Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[CH:27][NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])=[N:12][C:13]([NH:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1)=[CH:14]2
Reactant: N#Cc1cccc(O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3cccc(C#N)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-hydroxy-benzonitrile and (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give 3-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 358(MH+).
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25]([C:27]#[C:28][Si](C)(C)C)=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25]([C:27]#[CH:28])=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1
Reaction time: 3 h
Yield: 89 %

Procedure:
Using a procedure analogous to that of G. M. Whitesides et al (J. Org. Chem., 53: 2489-2496 (1988)), to a solution of 2-trimethylsilanylethynyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide (110 mg, 0.02 mmol) in methanol (0.5 ml) was added a 5% aqueous solution of potassium hydroxide (7 μL, 0.06 mmol). The reaction mixture was stirred for 3 h, concentrated to remove the methanol, diluted with water, and extracted with dichloromethane. The organic phase dried over MgSO4 and concentrated to give the title product (7 mg, 77%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)[C:10]([O:12][CH2:13]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C@](N=C=O)(CC1C=CC(O)=CC=1)C(OC)=O)(C)(C)C.[O-]S(C(F)(F)F)(=O)=O>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:25])=[O:24])=[CH:20][CH:21]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: COC(=O)[C@](Cc1ccc(O)cc1)(N=C=O)OC(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Product: COC(=O)[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
In a manner similar to the preparation of ethyl (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl)propionate (Example 1b), using 25 g (84.7 mmol) of methyl (R)-2-tert-butoxy-carbonylamino-3-(4-hydroxyphenyl)propionate, 33 g of triflate are isolated with a 91% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:24]([N:31]1[C:35](=[O:36])[C:34](=[C:37]2[N:41]([CH3:42])[C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[S:38]2)[S:33][CH2+:32]1SC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:35](=[O:36])[C:34](=[C:37]2[N:41]([CH3:42])[C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[S:38]2)[S:33][C:32]1=[N:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccncc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccncc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitropyridine was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.04-8.09 (2H, m), 7.53 (1H, d), 7.44-7.48 (2H, m), 7.27-7.38 (4H, m), 7.19 (1H, m), 7.07 (1H, d), 6.42 (1H, d), 5.19 (2H, s), 4.12 (1H, br t), 3.79 (3H, s), 3.02 (2H, m), 1.05 (3H, t); MS(ESI): 474 (MH+).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([O:6][C@@H:7]([CH2:25][CH3:26])[C@H:8]([O:17][Si](C(C)(C)C)(C)C)[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][C:31]=1[S:37]([NH2:40])(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[CH2:25]([C@@H:7]([C@H:8]([OH:17])[CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[O:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:32]=2)=[CH:28][CH:27]=1)[CH3:26]
Reactant: CC[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: NS(=O)(=O)c1cc(Br)ccc1F
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: CCO
Product: CC[C@H](Oc1ccc(-c2ccc(F)c(S(N)(=O)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 73.1 %

Procedure:
Prepared according to the method described in Example 12b) from from (3R,4S)-3-[4-(4-Bromophenoxy)-3-(t-butyldimethylsilanyloxy)hexyl]pyridine (0.20 g, Example 88b)), 2-fluoro-5-bromophenylsulfonamide (0.177 g, Example 35a)), 2M aqueous sodium carbonate (0.54 ml) and tetrakis(triphenylphosphine)palladium (0) (0.014 g) in ethanol (3 ml) with heating at 90 ° C. for 4 hours. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a foam (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:31])=[CH:25][C:26](Cl)=[N:27]4)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[NH2:32][NH2:33]>CCO>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][CH2:19][C:20]3[CH:29]=[C:28]4[C:23]([C:24]([Cl:31])=[CH:25][C:26]([NH:32][NH2:33])=[N:27]4)=[CH:22][CH:21]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Reactant: NN
Solvent: CCO
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc4c(Cl)cc(NN)nc4c3)c2)CCOCC1
Temperature: 60 °C

Procedure:
To 5b (1.7 g, 3.7 mmol) in EtOH (60 mL) was added hydrazine, anhydrous (10 mL), and the reaction was heated to 60° C. for 2 hours. After cooling to room temperature, the mixture was concentrated, and the residue was diluted with CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product, 5c.
Reaction SMILES: [CH3:1][C:2]1([N:13]([CH3:42])[C:14]2[C:15]([C:38]([F:41])([F:40])[F:39])=[CH:16][C:17]3[O:36][CH2:35][C:20]4=[N:21][N:22](COCC[Si](C)(C)C)[C:23](=[O:26])[CH:24]([CH3:25])[N:19]4[C:18]=3[CH:37]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:25][C@@H:24]1[C:23](=[O:26])[NH:22][N:21]=[C:20]2[CH2:35][O:36][C:17]3[CH:16]=[C:15]([C:38]([F:40])([F:39])[F:41])[C:14]([N:13]([CH3:42])[C:2]4([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:37][C:18]=3[N:19]12
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(N(C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(N(C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7 %

Procedure:
To a solution of tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.586 g, 0.360 mmol) in DCM (4 mL) was added TFA (0.8 mL) and the mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and dioxane (1 mL) and ammonium hydroxide (25%, 1 mL) were added and the reaction mixture was stirred for 1.5 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by HPLC (Table 3, Method 19) and further separated by chiral SFC (Table 2, Method 12) to give (R)-1-methyl-9-(methyl(3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (SFC (Table 1, Method 17) Rt: 6.57 min, 0.033 g, 7%)) as a pale solid. LC/MS (Table 1, Method 5) Rt=2.319 min.; MS m/z: 384 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=2)=[O:24])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:32][C:28]1[CH:27]=[C:26]([NH:25][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc([N+](=O)[O-])c4)cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(N)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N'-(3-nitrophenyl)urea (28 mg) was dissolved in N,N-dimethylformamide/ethyl acetate (5 ml/2.5 ml), 20% palladium hydroxide-carbon (97 mg) was added, and the admixture was stirred at room temperature under hydrogen for 3 hours. The reaction mixture was filtered using Celite, the filtrate was washed with brine and then dried with anhydrous sodium sulfate. The solvent was then removed by reduced-pressure distillation to obtain 13 mg of the title compound (yield: 51%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:13][C:3]1[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1F
Reaction time: 120 h

Procedure:
To a solution of methyl 5-amino-4-chloro-2-fluorobenzoate (248 mg, 1.22 mmol) and pyridine (0.12 mL, 1.46 mmol) in 5 mL CH2Cl2 was added methanesulfonyl chloride (0.10 mL, 1.34 mmol). After 5 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 280 (M−H)), which was hydrolyzed using aqueous NaOH to provide 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M−H)), which was used without further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([C:42]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH:43]=3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([C:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH:43]=3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(C4=CCNCC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A 50 mL round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (38.3 mg, 0.0503 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 60° C. for 4 hours. Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product 21.8 mg, the yield is 80.1%. LRMS (APCI pos): >99% purity, 254 nm, m/e 542 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 8.38 (d, 1H), 8.30 (d, 1H), 8.27 (d, 1H), 8.04 (dd, 1H), 6.82 (m, 2H), 7.59 (d, 1H), 7.49 (m, 1H), 7.42 (m, 2H), 6.69 (s, 1H), 6.31 (d, 1H), 3.39 (m, 2H), 2.94 (m, 2H), 2.58 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[C].[Pd].CO>[CH3:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][N:17]=1
Reactant: Cc1cc(N2CCN(Cc3ccccc3)CC2)ccn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2CCNCC2)ccn1

Procedure:
1-Benzyl-4-(2-methyl-4-pyridinyl)piperazine (10.3 g) obtained in Example 114a) and 10% palladium carbon (1.0 g) were added to methanol (200 ml), and mixed under hydrogen atmosphere at room temperature for 7 days. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate) and recrystallized from ethyl acetate-hexane to obtain the title compound as a colorless needle-like crystal (2.58 g, 38%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]1([CH3:16])[CH:10]=[CH:9][C:8]([S:11][Si](C)(C)C)=[CH:7][CH:6]=1>C(#N)C.CN(C)P(=O)(N(C)C)N(C)C>[C:5]1([CH3:16])[CH:10]=[CH:9][C:8]([S:11][CH2:3][CH:2]=[CH2:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S[Si](C)(C)C)cc1
Reactant: C=CCBr
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCSc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
5.1 ml (59 mmoles) of allyl bromide were added to a mixture of 10.04 g (51.2 mmoles) of p-tolylthio(trimethyl)silane in 20 ml of acetonitrile and 18 ml of hexamethylphosphoric triamide and the conversion was complete after stirring for 20 minutes at room temperature. The reaction mixture was treated as described in Example 3 to obtain 7.1 g (85% yield) of allyl p-tolyl sulfide boiling at 110°-111° C./14 mm Hg and having a refractive index of nD25 =1.5644.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]1[CH:10]2[O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:9]2[CH2:8][CH2:7][N:6]1[C:18](=[O:20])[CH3:19]>O>[N+:1]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH:10]3[CH2:5][N:6]([C:18](=[O:20])[CH3:19])[CH2:7][CH2:8][CH:9]3[C:13]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCC2c3ccccc3OC2C1
Solvent: O
Product: CC(=O)N1CCC2c3cc([N+](=O)[O-])ccc3OC2C1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Fuming (90%) nitric acid (2.9 g) was added to 1-(3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone (2.7 g, 12.5 mmol). The reaction mixture was stirred at 85° C. for 2 h, poured into H2O (350 mL) and the product was extracted with DCM (3×). The combined organic layers were washed with sodium hydrogenocarbonate and brine, and solvent was evaporated. Purification using silica gel chromatography (150 g SiO2) eluting with ethyl acetate yielded 1-(6-nitro-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridin-2-yl)-ethanone.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([N:16]([CH3:15])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-Fluoro-5-trifluoromethylbenzoyl chloride (80 mg, 0.35 mmol, CAS RN 67515-56-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (35 mg, 0.18 mmol, example 1, intermediate a) and DIPEA (92 μL, 0.53 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (33 mg, 48%) MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH2:25][CH2:24]1)(=O)C>>[Cl:37][C:34]1[CH:33]=[CH:32][C:31](/[CH:30]=[CH:29]/[C@H:26]2[CH2:27][CH2:28][C@H:23]([S:22][C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:24][CH2:25]2)=[CH:36][CH:35]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)S[C@H]1CC[C@H](/C=C/c2ccc(Cl)cc2)CC1
Product: C[C@@H](S[C@H]1CC[C@H](/C=C/c2ccc(Cl)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction and treatment were carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-1-(acetylthio)-4-[(E)-2-(4-chlorophenyl)vinyl]cyclohexane to obtain the desired compound having a melting point of 64 to 66° C. in a yield of 31%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(OCC)(=O)C>[NH+:1]1([O-:18])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: [O-][NH+]1C=Cc2cccnc21
Temperature: 20 °C
Yield: 169.3 %

Procedure:
A solution of 1H-pyrrolo[2,3-b]pyridine (1a) (2.973 kg) in ethyl acetate (22.562 kg) was cooled to 0 to 5° C. To the cooled solution was added a solution of mCPBA (6.872 kg, 1.22 eq) in ethyl acetate (14.884 kg) over the course of about 1.5 h. The residual mCPBA was washed into the reaction mixture by an additional portion of ethyl acetate (5.933 kg). The resulting solution was warmed to 16 to 24° C., and allowed to stir at this temperature until the starting azaindole 1a had been consumed (as judged by reversed phase HPLC analysis). The reaction mixture was then cooled to 0 to 10° C. The resulting slurry was filtered to collect the N-oxide as the meta-chlorobenzoic acid (m-CBA) addition salt 2a′. The solid was washed with additional ethyl acetate and then dried to provide 5.716 kg (78.2%) of 2a′.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([O:14][C:12]1[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=[C:2]([Cl:1])[CH:13]=1)[C:5]1[CH:12]=[CH:13][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)c1cc2c(O)cc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(OCc3ccccc3)cc(Cl)cc2o1
Reaction time: 1.5 h
Yield: 186.4 %

Procedure:
A stirred solution of 1-(6-chloro-4-hydroxybenzofuran-2-yl)ethanone (Example 37D, 1.18 g, 5.60 mmol) in dry DMF (10 mL, 129 mmol) at r.t. was charged with K2CO3 (0.774 g, 5.60 mmol) and DMF. The reaction mixture was stirred for 1.5 hours then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to give the title material (1.57 g, 5.22 mmol, 93% yield) as an amber colored oil. LC (Method B): 2.420 min. LCMS (APCI) calcd for C12H14ClO3 [M+H]+ m/z 301.06. found 301.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.00 (d, J=0.8 Hz, 1H), 7.53 (m, 3H), 7.44 (m, 2H), 7.38 (m, 1H), 7.10 (d, J=1.6 Hz, 1H), 5.53 (s, 2H), 2.54 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[N:4][C:5]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:27])=[N:4][C:5]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COC(=O)COc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(OCC(=O)O)c2Cl)ccc1O
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of 3,5-dichloro-2-fluoro-4-(3-isopropyl-4-methoxyphenoxy)-6-methoxycarbonylmethoxy-pyridine (120 mg) in CH2Cl2 (3.0 mL) was added a solution of BBr3 in CH2Cl2 (1 mL, 1.0 M) at ambient temperature. The resulting mixture was stirred for 2 h, poured to stirring water (50 mL), extracted with CH2Cl2 (20 mL×3) from water, dried (Na2SO4) and concentrated to dryness under reduced pressure. The residue was dissolved in THF:MeOH:H2O=3:1:1 (5 mL), treated with a solution of LiOH in water (1 mL, 1.0 M) and stirred at ambient temperature for 30 min. The reaction mixture was diluted with a 1.0 M solution of HCl (50 mL), extracted with ethyl acetate(50 mL×3), dried (Na2SO4) and concentrated under reduced pressure. Purification by HPLC afforded the title compound as a colorless oil (80 mg).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[C:15]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>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.COCCOC>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2ccncc2)cc1
Reaction time: 0.33 h

Procedure:
To 4-bromopyridine hydrochloride (Aldrich) (8.9 g, 46 mmol) and tetrakis(triphenylphosphine)palladium(0) (Aldrich) (1.6 g, 1.4 mmol) was added 1,2-dimethoxyethane (250 mL) with stirring under nitrogen. After 20 min, a solution of Na2CO3 (9.7 g in 70 mL of water) and 4-tert-butylbenzeneboronic acid (9.8 g, 55 mmol) were added sequentially to the mixture. The reaction was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to approximately ⅓ its original volume, and the mixture was extracted with EtOAc (2×100 mL). The combined EtOAc layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography (1:5 EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 212 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]([OH:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=[N:14]2)=[C:8]([F:24])[CH:7]=1>>[Cl:5][C:6]1[CH:7]=[C:8]([F:24])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=[N:14]2)=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[OH:12]
Reactant: O=c1cc(C(F)(F)F)cnn1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])O
Product: O=c1cc(C(F)(F)F)cnn1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (70%, 12 ml) was added to the ice-cooled 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-trifluoromethylpyridazin-3-one (1.25 g) and stirred at room temperature for 30 minutes. Crushed ice was added. The precipitate was collected by filtration and washed with water to give 1.20 g of the desired product, m.p. 146-8° C.