Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(F)c(Cl)c3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(F)c(Cl)c3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole (60 mg, 0.16 mmol) and 1,2,4-benzenetricarboxylic anhydride (31 mg, 0.16 mmol) the title compound was obtained (75 mg, 86%). 1H NMR (DMSO) δ 13.80(s, 1H), 8.43(d, 1H), 8.32(s, 1H), 8.21(d, 1H), 8.15(s, 1H), 8.10(d, 1H), 7.99(dd, 1H), 7.88(d, 1H), 7.75(m, 3H), 7.53(t, 1H), 7.47(d, 1H), 4.03(s, 3H). MS 542.6 m/z (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]1[C@H:30]2[C@H:26]([O:27][CH2:28][CH2:29]2)[O:25][CH2:24]1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33]1.C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]([O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][CH:9]([OH:19])[CH:8]([NH:20][C:21](=[O:31])[O:22][C@@H:23]3[C@H:30]4[C@H:26]([O:27][CH2:28][CH2:29]4)[O:25][CH2:24]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[O:34][CH2:33]1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCOCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1)C(O)CN(OC1CCOCC1)S(=O)(=O)c1ccc2c(c1)OCO2)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-2-hydroxy-3-[(tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate (0.23 mmol, 100 mg) was combined 1,3-benzodioxole-5-sulfonyl chloride (0.28 mmol, 61 mg), diisopropylethylamine (0.69 mmol, 0.12 mL) in anhydrous THF (2 mL) and allowed to stir 72 hours at room temperature under nitrogen. The reaction was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate solution, brine and was dried over magnesium sulfate. The solution was concentrated under vacuum and the crude product was purified by silica gel chromatography (1:5 hexanes/ethyl acetate). The purified oil was crystallized to provide 55 mg (39%) of white crystals. Rf=0.2 (1:5 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.38-7.13 (9H,m), 6.90 (1H,d), 6.10 (2H,s), 5.64 (1H,s), 5.02 (1H,m), 4.82 (1H,m), 4.41 (1H,m), 3.99-3.79 (6H,m), 3.72-3.59 (2H,m), 3.49-3.33 (2H,m), 3.25-2.51 (6H,m), 2.09-1.98 (2H,m), 1.69-1.43 (2H,m). MS (ESI): M+H=621.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:31])([F:30])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([CH:27]([F:29])[F:28])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[N:19][C:14]([C:13]([F:31])([F:12])[F:30])=[CH:15][CH:16]=1)[CH2:23][C:24]1([CH:27]([F:28])[F:29])[CH2:25][CH2:26]1)=[O:6]
Reactant: NCC(CC1(C(F)F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-trifluoromethyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=467.1, tR (minutes, Method G)=2.62
Reaction SMILES: [OH:1][N:2]=[CH:3][CH2:4][O:5][C@@H:6]([C@@H:10]1[CH2:14][CH2:13][CH2:12][O:11]1)[CH2:7][CH:8]=[CH2:9].C[C@@H]1C[C@H]1C1OCC2=NOCC2C1>>[O:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C@@H:6]1[O:5][CH2:4][C:3]2=[N:2][O:1][CH2:9][C@@H:8]2[CH2:7]1
Reactant: C=CC[C@@H](OCC=NO)[C@@H]1CCCO1
Agent: C[C@@H]1C[C@H]1C1CC2CON=C2CO1
Product: C1CO[C@H]([C@H]2C[C@H]3CON=C3CO2)C1

Procedure:
N-Hydroxy-2-({(1R)-1-[(2S)-tetrahydrofuran-2-yl]but-3-en-1-yl}oxy)ethanimine (C98) was converted to the product using the method described for the synthesis of 5-[(1R,2R)-2-methylcyclopropyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C85) in Example 20. Yield: 2.6 g, 13 mmol, 54%. LCMS m/z 198.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 4.73 (d, J=13.1 Hz, 1H), 4.61 (dd, J=10.0, 8.0 Hz, 1H), 4.19 (dd, J=13.6, 1 Hz, 1H), 3.72-3.89 (m, 4H), 3.38-3.48 (m, 2H), 2.35 (ddd, J=12.9, 6.4, 1.3 Hz, 1H), 1.78-2.02 (m, 4H), 1.44-1.53 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: O=C1NCCCn2c1cc1cc(O)ccc12
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Yield: 13 %

Procedure:
The title compound was synthesized in analogy to example 1, from 9-hydroxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow oil (13%).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C@@H:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:25][C@@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccccc1-c1ccccc1
Product: c1ccc(-c2ccccc2CN[C@H]2CCCc3ccccc32)cc1

Procedure:
[1,1′-Biphenyl]-2-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C[O:12][C:13]([CH3:15])=[CH2:14].[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]([O:12][CH:13]([CH3:15])[CH3:14])[O:5][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(C)OC
Reactant: OCc1ccc(Br)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(OC(C)C)c1ccc(Br)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2,4-dibromobenzyl alcohol (40 g, 0.15 mol) in tetrahydrofuran (300 ml) was added 2-methoxypropene (144 ml, 1.5 mol) at room temperature and then the mixture was cooled to 0° C. At the same temperature, pyridinium p-toluenesulfonic acid (75 mg, 0.30 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate cooled to 0° C., and extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the titled compound as an oil in quantitative yield. The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4]/[CH:5]=[CH:6]\[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].BrC/C=C\[Sn](CCCC)(CCCC)CCCC.N1CC[C@H]([O:44][C:45](=[O:47])[CH3:46])C1>>[CH2:8]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]\[CH2:4][N:3]1[CH2:1][CH2:2][C@H:21]([O:47][C:45](=[O:44])[CH3:46])[CH2:20]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: CC(=O)O[C@H]1CCNC1
Agent: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Product: CCCC[Sn](/C=C\CN1CC[C@H](OC(C)=O)C1)(CCCC)CCCC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 3, starting from ((Z)-3-bromoprop-1-en-1-yl)-tributyl-stannane (Intermediate 2) and acetic acid (S)-pyrrolidin-3-yl ester.
Reaction SMILES: [CH2:1]1[N:8]([CH2:9][CH2:10][NH+:11]([CH2:22][C:23]([O-:25])=[O:24])[CH2:12][CH2:13][N:14]2[CH2:21][C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]2)[CH2:7][C:5](=[O:6])[O:4][C:2]1=[O:3].C1CN2C(=NCCC2)C1.[NH2:35][NH2:36]>CS(C)=O>[C:16]([CH2:15][N:14]1[CH2:21][C:19](=[O:20])[NH:36][NH:35][C:5](=[O:6])[CH2:7][N:8]([CH2:1][C:2]([OH:4])=[O:3])[CH2:9][CH2:10][N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:12][CH2:13]1)([OH:18])=[O:17]
Reactant: NN
Reactant: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Agent: C1CN=C2CCCN2C1
Solvent: CS(C)=O
Product: O=C(O)CN1CCN(CC(=O)O)CC(=O)NNC(=O)CN(CC(=O)O)CC1
Reaction time: 48 h

Procedure:
A 500 mL three-neck flask is charged with 150 mL of dry DMSO and flushed with nitrogen. Two syringes are charged separately with solutions of diethylenetriaminepentaacetic acid dianhydride (2.82 g, 7.89 mmol) and DBN (2.94 g, 2.92 mL, 23.67 mmol) in 122 mL of DMSO and anhydrous hydrazine (0.25 g, 0.25 mL, 7.89 mmol) in 125 mL DMSO. The two solutions are added simultaneously at the rate of 40 mL/hour to the flask at ambient temperature, employing a syringe pump. After the completion of addition the reaction mixture is stirred for 48 hours, concentrated under vacuum to 10 mL, and water (10 mL) is added. The solution at pH 10.5 is applied to AGIX-8 (100-200 mesh, acetate form) resin and the column is eluted with 1N acetic acid. The product is obtained by removal of acetic acid, followed by lyophilization.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:34][S:35]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOS(C)(=O)=O)C2
Reaction time: 0.25 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.95 g) and triethylamine (1.11 ml) in acetonitrile (20 ml) was dropwise added methanesufonyl chloride (0.494 ml) with cooling with ice. After the stirring was continued for 15 min, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (2.36 g) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10]Cl)[C:4]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1>[Cl-].[Zn+2].[Cl-]>[Cl:13][C:14]1[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([OH:20])=[C:18]([CH:19]=1)[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10][C:18]2[CH:19]=[C:14]([Cl:13])[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[C:17]=2[OH:20])[C:4]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: Oc1c(CCl)cc(Cl)cc1CCl
Agent: [Cl-]
Agent: [Zn+2]
Product: O=[N+]([O-])c1cc(Cl)cc(Cc2cc(Cl)cc(Cc3cc(Cl)cc([N+](=O)[O-])c3O)c2O)c1O
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Zinc chloride (2 g) was added in small portions over 75 min to a melt of 2,6-bis(chloromethyl)-4-chlorophenol (1.2 g) and 4-chloro-2-nitrophenol (3 g) at a temperature of 120°. The mixture was stirred at this temperature for approximately 1 hr. The black product was extracted several times with acetone and the extract filtered to remove black inorganic material. The acetone was removed by distillation under reduced pressure and the residue chromatographed on silica gel. Elution with hexane containing 3% ethyl acetate gave unreacted 4-chloro-2-nitrophenol and elution with hexane containing 20% ethyl acetate gave the title compound (0.5 g) which was recrystallised from aqueous ethanol; m.p. 200°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[CH3:41].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:30]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([CH3:34])[CH:36]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH3:29])=[O:27])#[N:31]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(C#N)cc21
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Temperature: 100 °C
Yield: 95.6 %

Procedure:
A vial was charged with methyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (51 mg, 0.100 mmol), 3,4-dimethylphenylboronic acid (19.5 mg, 0.130 mmol), Na2CO3 (31.9 mg, 0.300 mmol), toluene (1 mL) and water (0.1 mL). The mixture was degassed with Argon for few minutes, and then Pd(PPh3)4 (5.8 mg, 0.005 mmol) was added. The vial was sealed and heated at 100° C. for 16 hours. The reaction was cooled and the crude material was purified by silica gel column chromatography to provide the desired product (0.051 g, 95%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]CC1C=CC=CC=1)[C:6]#[N:7])[CH3:2]>CCOC(C)=O.CCO.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7])[CH3:2]
Reactant: CCc1cc(C#N)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
3-ethyl-4-[(phenylmethyl)oxy]benzonitrile (Intermediate 112, 334 mg) was dissolved in 15 mL of EtOAc/EtOH (2/1) and 10% mol Pd/C (0.1 equiv) was added to the solution. The resulting mixture was stirred overnight at room temperature under hydrogen gas atmosphere. The reaction mixture was filtered under argon and the solvent was removed. The residue obtained was purified by chromatography on silica gel (Companion system, 40 g Si cartridge) using as eluent a gradient cyclohexane/ethyl acetate from 100:0 to 80:20. Evaporation afforded the title compound (148 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH3:34]>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH3:34])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.52 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 6.65 (s, 1H), 5.46 (s, 2H), 2.60 (s, 3H), 2.53 (s, 3H); MS (ES) m/z 480 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[I-].CN1C=C[N+]([C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=C1.C(N(CC)CC)C.O>ClCCl>[N:19]1([C:17]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CC2CNCC2C1
Reactant: Cn1cc[n+](C(=O)N2CCCCC2)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1CC2CN(C(=O)N3CCCCC3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL of dichloromethane, and 1-methyl-3-(piperidine-1-carbonyl)-1H-imidazol-3-ium iodide (0.96 g, 3 mmol) and triehtylamine (0.84 mL, 6 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 20 mL of water was then added to the mixture to quech the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(piperidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 4a (0.41 g, yield 87%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH3:22])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])C>C(O)C>[CH3:22][O:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(COC)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1ccc(-n2ncc(C(=O)O)c2C)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
1N Aqueous solution of sodium hydroxide (7.0 ml) was added at room temperature to a solution of 1-[4-(methoxymethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (401 mg) in ethanol (14 ml) and stirred at 70° C. for two hours. After completion of the reaction, ethanol was evaporated, water and 1N hydrochloric acid aqueous solution was added therein and the precipitated solid was collected by filtration to give the titled compound (314 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([CH3:14])=[O:13].ClC1C=C(C=CC=1)C(OO)=[O:20].C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([CH3:14])(=[O:20])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
A solution of 1,5-dichloro-2-(methylsulfinyl)-4-nitrobenzene (1.0 g, 3.9 mmol) in dichloromethane (50 ml) was added 3-Chloroperoxybenzoic acid (1.7 g, 9.8 mmol). The mixture was stirred under nitrogen at room temperature for 3 h. The mixture was added saturated aqueous NaHCO3 (20 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (2:1) to give 1 g (100%) of the title compound as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH:11]=[C:10]([CH3:13])[NH:9][C:8](=[O:14])[C:7]=2[CH:15]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:28]N1C(=O)CCC1=O>CC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][N:9]1[C:8](=[O:14])[C:7]2[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:12][CH:11]=[C:10]1[CH2:13][Cl:28]
Reactant: BrCCCCBr
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C(=O)NC(C)=CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(=O)N(CCCCBr)C(CCl)=CO2
Yield: 37 %

Procedure:
2.1 g of 4,5-dihydro-7-methoxy-3-methyl-1,4-benzoxazepin-5-one was dissolved in 50 ml of acetone, 5.5 g (2.5 equivalents) of 1,4-dibromobutane and 3.5 g (2.5 equivalents) of potassium carbonate were added, then the resultant mixture was heated and refluxed for 10 hours. This was allowed to cool, then was filtered, the filtrate was concentrated, and the residue was dissolved in 60 ml of carbon tetrachloride. 1.6 g (1.2 equivalents) of N-chlorosuccinimide was added and the resultant mixture was agitated at 90° C. for minutes 15 minutes. This was allowed to cool, then was filtered, the filtrate was concentrated, water was added, and extraction was performed by methylene chloride. The methylene chloride extract was washed with water and saturated saline and was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the above-referenced compound in an amount of 1.4 g (yield of 37%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[C:3]=1[CH3:12].[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][F:30])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:31])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][C:2]1[NH:11][C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:16](=[O:17])[C:15]3[C:19]([F:31])=[CH:20][CH:21]=[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][F:30])(=[O:25])=[O:26])[C:14]=3[F:13])[CH:9]=[C:4]2[C:3]=1[CH3:12]
Reactant: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Reactant: Cc1[nH]c2ncc(N)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCCF)c3F)cc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.8 %

Procedure:
2,3-Dimethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.048 g, 0.298 mmol), 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid (0.097 g, 0.328 mmol), EDCI (0.063 g, 0.328 mmol) and HOBt (0.040 g, 0.298 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give N-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(3-fluoropropylsulfonamido)benzamide (0.043 g, 33%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.24 (s, 1H), 10.80 (s, 1H), 9.93 (br s, 1H), 8.18 (d, 2H), 7.61-7.46 (m, 1H), 7.35-7.19 (m, 1H), 4.68-4.56 (m, 1H), 4.56-4.44 (m, 1H), 3.29-3.16 (m, 2H), 2.32 (s, 3H), 2.23-2.04 (m, 5H); m/z (ES-MS) 441.1 (98.2%) [M+1]. One methyl peak was hidden under solvent signal.