Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[F:37][C:38]1[CH:46]=[C:45]2[C:41]([C:42]([Sn](CCCC)(CCCC)CCCC)=[N:43][NH:44]2)=[CH:40][CH:39]=1>CN(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.[Cu]I>[C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:42]3[C:41]4[C:45](=[CH:46][C:38]([F:37])=[CH:39][CH:40]=4)[NH:44][N:43]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1)=[O:31])([CH3:35])([CH3:34])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 85 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
In a round-bottomed flask, 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (600 mg, 1.12 mmol) and 6-fluoro-3-(tributylstannyl)-1H-indazole (475 mg, 1.12 mmol) were dissolved in DMF (10 mL) under nitrogen. Pd(PPh3)4 (65 mg, 0.056 mmol) and CuI (43 mg, 0.224 mmol) were added and the mixture sonicated for 5 min while bubbling nitrogen. The reaction mixture was stirred at 85° C. for 16 hours. After solvent removal, the concentrated mixture was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (3:1 v/v) to give N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 27%) as a white solid. LCMS: (M+H)+=595; 1H NMR (300 MHz, DMSO): δ 13.60 (s, 1H), 8.78 (s, 1H), 8.45-8.40 (m, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.45-7.33 (m, 10H), 7.21-7.09 (m, 7H), 1.50 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(OCC)C>[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Product: C#Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A solution of 1-(3-nitrophenyl)-2-trimethylsilylacetylene (43 g, 0.197 mol) in diethylether (800 mL) is cooled to 0° C. under argon atmosphere. To this solution is added, dropwise over 30 min, a solution of TBAF (1M in THF, 217 mL, 0.217 mol) maintaining temperature below 10° C. The reaction mixture is stirred for 30 min at 0° C. The reaction mixture is poured into water and extracted with diethyl ether (×2). The organic layers are combined, washed with brine, and dried (Na2SO4). The solvents are removed under reduced pressure. The residue is purified by silica-gel chromatography with Hexane/EtOAc=20/1 to give orange oil (26 g).
Reaction SMILES: [O:1](CCCCCCCC)P(OP([O-])([O-])=O)(=O)OCCCCCCCC.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[C:34]([OH:1])[C:33](=[CH:32][CH:31]=1)[OH:36])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCCCCCCOP(=O)(OCCCCCCCC)OP(=O)([O-])[O-]
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 75 %

Procedure:
The procedure of Example 7 was repeated, except 0.2% by weight of dioctyl pyrophosphate was used in place of Na5R'5 (P3O10)2. Consequently, the conversion of para-tert.-butyl phenol was 7.2%, 4-tert.-butyl pyrocatechol was formed in a yield of 75% based on the converted butyl phenol and the conversion of peracetate was 99.0%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>ClCCl.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of 4-bromo benzylbromide (1.0 g, 4.1 mmol) in dichloromethane (20 ml) and diisopropyletylamine (1 ml) was added tert-butyl 4-piperidinylcarbamate (1.0 g, 5.0 mmol). The solution was then stirred at room temperature over night. The solvent was evaporated and 25 ml of 50% TFA in dichloromethane was added to the resulting white solid. The mixture was then stirred at room temperature for 2 h and then evaporated to dryness. The resulting solid was dissolved in water and extracted with toluene. After removal of the toluene the water phase was made basic with 1M NaOH giving a pH of 13. The water phase was then extracted with dichloromethane 3 times and the combined extracts were dried and then evaporated to give the pure product as a slightly yellow oil (0.96 g, 3.6 mmol)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:23]=1.C(=O)([O-])[OH:25].[Na+]>O1CCOCC1.O>[I:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:23]=[C:3]([CH2:2][OH:25])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: O=C([O-])O
Reactant: ClCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccn1)c1cc(I)ccc1-2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
A solution of 1.15 g of 2-chloromethyl-8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine in 40 ml of dioxan was treated with a solution of 0.28 g of sodium hydrogen carbonate in 10 ml of water and stirred at 80° C. for 1.5 h. The mixture was evaporated in a vacuum. The residue was partitioned between chloroform and aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with chloroform. The chloroform extracts were dried over sodium sulphate, concentrated to 30 ml in a vacuum and chromatographed over 50 g of silica gel. 1.05 g of the desired product were eluted with chloroform/ethanol mixtures containing 3 to 7% ethanol. After recrystallization from ethyl acetate/diethyl ether there was obtained 0.955 g of 8-iodo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 206-207° C. which was converted into the hydrochloride (dec. above 300° C.).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH:20][NH2:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17]>C(O)C.O>[CH:1](=[N:21][NH:20][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1ccc(Cl)cc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Cl)ccc1NN=Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzaldehyde (1.48 g) in ethanol (10 ml) was added to a stirred suspension of 5-chloro-2-hydrazinobenzoic acid hydrochloride (described in U.S. Pat. No. 4,105,766; 5.2 g) in water (100 ml). Stirring was continued for 1 hour. The mixture was then left unstirred for 16 hours and then extracted with ether. The extracts were dried (MgSO4) and evaporated to give 2-(benzylidenehydrazino)-5-chlorobenzoic acid (3.5 g) which was used without purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH2:33])([CH3:27])([CH3:26])[CH3:25].CC(O)=O>CCO>[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH:33][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (62 mg, 0.39 mmol) in EtOH (9 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.2 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and washed with 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 113 mg of the title compound as an off-white solid. MS: (−) m/z 437.33 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[Si:10]([O:17][C@@H:18]1[C@H:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@@H:20]([NH2:32])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(O)C>[Si:10]([O:17][C@@H:18]1[C@H:22]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH2:21][C@@H:20]([NH:32][C:2]2[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=2)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc(Cl)c2F)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 77.6 %

Procedure:
A solution of 4,6-dichloro-5-fluoropyrimidine (102 mg, 0.61 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine (200 mg, 0.56 mmol), and triethylamine (0.16 mL, 1.11 mmol) in ethanol (2.00 mL) was heated in a sealed tube under microwave irradiation at 140° C. for 1 h. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 15% ethyl acetate/hexanes) to afford the title compound (213 mg, 70%) as a light yellow solid. LC/MS: Rt=2.60 min, ES+ 490.5 (AA standard).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccc(Br)c1
Product: CCC(NC(=O)Cc1cccc(Br)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:19][NH:20][C:21]([NH2:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (108 mg, 0.49 mmol), semicarbazide hydrochloride (57 mg, 0.51 mmol) and potassium carbonate (58 mg, 0.42 mmol) in ethanol (3.0 mL) was refluxed under a nitrogen atmosphere overnight (14 h). The reaction mixture was cooled to room temperature, water was added, and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4. After filtration and concentration, the crude material was purified by Biotage chromatography to afford phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone semicarbazone as two isomers, Example 62 (5.3 mg, 4%) and Example 63 (5.9 mg, 4%), as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH3:19])[CH2:15][C:16](O)=O)=[O:13])[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([NH2:29])=[CH:26][C:27]=1[F:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C=O)C>[ClH:1].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][C:25]2[N:29]=[C:16]([CH2:15][N:14]([CH3:19])[C:12](=[O:13])[CH2:11][N:7]3[C:6]4[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[S:9][C:8]3=[O:10])[NH:30][C:24]=2[CH:23]=1
Reactant: CN(CC(=O)O)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1nc2cc(F)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To a mixture of N-[(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetyl]-N-methylglycine (150 mg), 4-chloro-5-fluorobenzene-1,2-diamine (81 mg), and DMF (5 mL) were added HOBt (77 mg) and WSC.HCl (107 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. To the residue was added acetic acid (5 mL), followed by heating and stirring at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The obtained solid was washed with EtOAc and then with MeOH, and suspended in MeOH (3 mL). 4 M hydrogen chloride/EtOAc (120 μL) was added thereto, followed by stirring at room temperature for 1 hour. The resulting solid was collected by filtration and then washed with MeOH to obtain N-[(6-chloro-5-fluoro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide hydrochloride (146 mg).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>ClCCl>[Cl:17][C:18]1[N:23]=[C:22]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCCC1
Yield: 71.2 %

Procedure:
Cyclohexylamine (5.72 ml) and N,N-diisopropylethylamine (12.4 ml) were dissolved into 125 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (9.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 80 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (9.1 g) in a yield of 71.2%. ESI-MS (m/z, %) 258 (M−H)+; 1H NMR (400 MHz, CDCl3): δ9.04 (s, 1H), 8.35 (s, 1H), 4.34 (m, 1H), 2.03 (m, 2H), 1.79 (m, 2H), 1.53-1.25 (m, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].FC(F)(S([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.CN(C=O)C.[Cl:36][C:37]1[C:46](O)=[C:45]([S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]>O>[Cl:36][C:37]1[C:46]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[C:45]([S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40]
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(F)(F)C(F)F
Temperature: 120 °C

Procedure:
1.200 g (4.3 mmol) of potassium tert-butoxide and 1.917 g (4.3 mmol) of 2,2,3,3-tetrafluoropropyl perfluorobutanesulfonate were introduced into 30 ml of DMF in a vessel. At RT, 1200 g (4.3 mol) of methyl 2-chloro-3-hydroxy-4-ethylsulfonylbenzoate were added and the mixture was then heated at 120° C. for 7 h. It was subsequently introduced into water and subjected to extraction with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4, and concentrated. Drying under an oil pump vacuum gave methyl 2-chloro-3-(2,2,3,3-tetrafluoropropyloxy)-4-ethylsulfonylbenzoate as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[NH2:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(5-chloro-2-nitrophenyl)amino]-piperidinecarboxylate D27 (6.3 g) was dissolved in ethanol (100 mL) and Raney nickel (50% aqueous suspension, 5 mL) was added at room temperature; the mixture was heated to 40° C. and hydrazine monohydrate (3.0 mL) was added over 30 min. After 30 min more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated to yield the title compound, 5.8 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Bromo-1H-pyrazolo[3,4-b]pyridine (1.39 g) in DMF (6 ml) was cooled in an ice-bath under nitrogen and treated portionwise with sodium hydride (0.308 g) (60% dispersion in oil) over a period of about 15 min. The reaction was left to stir in the ice-bath for 40 min, then treated with tosyl chloride (1.469 g) in DMF (2 ml). The reaction was left to stir in the ice-bath under nitrogen and the ice left to melt overnight. The reaction was stirred for a total of 20 h. The reaction was treated cautiously with water (6 ml) and stirred for 5 min. The reaction was poured onto water (60 ml), filtered and the residue treated with DCM (20 ml). The mixture was stirred, and then pushed through a frit into a cartridge with a hydrophobic frit. The solution was allowed to drip through, and then this procedure was repeated with further DCM (2×15 ml). The combined filtrates were evaporated to dryness to give the title compound as a brown solid, 1.802 g.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 85.6 %

Procedure:
The title compound (113 mg) was prepared as in Example 177, Steps C and D, using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 185 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H22FN3, 299.18. found, m/z 300.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.45-7.39 (m, 2H), 7.35-7.29 (m, 2H), 4.53 (m, 1H), 3.48-3.42 (m, 2H), 3.36-3.28 (m, 2H), 3.28-3.23 (m, 2H), 2.84-2.78 (m, 2H), 2.08-1.85 (m, 6H), 1.67-1.56 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25]CC)=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(CC(C)(C)CC(=O)O)ccc1OCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of STEP 8 (67.5 mg, 0.17 mmol) was dissolved in 5 ml methanol and 5 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 16 h, and acidified with trifluoroacetic acid (1.0 ml). Solvents were evaporated and residue was purified on HPLC using acetonitrile gradient 10-50% in 30 min to yield 31.5 mg. FAB-MS: (MH+)=373. H NMR(CDCl3) δ1.03 (s, 6H), 2.21 (p, 2H), 2.22 (s, 2H), 2.61 (s, 2H), 3.60 (q, 2H), 3.84 (s, 2H), 4.13 (t, 2H), 6.65-6.82 (m, 4H), 6.96 (d, 1H), 7.68-7.80 (m, 2H); Anal Calcd. for C21H28N2O4 plus 1.5 CF3COOH: C, 52.17; H, 5.56; N, 5.07. Found: C, 52.44; H, 5.62; N, 4.88.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19](=[S:21])[NH2:20])=[C:12]2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH:24]([C:29](OC)=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19]3[S:21][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([OH:30])[N:20]=3)=[C:12]2[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=S
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2c(C)nn3ccc(OCc4ccccc4)cc23)nc1O
Temperature: 100 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride(3.45 g, 10.3 mmol) in DMF (100 mL), was added 94% dimethyl chloromalonate (2.79 mL, 20.6 mmol) and the mixture was stirred for 7.5 h at 100° C. The reaction mixture was allowed to cool to 50° C. and then was dropwise added water (100 mL). The resulting precipitate was collected by filtration and then washed with EtOH (20 mL) and diethyl ether (20 mL) to obtain methyl 2-[5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-4-hydroxy-1,3-thiazole-5-carboxylate as a orange solid, which was used in the next step without further purification. 1H-NMR (DMSO-d6, 300 MHz) δ 2.59 (3 H, s), 3.75 (3 H, s), 5.27 (2 H, s), 6.87 (1 H, dd, J=2.6, 7.6 Hz), 7.32-7.51 (3 H, m), 7.52-7.64 (2 H, m), 7.88 (1 H, d, J=2.6 Hz), 8.67 (1 H, d, J=7.6 Hz), 11.79 (1 H, br s).