Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:21]([F:22])=[C:20]([O:23]C)[C:19]([F:25])=[C:18]([F:26])[C:4]=1[C:5]([C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=[O:6]>C(O)(=O)C.Br>[OH:2][C:3]1[C:21]([F:22])=[C:20]([OH:23])[C:19]([F:25])=[C:18]([F:26])[C:4]=1[C:5]([C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17])=[O:6]
Reactant: COc1c(F)c(F)c(C(=O)c2c(F)c(F)c(F)c(F)c2F)c(OC)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1c(O)c(F)c(O)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Yield: 86.4 %

Procedure:
A solution of Compound 45 (450 mg, 1.17 mmol) in 5 mL acetic acid and 5 mL 48% hydrobromic acid is heated for 48 hours at reflux. The reaction mixture is worked up as above, and the crude product is purified by column chromatography to yield 362 mg (87%) of Compound 46 as a colorless solid. 19F-NMR (d6 -DMSO) 139.80 (m, 1 F); 141.69 (dd, J=10.0, 20.1 Hz, 1 F); 143.05 (dt, J=5.8, 23.1 Hz, 1 F); 155.48 (dd, J=10.2, 22.8 Hz, 1 F); 155.67 (s, 1 F); 156.27 (dd, J=5.8, 20.5 Hz, 1 F); 158.57 (t, J=22.2 Hz, 1 F); 162.5 (b, 1 F).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:27]([CH3:31])[C:28]([OH:30])=[O:29].C1(O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:27]([CH3:31])[C:28]([OH:30])=[O:29])=[CH:9][CH:10]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Solvent: C1COCCO1
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Reaction time: 4 h

Procedure:
28.9 g of 4-(2-chloro-4-trifluoromethylphenoxy)phenol was added to 50 ml of dioxane, and with stirring at 30° to 40° C., 13.8 g of potassium carbonate was added. The mixture was heated to 40° to 60° C., and 10.8 g of α-chloropropionic acid was added. The reaction was performed for 4 hours. The disappearance of the starting phenol was confirmed by gas chromatography, and the reaction product was poured into a suitable amount of water. Sodium carbonate was added to transfer the final product into the aqueous phase. The oily phase was separated and removed, and then hydrochloric acid was added to afford 20 g of a solid precipitate. The final product obtained had a melting point of 90° to 92° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:26][N:27]([CH3:39])[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([C:33]5[CH:34]=[CH:35][C:30]([C:28]([N:27]([CH3:39])[CH3:26])=[O:29])=[CH:31][CH:32]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Yield: 19.5 %

Procedure:
1-(Benzo[d][1,3 ]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropane-carboxamide (40 mg, 0.10 mmol), 4-(dimethylcarbamoyl)phenylboronic acid (29 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 20%). ESI-MS m/z calc. 467.2, found 468.5 (M+1)+; retention time 2.96 minutes.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH2:32][CH3:33]>>[CH2:32]([N:31]([CH3:30])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:33]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C22H20FN5O2, 405.2
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]1[C:14](=O)[N:13](Br)[C:11](=O)[CH2:10]1.CC(N=NC(C#N)(C)C)(C#N)C.C(NCC)C>C(Cl)(Cl)(Cl)Cl>[CH2:11]([N:13]([CH2:14][CH3:9])[CH2:8][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(I)ccn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCNCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC)Cc1cc(I)ccn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Combine 4-iodo-2-methyl-pyridine (1.1 g, 5 mmol), NBS (0.98 g, 1.1 equiv.) and carbon tetrachloride (50 mL) in a round bottomed flask under nitrogen. Add AIBN (82 mg, 0.1 equiv.) and heat reaction overnight at reflux. Filter the reaction, washing with hexanes. Concentrate filtrate to approximately 10-20 mL volume. Redissolve in THF (20 mL) and cool to 0° C. under nitrogen. Add diethylamine (1.04 mL, 2 equiv.) dropwise via syringe and stir one hour at 0° C. Remove cooling bath and let warm to room temperature. After 6 hours total, concentrate to dryness and purify by silica gel (1:1 Hexanes:Ethyl Acetate→Ethyl Acetate) to give a tan liquid (0.51 g, 35% over 2 steps). MS (ES), m/z 291.0 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:10]=1
Reactant: [O-][n+]1c(CCCCCCCCCCCO)cc(OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: [O-][n+]1c(CCCCCCCCCCCO)cc(O)c2ccccc21
Yield: 57.5 %

Procedure:
In this example, 4-benzyloxy-2-(11-hydroxyundecyl) quinoline-N-oxide is dissolved in methanol and catalytically reduced with a catalyst of 10% palladium-carbon under the atmospheric pressure. Then, the catalyst is removed therefrom by filtration, and the solvent is also removed therefrom by distillation. The residue is recrystallized from ethanol, whereby the cationed compound is obtained (yield: 57.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21](Br)([CH3:23])[CH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)Br
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C(C)C

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isopropyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(2-propyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>CS(O)(=O)=O.C1(C)C=CC=CC=1>[C:14]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:15])[C:13]1[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:21]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCC
Yield: 103.4 %

Procedure:
567 g of nonyl alcohol produced in Example 1 was combined with 280 g of phthalic anhydride, 200 g of toluene and 5.5 g of methanesulfonic acid. The reaction was set up for reflux through a Dean-Stark trap using a nitrogen purge and slow stirring. The reactor contents were refluxed for 5 hours. Residual catalyst was neutralized with a 10% NaCO3 solution and the product was water washed. The product was purified by vacuum stripping and distillation to yield 818 g of dinonyl phthalate.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.Br[C:30]1[CH:31]=[CH:32][C:33]([O:53][C:54]([F:57])([F:56])[F:55])=[C:34]([NH:36][C:37]2[N:46]=[CH:45][C:44]3[CH2:43][CH2:42][C:41]4[C:47]([C:50]([NH2:52])=[O:51])=[N:48][NH:49][C:40]=4[C:39]=3[N:38]=2)[CH:35]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:68][N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:68][N:69]1[CH2:74][CH2:73][N:72]([C:30]2[CH:31]=[CH:32][C:33]([O:53][C:54]([F:57])([F:56])[F:55])=[C:34]([NH:36][C:37]3[N:46]=[CH:45][C:44]4[CH2:43][CH2:42][C:41]5[C:47]([C:50]([NH2:52])=[O:51])=[N:48][NH:49][C:40]=5[C:39]=4[N:38]=3)[CH:35]=2)[CH2:71][CH2:70]1
Reactant: NC(=O)c1n[nH]c2c1CCc1cnc(Nc3cc(Br)ccc3OC(F)(F)F)nc1-2
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(OC(F)(F)F)c(Nc3ncc4c(n3)-c3[nH]nc(C(N)=O)c3CC4)c2)CC1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3, (2.3 g, 2.5 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (950 mg, 2.4 mmol), 8-[5-bromo-2-trifluoromethoxy-phenylamino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (14.8 g, 31.54 mmol) in THF (160 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 630 mL) and N-methylpiperazine (69 mL, 50.64 mmol) were added and the reaction mixture refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/MeOH 95/5) to afford 9.2 g (60% yield) of the title compound.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12](O)=[C:11](O)[CH:10]=1)=[O:8])([CH3:4])[CH3:3].C(Cl)(=O)CCCCCCCCC=CCC=CCCCC>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: CCCCC=CCC=CCCCCCCCCC(=O)Cl
Agent: Cl
Product: CC(C)NCC(=O)c1ccccc1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 10,13-octadecadienoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(10,13-octadec a dienoyloxy) phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesuflonate is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate. By catalytic hydrogenation of 3-hydroxy-4-(10,13-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([O:9]C)=[O:8])=[CH:5][N:6]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: COC(=O)c1cnc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(Br)s1

Procedure:
A mixture containing 10 g. of 2-bromo-5-methoxycarbonylthiazole, 100 ml. of 10% aqueous sodium hydroxide and 200 ml. of methanol is stirred at 0° C for 5 minutes. The methanol is distilled off in vacuo and the resulting concentrate extracted twice with ethyl acetate. The remaining aqueous phase is acidified by the careful addition of dilute aqueous hydrochloric acid resulting in the formation of a precipitate which is then recovered by filtration and dried under vacuum yielding 2-bromo-5-carboxythiazole.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[CH:22][CH:21]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].CC([C:43]1C=C(N2CCOC[C@@H]2C)N=C(C2C=CC(NC(=O)OC3C=CC=CC=3)=CC=2)[N:44]=1)(S(C)(=O)=O)C>>[CH3:43][NH:44][C:27](=[O:28])[NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:9]=[C:8]([C:2]([S:4]([CH3:7])(=[O:5])=[O:6])([CH3:3])[CH3:1])[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1)S(C)(=O)=O
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOCC3)cc(C(C)(C)S(C)(=O)=O)n2)cc1

Procedure:
The following compounds were prepared in analogous fashion from either phenyl (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)carbamate or phenyl (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)carbamate and the appropriate amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=O)[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.CO.O.C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)N(c2cccc(Br)c2)C1=O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCN(c2cccc(Br)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
1-(3-Bromophenyl)-3,3-dimethyl-pyrrolidine-2,5-dione (10.6 g, 37.7 mmol) was suspended in 200 ml of THF. Borane dimethyl sulfide complex (33 ml of a 10.1 M solution) was added and the reaction was stirred at room temperature for 3 hrs. The reaction was cooled in an ice bath. Methanol (100 ml) was added dropwise, followed by 300 ml of water. This mixture was transferred to a separatory funnel and DCM was added. The organic phase was isolated, washed with brine, filtered through Celite and concentrated. The product was chromatographed using a gradient of 0% to 5% ethyl acetate in hexanes, concentrated, triturated with methanol and filtered to give 8.0 g (84%) of 1-(3-bromophenyl)-3,3-dimethyl-pyrrolidine.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].CON(C)[C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=1>C1COCC1>[CH3:7][N:6]1[C:2]([C:18]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)=[O:29])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Cn1cncc1Br
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 5.300000190734863 °C
Reaction time: 1 h

Procedure:
To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex [1.3 M in THF] (246.8 mL, 320.8 mmol) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 36: step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2N aqueous HCl to a pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase split and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered, and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.
Reaction SMILES: C[N:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)[NH:3]1.[OH-].[Na+].Cl.[CH3:25]O>C1COCC1>[CH3:25][N:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[N:5][N:6]=[N:2]1
Reactant: CO
Reactant: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nnnc1-c1ccc2c(c1)C=C(C(=O)O)CCO2
Temperature: 50 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
In methanol (3 ml) and THF (3 ml) was dissolved methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (76 mg, 0.27 mmol), and to the mixture was added 1N sodium hydroxide solution (0.8 ml). The mixture was stirred at 50° C. for 4 hours, and to the mixture was added, under ice-cooling, 1N hydrochloric acid (0.8 ml). The mixture was concentrated under reduced pressure, and to the residue was added water. Insoluble materials were filtered, which were washed with water and dried under reduced pressure to give 7-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (69 mg, 0.25 mmol, 95%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>[Cu]I.O.CS(C)=O>[F:9][C:4]1[CH:3]=[C:2]([S:11]([CH3:10])(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)cc1F
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(N)c(F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
4-bromo-2-fluoroaniline (10.0 g, 52.62 mmol, 1.0 eq), sodium methansulfinate (9.5 g, 1.5 eq), copper(I) iodide (1.0 g, 0.1 eq), L-Proline (1.2 g, 0.2 eq) and sodium hydroxide (0.4 g, 0.2 eq) were placed in a sealed tube, and dimethylsulfoxide (100 mL) was added thereto. The reaction mixture was stirred at 90° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added thereto, followed by extraction three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound was purified using column chromatography (MC:MeOH=50:1) to obtain the title compound (9.9 g).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18](Cl)([F:20])[F:19])=O)(C)(C)C.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>>[Br:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C:18]([F:19])([F:20])[O:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:31])[F:32])=[CH:25][CH:26]=3)=[N:10][C:11]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)n1c(C(F)(F)Cl)nc2cc(Br)ccc21
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(OC(F)(F)c2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-2-(chloro-difluoro-methyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (1.00 g, 2.62 mmol), 4-trifluoromethyl-phenol (0.42 g, 3.93 mmol), and N,N-diisopropylethylamine (0.6 mL, 3.44 mmol) was heated to 85° C. for 14 hours. The crude product was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a yellow oil (0.58 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([F:8])[C:3]=1[OH:9]
Reactant: Oc1c(F)cccc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(O)c(Cl)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A solution of 2-chloro-6-fluorophenol (1.0 g, 6.82 mmol) in concentrated acetic acid (3.0 mL) was cooled to 0° C. Fuming nitric acid (559 mg, 8.87 mmol) was added dropwise, maintaining the reaction temperature between 10 to 20° C. The reaction was allowed to stir at 0° C. for 3 h. The mixture was poured over ice and was allowed to warm to room temperature. The aqueous was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude red solid was purified using the Biotage Quad 4 (25 M column) eluting with 9:1 Hexanes/EtOAc to afford the title compound as a yellow solid (326 mg, 1.70 mmol; 25% yield). 1H-NMR (DMSO-d6) δ 11.74 to 12.77 (broad s, 1H), 8.10 to 8.16 (m, 2H).
Reaction SMILES: C(OC([O:7][CH2:8][C:9]1[CH:54]=[CH:53][CH:52]=[CH:51][C:10]=1[C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12])=O)C=C.C([SnH](CCCC)CCCC)CCC.C(OCC)(=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[OH:7][CH2:8][C:9]1[CH:54]=[CH:53][CH:52]=[CH:51][C:10]=1[C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12]
Reactant: C=CCOC(=O)OCc1ccccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1CO)c1ccc(F)cc1F
Yield: 81 %

Procedure:
A chemical reaction was carried out according to a similar procedure to that described in Example 11-(4) using (1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 2-[(allyloxycarbonyl)oxymethyl]benzoate (1.52 g, 2.00 mmol), bis(triphenylphosphine)dichloropalladium (5 mg), and tributyltin hydride (620 mg, 2.13 mmol). The obtained crude product was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:1˜1:0) to afford the title compound (1.096 g, 81% yield) as a colorless amorphous solid.