Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.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.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:15]=[C:16]([F:18])[CH:17]=2)[O:9][N:8]=1
Reactant: Fc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1ccncc1
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: CCOC(C)=O
Solvent: CCCCCC
Solvent: COCCOC
Product: Fc1cc(-c2ccncc2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 6.8 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (30 mg, 0.093 mmol), pyridine-4-boronic acid (17.1 mg, 0.093 mmol), and Pd(PPh3)4 (10.4 mg, 0.0093 mmol) in a solution of and ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 2 mg (7%) of 3-(2-pyridyl)-5-(3-fluoro-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.88 (d, 1H), 8.79 (d, 2H), 8.40 (s, 1H), 8.25 (d, 1H), 8.06 (md, 1H), 7.90 (td, 1H), 7.60 (m, 3H), 7.50 (ddd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].[CH3:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23](Cl)=[O:24])[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:23](=[O:24])[CH2:22][C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: Cc1cc(C)cc(CC(=O)Cl)c1
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-4-chloro-5-iodobenzoic acid methyl ester (2.26 g in 25 mL dichloroethane) was added (3,5-dimethylphenyl) acetyl chloride (1.2 g in 15 mL dichloroethane) and the mixture heated to 75° C. on an oil bath. After 3 hours, the reaction was cooled and the solvent removed in vacuo. The title compound was isolated by crystallization from methanol (2.7 g).
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)[CH:16]=[N:15][CH:14]=1.[CH:26]1([NH:29][C:30]([C:32]2[CH:33]=[CH:34][C:35]([F:41])=[C:36](B(O)O)[CH:37]=2)=[O:31])[CH2:28][CH2:27]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[NH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]2[N:18]=[C:13]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([C:34]5[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=5[F:41])[C:30]([NH:29][CH:26]5[CH2:27][CH2:28]5)=[O:31])[CH:5]=4)[NH:9][N:8]=3)[CH:14]=[N:15][CH:16]=2)[CH2:20][CH2:21]1
Reactant: O=C(NC1CC1)c1ccc(F)c(B(O)O)c1
Reactant: NC1CCN(c2cncc(-c3n[nH]c4ccc(Br)cc34)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2cncc(-c3n[nH]c4ccc(-c5cc(C(=O)NC6CC6)ccc5F)cc34)n2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a 5 mL conical microwave vial was added Pd(dppf)Cl2 (15.53 mg, 0.02 mmol), 1-(6-(5-bromo-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine dihydrochloride salt (Example 1) (71 mg, 0.19 mmol), and 5-(cyclopropylcarbamoyl)-2-fluorophenylboronic acid (46.7 mg, 0.21 mmol), capped, degassed and backfilled with argon (3×). Dioxane (1.9 mL) and 2N Na2CO3 aqueous solution (0.2 mL, 0.48 mmol) were added. The reaction mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixtures were filtered before concentrating under reduced pressure. The crude reaction mixture was purified by preparative HPLC using water with 0.1% NH4OH and ACN with 0.1% NH4OH (Column: Phenomenex Gemini-NX C18 110 A 5 μm, 21×100 mm) to afford the title compound. MS (ESI, pos. ion) m/z: 472 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:16])[CH3:15]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(C)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of concentrated nitric acid (20 mL) and concentrated sulfuric acid (20 mL) was cooled in an ice-salt bath to 0° C. N-(2,4-dimethylphenyl)acetamide (9.5 g) was added portionwise at such a rate to maintain the temperature below 5° C. The mixture was then allowed to stir in the cold for an additional one hour.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[S:10][C:11]2[C:17]([NH:18][NH2:19])=[C:16]([F:20])[CH:15]=[C:14]([Cl:21])[C:12]=2[N:13]=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:8][C:9]1[S:10][C:11]2[C:17]([N:18]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:19])=[C:16]([F:20])[CH:15]=[C:14]([Cl:21])[C:12]=2[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNc1c(F)cc(Cl)c2nc(Cl)sc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)N(N)c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.6 ml Triethylamine was added to a solution of 4.8 g 2,4-dichloro-6-fluoro-7-hydrazinobenzothiazole in 38 ml toluene. 2.4 ml Pivaloyl chloride was added dropwise and the mixture stirred for 2 hours at room temperature. It was then treated with ethyl acetate and washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography. Yield: 1.36 g=21% of theory
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:25]([C:38](O)=[O:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.[NH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54].Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@H:25]([C:38]([NH:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[O:39])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:31][CH:32]=1
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.4 ml (50 mmoles) of N-ethylmorpholine and 11.33 g (55 mmoles) of DCC are added at 0° C. and while stirring to a solution of 18.55 g (50 mmoles) of Z-Tyr(But)-OH, 6.98 g (50 mmoles) of H-Gly-OEt.HCl and 6.75 g (50 mmoles) of HOBt in 75 ml of dimethylformamide. The mixture is stirred for 2 hours at 0° C. and is allowed to stand overnight at room temperature. The precipitate is filtered off and the filtrate is concentrated in a high vacuum. The residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking with NaHCO3 solution, a KHSO4 /K2SO4 buffer and water, and is dried over Na2SO4 and concentrated. The residue is dissolved in diisopropyl ether. Undissolved material is filtered off and petroleum ether is added to the filtrate. The mixture is cooled for a few hours in an ice bath and the precipitate is filtered off. Yield 20.63 g (89%), melting point 108° C. [α]D22 =-13.4° (c=1, methanol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][OH:11].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[C:13]([F:12])([F:24])[F:25]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: Cn1c([N+](=O)[O-])cnc1CO
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
m.p. 153° C, from 1-methyl-2-hydroxymethyl-5-nitro-imidazole and 2-trifluoromethyl-4-nitro-fluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31].FC(F)(F)S([O-])(=O)=O.[Sm+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C1COCC1.C(Cl)Cl>[CH2:34]([O:33][C:29](=[O:32])[CH2:30][CH2:31][N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])[CH3:35]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sm+3]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CCN1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 160 °C
Yield: 32.5 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.6 mg, 0.0723 mmol), ethyl acrylate (73.7 mg, 0.728 mmol, Aldrich) and samarium(III) trifluoromethanesulfonate (34.9 mg, 0.0572 mmol) in THF (1.5 mL) were heated for 3 h at 160° C. in a microwave tube. The reaction mixture was then diluted with CH2Cl2, extracted with water, and saturated NaCl. The organic phase was separated, dried over Na2SO4, and purified by flash column to give rac-3-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-propionic acid ethyl ester (12.3 mg, 32.5%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][CH2:16][C:17]1([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=3)[CH:23]=[C:22]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:19][CH2:18]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH2:16][C:17]1([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:28]=3)[CH:23]=[C:22]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CC3)c2c1
Reaction time: 2 h
Yield: 107.5 %

Procedure:
TFA (120 mL) is added to a solution of crude diethyl 1-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)methyl]-1H-indole-2,6-dicarboxylate (36 g, 81 mmol) in CH2Cl2 (700 mL) at room temperature. The reaction mixture is stirred for 2 h and the solvent is evaporated. The residue is dissolved in EtOAc (600 mL) and is washed with saturated NaHCO3 until the pH is about 7. The aqueous layer is extracted with EtOAc (2×100 mL) and the combined organic layers are dried (Na2SO4), and concentrated to afford the title compound (30 g, >99%) as a light yellow colored oil which is used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[C:14]1(C)C=CC=C[CH:15]=1>OS(O)(=O)=O.C(O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Cl)s1
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc(S(N)(=O)=O)sc1Cl

Procedure:
To a round bottom flask were added 5-chloro-4-carboxythiophene-2-sulfonamide (5.0 g, 20.7 mmole) along with toluene (25 mL), ethanol (20 ml), and conc. H2SO4 (25 drops). The reaction mixture was refluxed for 96 hours. The reaction mixture was cooled and the solvent was removed under vacuum. The residue was then poured onto ice and the pH adjusted to ~8.0 using 10% sodium carbonate. The basic aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine, and dried (MgSO4). Solvent removal yielded 3.92 g (70%) of an off white solid which was used as is: mp =98°-99° C.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][C:35]([C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:37])[CH3:36]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][C@H:38]([C:35]([OH:34])([CH3:37])[CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC(C)(O)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](C(C)(C)O)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-(1-hydroxy-1-methyl-ethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.40 (s, 1H), 4.14 (s, 1H), 3.74 (m, 1H), 3.65 (m, 1H), 3.36 (m, 2H), 3.28 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 6H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 460 [M+H]
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:21][C:2]2[C:7]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CO)cc1
Reactant: Clc1nccnc1N1CCNCC1
Product: COc1ccc(COc2nccnc2N2CCNCC2)cc1
Yield: 72 %

Procedure:
The title compound was prepared according to the procedure of Example 90, Step 2, starting from 2-chloro-3-(1-piperazinyl)pyrazine (0.80 g, 4.0 mmol; from Example 90, Step 1) and 4-methoxybenzyl alcohol (0.88 g, 6.4 mmol). Oil; yield 72%. MS m/z 301 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21]#[N:22])=[CH:5]/[CH3:6].CC1SC=C(C)C=1C1N(C2C=CC(O)=CC=2F)N=C(C)C=1C#N>CO>[CH3:3]/[C:4](/[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[F:19])[N:10]=[C:9]([CH3:20])[C:8]=1[C:21](=[NH:22])[NH:1][OH:2])=[CH:5]/[CH3:6]
Reactant: C/C=C(/C)c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Reactant: NO
Agent: Cc1csc(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Solvent: CO
Product: C/C=C(/C)c1c(C(=N)NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Yield: 47 %

Procedure:
Hydroxylamine (50 wt % solution in water, 0.5 mL, 8.11 mmol) was added to (Z)-5-(but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (22 mg, 0.08 mmol) dissolved in MeOH (1.0 mL) or Hydroxylamine (50 wt % solution in water, 0.24 mL, 3.97 mmol) was added to 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (13 mg, 0.04 mmol) dissolved in MeOH (0.8 mL). The reaction was heated at 150° C. in the microwave for 15 min. Purification using preparative HPLC gave 5-((Z)-but-2-en-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E51) (11.44 mg, 46%), ES/MS m/z: 305.08 (M+H), 303.13 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.22 (m, 1H), 6.76-6.71 (m, 2H), 5.65 (m, 1H), 2.30 (s, 3H), 1.83 (s, 3H) and 1.39 (d, 3H, J=6.7 Hz) or 5-(2,4-dimethylthiophen-3-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (E52) (4.31 mg, 30%) ES/MS m/z: 361.05 (M+H), 359.17 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.14 (t, 1H, J=8.8 Hz), 6.83 (q, 1H, J=1.0 Hz), 6.66 (m, 1H), 6.61 (dd, 1H, J=11.9, 2.7 Hz), 2.38 (s, 3H), 2.16 (s, 3H) and 1.94 (d, 3H, J=1.0 Hz).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37](C3)C1)C2.C1(CCCO)CCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH2:35][CH2:44][CH:39]2[CH2:40][CH2:41][CH2:43][CH2:37]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCCCC1CCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-cyclopentylpropan-1-ol, the title compound was obtained as a colorless solid (0.22 g, 54%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.4 Hz, 1H), 4.14 (t, J=6.4 Hz, 2H), 2.87 (s, 6H), 1.86-1.70 (m, 5H), 1.64-1.40 (m, 6H), 1.14-1.02 (m, 2H); MS (ES−) m/z 405.2, 407.2 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH:21]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:24]([NH2:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:26][CH2:24][CH3:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (4′-Fluoro-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[C:16]([CH3:40])=[C:17]([N:21]([CH2:25][C:26]2[CH:38]=[CH:37][C:29]([O:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:28]([CH3:39])[CH:27]=2)[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][CH:20]=1>>[CH3:39][C:28]1[CH:27]=[C:26]([CH2:25][N:21]([C:17]2[C:16]([CH3:40])=[C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23][CH3:24])[CH:38]=[CH:37][C:29]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1C

Procedure:
Prepared from 4-(trifluoromethyl)phenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][O:30][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2]>N1C=CC=CC=1.O1CCCC1.F.N1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][OH:30])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1CO
Reaction time: 17 h
Yield: 91.3 %

Procedure:
To a solution of (2R,3S,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-yl acetate (440 mg, 0.84 mmol) in pyridine/tetrahydrofuran (1:1, 3.4 mL) was added approximately 20 drops of hydrofluoric acid in pyridine (2.0 M). After stirring for 17 h, the reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via flash chromatography (40 to 100% EtOAc/hexanes) afforded 314 mg (91%) of the title compound.
Reaction SMILES: C[C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[NH:4][C:3]1=[O:14]>CO.[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3](=[O:14])[NH:4]2
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1C(=O)Nc2cccc(N)c21
Reaction time: 16 h

Procedure:
A mixture of (±)-ethyl (3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (2.56 g, 9.69 mmol) and 10% Pd/C (500 mg) was stirred vigorously in MeOH (50 mL) under an atmosphere of hydrogen (ca. 1 atm). After 16 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(N(C)C)=O>[N:21]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[N+:22]=[N-:23]
Reactant: COC(=O)c1cc(CBr)ccc1Cc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(CN=[N+]=[N-])ccc1Cc1ccc(F)cc1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of methyl 5-bromomethyl-2-(4-fluorobenzyl)benzoate (3.8 g), sodium azide (2.9 g) and dimethyl acetamide (50 ml) was stirred under an inert atmosphere for 16 hours. The dimethyl acetamide was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried, evaporated to dryness and purified by flash chromatography using iso-hexane/ethyl acetate (80:20) as eluant to give methyl 5-azidomethyl-2-(4-fluorobenzyl)benzoate (3.23 g) as a colourless gum.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[I-].[K+]>C(Cl)(Cl)Cl.[Ag]=O>[O:13]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH:11]=[C:2]1[O:1][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: O=[Ag]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)COC1=CC(=O)c2ccccc2C1=O

Procedure:
a mixture of 2-hydroxynaphthalene-1,4-dione (6, 0.52 g, 3.0 mmol), tert-butyl 2-bromoacetate (0.78 g, 4.0 mmol), silver oxide (0.93 g, 4.0 mmol) and potassium iodide (0.05 g, 0.3 mmol) were refluxed in 10 ml of chloroform overnight under Ar. The reaction mixture was filtered and washed with DCM (3×20 ml), the filtrate was concentrated and purified with flash chromatography to give compound 7c as a light yellow solid, 13%, m.p.=120-122° C.