Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16](N2C=CC(=O)NC2=O)[CH2:15]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:16]2[O:17][C@H:18]([CH2:19][OH:20])[C@@H:14]([F:13])[CH2:15]2)=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc2[nH]cnc12
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CSc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 408 h
Yield: 47.1 %

Procedure:
2-Amino-6-methylmercapto-9H-purine (0.49 g 2.7 mmoles, Aldrich Chemical Company), and 2',3'-dideoxy-3'-fluorouridine (0.50 g 2.2 mmoles) were suspended in potassium phosphate buffer 50 ml (10 mM), pH 6.8, containing 0.04% potassium azide. Purified purine nucleoside phosphorylase (7850 I.U.) and thymidine phosphorylase (2000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) were added to the reaction mixture and the suspension stirred at 45° C. After 17 days, additional purine nucleoside phosphorylase (7850 I.U.) and thymidine phosphorylase (2000 I.U.) were added. After another 104 days, additional purine nucleoside phosphorylase (15,700 I.U.) and thymidine phosphorylase (52,500 I.U.) were added. Four days later the reaction was poured into methanol 600 ml and denatured protein was removed by filtration through Celite. The filtrate was applied to an AG1-X2 column (2.5×10 cm, OH- form) and the product was eluted with methanol. Solvent was removed in vacuo and the residue flash chromatographed on silica gel (2.5×20 cm) using dichloromethane:methanol (95:5). Solvent was removed and lyophilization yielded 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-methylmercapto-9H-purine (0.31 g).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:20]([N+:26]([O-:28])=[O:27])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CBr
Reactant: CCOC(=O)c1ccc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn1Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 493 mg of potassium tert-butoxide in 5 mL of dimethylformamide (anhydrous) is added dropwise a solution of 556 mg of ethyl pyrrole-2-carboxylate (prepared as described in Organic Synthesis, Vol. 51, p. 100) in 5 mL of anhydrous dimethylformamide. On completion of the addition the mixture is allowed to stir at room temperature for 1 hour. To this mixture is added a solution of 1 g of 4-chloro-2-nitrobenzyl bromide in 5 mL of dimethylformamide. The reaction mixture is then heated to 75° and maintained at this temperature for 18 hours, then allowed to cool to room temperature. The reaction mixture is poured into 20 mL of ice-water and extracted with 2×30 mL of ether. The combined ethereal extracts are washed with 2×30 mL of water followed by 30 mL of saturated sodium bicarbonate solution. The ethereal extracts are dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield ethyl 1-(4-chloro-2-nitrobenzyl)-pyrrole-2-carboxylate melting at 104°-106°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccccc1Cl
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4Cl)cc3)c2)o1

Procedure:
N-(2-Chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-chlorobenzylamine using method N. NMR; δH [2H6]—DMSO 9.15,(1H, t), 8.03,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.53,(3H, m), 7.47,(1H, m), 7.39,(1H, m), 7.35-7.28,(2H, m), 4.57,(2H, d), 2.56,(3H, s), LCMS; retention time 3.53 min, MH+ 418/420.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:17](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)[CH3:2]>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([NH2:17])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([F:16])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(OCC)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC(N)c1ccc(OCC)c(F)c1
Reaction time: 12 h

Procedure:
A solution of the dibenzylamine 15-4 (30.0 gm, 66.8 mmol) in EtOH/HOAc (340/30 mL) was purged with argon and treated with Pd(OH)2 (6 g) and placed under 1 atm of H2 for 12 h. Additional portions (2.5 g) of Pd(OH)2 were added after 24 h and 48 h. The reaction mixture was purged with argon, filtered through Celite, and the filtrate collected. The filtrate was concentrated to yield the desired amine 15-5.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH2:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:7][CH:6]=1)=O.[OH-].[NH4+:20]>>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH2:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:7][CH:6]=1)(=[O:2])[NH2:20]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(CCC2=NNC(=O)C2)cc1
Agent: [OH-]
Product: NC(=O)c1ccc(CCC2=NNC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(4-methoxycarbonylphenylethyl)-2-pyrazolin-5-one (7.7 mmol) in ammonium hydroxide 25% (30 ml), was stirred at room temperature for 12 hours. The solvent was concentrated in vacuo and the solid product formed was filtered and dried.
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:9]([OH:36])[CH2:10][C@@H:11]([NH:25]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:10][C@H:9]([OH:36])[C@@H:8]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2cccnc2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccc(-c2cccnc2)cc1
Reaction time: 18 h

Procedure:
The product from Example 148B (0.170 g, 0.29 mmol) was dissolved in a mixture of ethyl acetate (1.5 mL) and methanol (1.5 mL) and 20% Pd(OH)2 on carbon (0.080 g) and a solution of HCl in dioxane (0.070 mL, 4 N) were added, and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 18 hours. The mixture was filtered through celite® and the solvent was evaporated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14](CS(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH2:31]>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:27])([CH3:28])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:31]=[CH:30][S:32]([CH3:35])(=[O:34])=[O:33])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Product: CC(C)(Cc1c[nH]c2c(C=CS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C

Procedure:
{2-[7-(2-Methanesulfonyl-vinyl)-1H-indol-3-yl)-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and methyl vinyl sulfone as described for the preparation of Amine 23 (98%). FDMS m/e=392.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29](Br)[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]([O:46][CH2:47][CH3:48])=[CH2:45])CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:44]([O:46][CH2:47][CH3:48])=[CH2:45])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Yield: 78.2 %

Procedure:
A suspension of 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.93 g, 0.010 mol, prepared as in Example 34) tetrakis(triphenylphosphine)palladium(0) (1.40 g, 0.00121 mol), and tributyl(1-ethoxyvinyl)tin (5.32 mL, 0.0157 mol) in toluene (30 mL) was heated under reflux for 3.5 hours. The mixture was cooled and filtered to give a solid. Purification of the solid by silica gel chromatography using a gradient of 5-66% ethyl acetate/hexane over 15 minutes gave 4-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow foam (4.50 g, 78%). MS (APCI) M++1; Calc'd 576.2. Found, 576.3.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1.[C:31](=[NH:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31](=[N:44][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(Cl)nc3c2)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(N=C(c4ccccc4)c4ccccc4)nc3c2)c1
Temperature: 80 °C

Procedure:
10n (500 mg, 1.8 mmol), benzophenone imine (0.31 mL, 1.8 mmol), sodium tert-butoxide (265 mg, 2.8 mmol), BINAP (115 mg, 0.2 mmol), and Pd2dba3 (42 mg, 0.05 mmol) were dissolved in toluene (10 mL) and degassed for 10 minutes with N2. The reaction was then sealed and heated to 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with EtOAc and brine, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10p.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH3:13].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15].N1C=CN=C1>ClCCl>[Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[N:7]=1
Reactant: CCCOc1ccc(CO)nc1Cl
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCOc1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6-chloro-5-propoxy-pyridin-2-yl)-methanol (0.93 g, 4.61 mmole), 20 mL of dichloromethane, tri(isopropyl)silyl chloride (1.0 g, 5.19 mmole) and imidazole (0.47 g, 6.9 mmole) is stirred overnight at ambient temperature. The reaction mixture is washed with water, dried over sodium sulfate, filtered and evaporated in-vacuo to give an oil which is chromatographed on silica gel with 10:1 hexane/ethyl acetate to give 2-chloro-3-propoxy-6-triisopropylsilanyloxymethyl-pyridine as a clear liquid, 1.06 g, (64%); MS (ES+): m/z 358.2, 360.2 (M+H). A portion of this (716 mg, 2.0 mmole) and 5 mL of 1M sodium benzyloxide in benzyl alcohol is heated in a microwave reactor 5 minutes at 120° C. The reaction mixture is cooled, transferred to a separatory funnel with ethyl acetate, washed with water, the organic layer is dried, filtered, evaporated and chromatographed on silica gel with hexane/ethyl acetate to give a clear liquid, 524 mg, (61%); MS (ES+): m/z 430.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4](C)[CH:3]=1.BrC1C=CC(C=C)=[C:15]([O:21]CC)[CH:14]=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([O:21][CH2:15][CH3:14])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1OCC
Reactant: Cc1cc(Br)ccc1CCO
Agent: B1C2CCCC1CCC2
Product: CCOc1cc(Br)ccc1CCO
Yield: 82 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 62D (700 mg, 3.3 mmol) was heated in a pressure vessel with 9-BBN at 100° C. for 10 h and worked up as in 30B to yield 62E (620 mg, 82%) as solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (t, J=6.95 Hz, 3 H) 2.85 (t, J=6.32 Hz, 2 H) 3.81 (t, J=6.32 Hz, 2 H) 4.02 (q, J=7.07 Hz, 2 H) 6.96 (s, 1 H) 6.99-7.03 (m, 2 H).
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:29]C)=[N:25][CH:26]=[CH:27][CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1>O1CCOCC1.Cl>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:31])=[C:21]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)[N:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc[nH]c1=O
Temperature: 90 °C

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) was dissolved in a mixture of 1 mL of 1,4-dioxane and 0.5 mL of 4M aqueous hydrochloric acid. This solution was heated at 90° C. for 3 hours. The crude product was then purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 425.1. found 426.0 (M+1)+. Retention time 1.33 minutes.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[C:14]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C@H:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH3:48])[CH2:30]/[C:31](/[C:34]3[CH:39]=[CH:38][N+:37]([O-])=[C:36]([CH3:41])[CH:35]=3)=[N:32]\[OH:33])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)([OH:16])=[O:15].[OH-].[Na+]>ClCCl>[OH:33]/[N:32]=[C:31](/[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH2:41][OH:4])[CH:35]=1)\[CH2:30][C@H:29]([C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([C:14]([OH:16])=[O:15])[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1[C@H](C/C(=N\O)c1cc[n+]([O-])c(C)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnc(CO)c1)c1ccc(N2CCC(C(=O)O)CC2)cc1
Reaction time: 1 h
Yield: 13.7 %

Procedure:
Trifluoroacetic anhydride (421 mg, 2.01 mmol) was added at 0° C. to a suspension of (R,E)-4-(3-(4-(4-carboxypiperidin-1-yl)phenyl)-1-(hydroxyimino)-3-o-tolylpropyl)-2-methyl-pyridine 1-oxide (95 mg, 201 μmol) in dichloromethane (3 mL) to give a white suspension, then after 1 h another portion of trifluoroacetic anhydride (421 mg, 2.01 mmol) was added. The reaction mixture was allowed to reach room temperature over 1 h, then treated with 1 M aq. sodium hydroxide solution and stirred for another 90 min. After extraction with dichloromethane, the organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to produce the title compound (13 mg, 14%). Light yellow oil, MS (ESI+): m/z=474.4 ([M+H]+).
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.CO.O1CCOCC1.[Cl-].[NH4+]>O.[Fe]>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(I)c2occc2c1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
7-Iodo-5-nitro-1-benzofuran (2.5 g, 8.6 mmol) and iron (2.51 g, 45.0 mmol) were added to a round bottom flask. Methanol (25 mL), 1,4-dioxane (25 mL) and ammonium chloride (2.5 g, 46.7 mmol), dissolved in water (50 mL), were added and the mixture was heated at 100° C. for 16 h. The reaction mixture was filtered through Celite and volatiles were evaporated off. The residue was dissolved in a mixture of methanol (10 mL) and DCM (90 mL). This mixture was filtered through a silica plug and the solvent was evaporated yielding 2.22 g (99%) of the title compound as a brown oil. HPLC purity 70%, RT=1.26 min (System A; 10-97% MeCN over 3 min). MS (ESI+) for C8H6INO m/z is 260 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][S:28][CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 37 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using thiomorpholine instead of 2,2,2-trifluoroethylamine, to the title compound (46 mg, 37%) which was obtained as a light yellow solid. MS: m/e=414.4 [M+H]+.
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@H:5]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:4]1>ClCCl>[ClH:1].[OH:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:4]1
Reactant: C=CCOC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrochloric acid (4.2 M solution in dioxane, 5 mL, 21 mmol) was added to a solution of 2-allyl 1-tert-butyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.05 g, 4.87 mmol) in dichloromethane (20 mL). The resulting mixture was stirred at room temperature for 4 hours then concentrated under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[Br:15]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:14])=[C:7]([Br:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(N)ccc2cn[nH]c12
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c(Br)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To a mixture of 3.4 g (17.78 mmol) of 6-amino-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 10, in 34 mL of N,N-dimethylformamide is added 3.16 g (17.78 mmol) of N-bromosuccinimide. The reaction is stirred at ambient temperature 4 hours. After concentration in vacuo the residue is triturated in ethyl acetate and after filtration 3.38 g of a brownish solid are obtained. The filtrate is evaporated and submitted to column chromatography purification on silica gel with hexanes and ethyl acetate as eluents to afford 563 mg of a white solid. In totality 3.95 g (82%) of a product are obtained; LC/MS:270/272 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:15]([O-:17])=[O:16])=[C:7]([O:11][C:12](=[O:14])[CH3:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(OC(C)=O)c1
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(OC(C)=O)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Acetic acid 3-acetylamino-phenyl ester (21.7 g, 112.4 mmol) was added portionwise, at −15° C., to fuming nitric acid (109 mL) maintaining the temperature below −10° C. The reaction mixture was stirred at −10° C. for 3 hours and then was poured into ice. The resulting mixture was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 1/1) to afford 20.608 g (77% yield) of acetic acid 5-acetylamino-2-nitro-phenyl ester as a cream colored solid.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].[F:7][C:8]([F:14])([F:13])[C:9]([O:11][CH3:12])=O.CO/C=C/C(=O)C>C(OCC)C>[F:7][C:8]([F:14])([F:13])[C:9]1[O:11][CH:12]=[CH:1][C:2](=[O:5])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(F)(F)F
Agent: CO/C=C/C(C)=O
Agent: [K+]
Solvent: CCOCC
Product: O=c1ccoc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of KOtBu (729 mg, 6.49 mmol) in diethyl ether (10 mL) at 5° C. were added methyl 2,2,2-trifluoroacetate (767 mg, 5.99 mmol) and (E)-4-methoxybut-3-en-2-one (500 mg, 4.99 mmol). The reaction mixture was stirred at rt for 3 h, and quenched with water and then extracted with ether. Combined organic portions were dried over Na2SO4, filtered and concentrated. The residue was dissolved in isopropanol (150 mL) and 35% solution of hydrochloric acid (0.5 mL) and refluxed for 45 min. Then the solution was concentrated to remove alcohol and fractionated at reduced pressure to get the title product as yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: ON=Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
10.6 g of benzaldehyde, 7.0 g of hydroxylamine HCl salt and 14.0 g of potassium carbonate were suspended in 200 ml of methanol, and were stirred at room temperature for 5 hours. The reaction mixture was filtered, and the methanol was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain 12.0 g of the above identified compound as a white crystal (yield 99%).