2:19][CH:20]([OH:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]([CH3:18])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:23][C:21]([CH3:22])([CH3:24])[C:20](=[O:25])[CH2:19][N:11]1[C:10](=[O:26])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][C:36](=[O:38])[O:35][N:34]=3)=[CH:3][C:2]=2[F:1])=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]=[C:12]1[CH3:18]
Reactant: CCCc1nc(C)n(CC(O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A mixture of 5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-propylpyrimidin-4(3H)-one (0.28 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.34 g) and methylene chloride (15 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate pentahydrate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:41])=[N:17][C:18]([CH3:40])=[C:19]([C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([O:32]CC)=[O:31])[C:20]=2[N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CCO.O>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]([CH3:41])=[N:17][C:18]([CH3:40])=[C:19]([C@H:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:30]([OH:32])=[O:31])[C:20]=2[N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3)nc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccccc2)nc1
Yield: 68 %

Procedure:
A solution of (S)-ethyl 2-(6′-(benzyloxy)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)-2-(tert-butoxy)acetate (0.014 g, 0.025 mmol) and LiOH (5.99 mg, 0.250 mmol) in 9:1 EtOH/H2O (2 mL) was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(6′-(benzyloxy)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-[3,3′-bipyridin]-5-yl)-2-(tert-butoxy)acetic acid (0.0089 g, 0.017 mmol, 66.9% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=2.2 Hz, 0.5H), 7.99 (d, J=1.7 Hz, 0.5H), 7.46-7.54 (m, 3H), 7.33-7.45 (m, 3H), 6.94 (dd, J=5.8, 8.4 Hz, 1H), 5.93 (br. s., 1H), 5.40-5.55 (m, 2H), 3.40-3.70 (m, 0.5H), 2.74-3.11 (m, 0.5H), 2.67 (s, 3H), 2.28 (s, 1.5H), 2.25 (s, 1.5H), 1.94-2.20 (m, 1H), 1.27-1.40 (m, 4H), 1.25 (s, 4.5H), 1.24 (s, 4.5H), 0.80 (br.s., 6H). LCMS (M+H)=532.4.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCC2(CC1)OCCO2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(C2=CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.3 %

Procedure:
To a solution of Intermediate 3A (1.87 g, 6.19 mmol) and Et3N (1.724 mL, 12.37 mmol) in DCM (30 mL) was added a solution of methanesulfonyl chloride (0.53 mL, 6.8 mmol) in DCM (10 mL) over 1 h at rt. The reaction mixture was stirred at rt for 2.5 h. Additional Et3N (1.724 mL, 12.37 mmol) and methanesulfonyl chloride (0.53 mL, 6.8 mmol) were added and stirred for another 1 h. The reaction mixture was partitioned between 1 N HCl and DCM. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give Intermediate 3B (1.7 g, 5.9 mmol, 97% yield). LC-MS (ESI) m/z 285 (M+H), RT=3.43 min (Method C).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:34]([CH3:35])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[Cl:36]>>[Cl:36][C:28]1[CH:29]=[C:30]([C:31]#[N:32])[CH:33]=[C:34]([CH3:35])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: Cc1cc(C#N)cc(Cl)c1N
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3c(C)cc(C#N)cc3Cl)cnc(OC)c2o1
Yield: 42.6 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (200 mg) and 4-amino-3-chloro-5-methylbenzonitrile (195 mg). Purification by column chromatography on silica eluting with 2% methanol in dichloromethane gave the title compound (92 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:30])[C:12]([OH:29])=[C:13]([C:15]([NH:17][CH2:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:16])[N:14]=[C:3]21.[CH3:31][N:32]([CH3:38])[C:33](=[O:37])[C:34](O)=[O:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:19](=[O:28])[CH2:18][NH:17][C:15]([C:13]2[N:14]=[C:3]3[C:2]4([NH:1][C:34](=[O:35])[C:33]([N:32]([CH3:38])[CH3:31])=[O:37])[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]4)[CH2:5][N:4]3[C:11](=[O:30])[C:12]=2[OH:29])=[O:16])=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCC(=O)Cc2ccc(F)cc2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCC(=O)Cc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 10-amino-N-(3-(4-fluorophenyl)-2-oxopropyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide, Intermediate 14 (318 mg, 0.705 mmol) in DMF (8 mL) were added 2-(dimethylamino)-2-oxoacetic acid (165 mg, 1.411 mmol), N,N-diisopropylethylamine (0.739 mL, 4.23 mmol), HATU (536 mg, 1.411 mmol) and DMAP (17.23 mg, 0.141 mmol) and the resulting mixture was stirred at room temperature for 3 h. The mixture was then purified by preparative HPLC to afford the title compound (210 mg, 0.409 mmol, 58.0% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 11.67 (1H, br. s.), 8.54 (1H, t, J=5.49 Hz), 8.03 (1H, s), 7.19 (2H, dd, J=8.55, 5.19 Hz), 6.99-7.05 (2H, m), 4.26 (2H, d, J=5.49 Hz), 4.17 (2H, d, J=3.97 Hz), 3.77 (2H, s), 3.28 (3H, s), 2.92 (3H, s), 2.46-2.57 (5H, m), 2.09-2.17 (2H, m), 1.91-2.01 (2H, m), 1.67-1.77 (2H, m). LCMS (M+H)=514.26.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:7]=1.F[C:18]1C=C(C)C=CC=1C#N>>[F:16][C:5]1[CH:4]=[C:3]([CH3:18])[CH:2]=[CH:7][C:6]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: O=C(O)c1csc(-c2cc(Br)ccc2F)n1
Product: Cc1ccc(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 129, replacing 5-bromo-2-fluoro-benzonitrile with 2-fluoro-4-methylbenzonitrile gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=2[CH:30]=1)=[NH:19].C(N=C=NCCCN(C)C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=4[CH:30]=3)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: N=C(NO)c1ccc2oc(CO)cc2c1
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3ccc4oc(CO)cc4c3)no2)cc1OCC
Temperature: 120 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
A mixture of 3,4-diethoxybenzoic acid (0.21 g; 1 mmol), the product of Step C (0.2 g; 0.97 mmol) and hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.22 g; 1.15 mmol) in anhydrous dimethylsulfoxide (DMSO) (2 ml) was stirred for 20 min at ˜40° C. under N2. To it 1 M tetra-n-butylammonium fluoride (TBAF) in terahydrofuran (THF) (0.4 ml) was added and the resulting mixture was stirred for 1 h at ˜120° C., then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H2O (5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.13 g; 34%), as greyish solid. 1H-NMR (CDCl3) 8.36 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 9 Hz); 7.79 (dd, 1H, J=3, 9 Hz); 7.68 (d, 1H, J=3 Hz); 7.55 (d, 1H, J=9 Hz); 6.98 (d, 1H, J=9 Hz); 6.73 (s, 1H); 4.8 (s, 2H); 4.2 (m, 4H); 2.02 (s, 1H); 1.51 (m, 6H);
Reaction SMILES: B(O)O.[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][N:6]=1.N1C=CC=CC=1.CC1N([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)N=C(C(OCC)=O)C=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:4][C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=3)[CH:28]=2)[N:6]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccc3cc(OC)ccc3c2)n1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C)nn1-c1ccc2cc(OC)ccc2c1
Reaction time: 96 h
Yield: 37 %

Procedure:
To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was stirred for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (×2), dried, concentrated and purified by flash column to separately afford ethyl 3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc:hexane). ES-MS: (M+H)+311] and ethyl 5-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-3-carboxylate [25% yield. Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)+311]in a 1.5:1 ratio.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[N:42]1[CH2:48][CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH3:29]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:45]2[CH2:46][CH2:47][CH2:48][N:42]([C:34]3[N:33]([CH2:32][CH2:31][O:30][CH2:28][CH3:29])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)[CH2:43][CH2:44]2)([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: CS(=O)(=O)OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccccc4)CCN(Cc4ccccc4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=O)[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N)CCCC>ClCCl>[CH2:33]([NH:32][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: c1ccncc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCN
Product: CCCCCNC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
A 5-L, 3-necked flask was charged with N-CBZ-L-serine (110 g, 0.46 mole) (CBZ=carbobenzyloxy) followed by dichloromethane (2.1 L). The resulting slurry was stirred under argon and treated with triethylamine (61.7 mL, 0.443 mole) over several minutes. The resulting hazy solution was cooled to an internal temperature of -35° and treated over 10 min with trimethylacetylchloride (51.06 mL, 0.415 mole) such that the internal temperature did not rise above -30°. The reaction was stirred an additional 40 min at -25° to -30°, treated with pyridine (35.2 mL, 0.435 mole) over 5 min and stirred an additional 10 min. Amylamine (51 mL, 0.44 mole) was added over 10 min while maintaining the internal temperature at -25° to -29°. The reaction was stirred for 30 min while warming to -25°. A precipitate formed during this warming. The reaction was further warmed to -10° over 40 min during which time the precipitate redissolved. After stirring an additional 20 min at -10°, the reaction was quenched by the addition of 500 mL of 1N HCl. The biphasic mixture was stirred for 20 min and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (2×75 mL). The combined dichloromethane solutions were concentrated in vacuo to a weight of 500 g. Ethyl acetate (EtOAc) (2.25 L) was added and the organic solution was washed with 1N HCl (2×400 mL) and 1N K2CO3 (1×700 mL and 2×500 mL). The organic solution was dried (magnesium sulfate), filtered and concentrated in vacuo to the title compound which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:12]3[CH:21]=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]=3[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[CH:9][C:8]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:7][N:6]=1.[OH-].[K+].O>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.O1CCOCC1>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[C:10]([C:11]2[C:12]3[CH:21]=[CH:20][NH:19][C:13]=3[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)=[CH:9][C:8]([CH2:32][S:33]([CH3:36])(=[O:34])=[O:35])=[CH:7][N:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(CS(C)(=O)=O)cnc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(CS(C)(=O)=O)cnc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 100 °C
Yield: 56.9 %

Procedure:
The product from Example 311f (0.083 g, 0.138 mmol), potassium hydroxide (0.194 g, 3.46 mmol) and N,N,N-trimethylhexadecan-1-aminium bromide (2.52 mg, 6.92 μmol) were combined in dioxane (1.8 mL)/water (0.9 mL) and heated at 100° C. for 4 hours, cooled, and partitioned into ethyl acetate adjusting the pH to 7 with 1 M HCl. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-4% methanol in dichloromethane) afforded the title compound (0.035 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.14 (s, 1H) 8.03 (dd, J=22.74, 2.29 Hz, 2H) 7.30-7.51 (m, 4H) 7.03-7.17 (m, 1H) 6.39 (d, J=2.14 Hz, 1H) 4.57 (s, 2H) 3.60 (s, 3H) 3.00 (s, 3H). MS (ESI+) m/z 446 [M+H]+.
Reaction SMILES: [H-].[Na+].Br[CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=2)[O:6][C:5]1([CH3:25])[CH3:24]>CS(C)=O>[O:14]1[CH:13]2[CH:4]1[C:5]([CH3:25])([CH3:24])[O:6][C:7]1[C:12]2=[CH:11][C:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:9][CH:8]=1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C(O)C1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C2OC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 ml of absolute DMSO are added 1.8 g (0.06 mol) of NaH as an 80% strength suspension in oil and, dropwise, 20 g of 3-bromo-4-hydroxy-2,2-dimethyl-6-phenylsulfonylchroman, dissolved in 80 ml of DMSO, the reaction temperature being kept at 25°-28° C. After stirring at room temperature for 2 hours, the mixture is stirred into ice water and the resulting precipitate is filtered off with suction. Further purification can be achieved by dissolving the crude product in ethyl acetate and treating it with active carbon. After evaporating the solvent, the residue is treated with diisopropyl ether until crystallization starts. Yield: 14.5 g; m.p.: 103°-105° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc([N+](=O)[O-])cc1N
Product: COc1ccc([N+](=O)[O-])cc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-5-nitroaniline to yield 2-[(2-methoxy-5-nitrophenyl)amino]phenylacetic acid.