Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1ccc(OC2CCCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1ccc(OC2CCCC2)nc1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.42 g (2.1 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.42 g (2.0 mmol) of 6-cyclopentyloxynicotinic acid, followed by the addition of 0.35 g (4.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether: hexane=1:7) to obtain 0.44 g (yield: 70%) of 4,4-difluoro-3-methyl-3-butenyl 6-cyclopentyloxynicotinate.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]=O>C(O)=O>[CH3:1][C:2]1([CH3:19])[CH:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7][N:8]1[CH3:20]
Reactant: C=O
Reactant: CC1(C)NCCc2ccccc2C1c1ccccc1
Solvent: O=CO
Product: CN1CCc2ccccc2C(c2ccccc2)C1(C)C
Yield: 76 %

Procedure:
A solution of 2,3,4,5-tetrahydro-4,4-dimethyl-5-phenyl-1H-3-benzazepine (7.54 g., 0.03 mole) and 15 ml. of 36% aqueous formaldehyde in 25 ml. of 90% formic acid is refluxed for 8 hours. After the solution is concentrated to a low volume, ice and K2CO3 are added to pH 8.5 and extracted twice with 50 ml. of ethyl acetate. The combined organic extracts were washed, dried (Na2SO4) and evaporated to dryness in vacuo. Crystallization of the residue from isopropanol gives 6.0 g. (76% yield) of pure product as white crystals, m.p. 92°-93° C.
Reaction SMILES: [OH:1][C:2]1([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CO>C1COCC1>[OH:1][C:2]1([C:8]2[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: N#Cc1cccc(C2(O)CCOCC2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cccc(C2(O)CCOCC2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.8 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-carbonitrile (ca. 18.9 mmol) was dissolved in anhydrous THF (80 mL) and a 1 M solution of BH3 in THF (95 mL, 95 mmol) added. The solution was stirred at ambient temperature for 2.5 hours, then quenched with methanol. The solution was adjusted to pH 1 by addition of 2 N hydrochloric acid solution and then neutralised to pH 5 with a 5 N solution of sodium hydroxide. Extraction with dichloromethane was followed by addition of further 2 N sodium hydroxide to the aqueous phase until the pH reached 14. This phase was twice extracted with dichloromethane and these combined extracts were evaporated to give a yellow gum. The aqueous extracts were acidified with 2 N hydrochloric acid and concentrated to dryness to yield a white residue. Three trituration of this residue with methanol and concentration of the methanolic liquors yielded a second crop of yellow gum. Drying in vacuo gave the title compound (2.51 g, 64%) as a foamy yellow solid; NMR δH (400 MHz, DMSO) 8.53 (1H, br s), 7.85 (1H, t, J 7.8 Hz), 7.62 (1H, d, J 7.8 Hz), 7.34 (1H, d, J 7.5 Hz), 5.75 (1H, s), 3.72 (4H, m), 3.16 (2H, s), 2.29 (2H, m), 1.42 (1H, d, J 12.3 Hz); LC-MS Retention time 0.43 min, (M+H)+ 209.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH2:16][CH2:17]O)=[N:8]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]2[C:30](=[O:36])[NH:31][CH:32]=[CH:33][C:34]=2[CH3:35])[CH:27]=1)[C:23]#[N:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]2[C:30](=[O:36])[N:31]([CH2:17][CH2:16][C:9]3[C:10]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:32]=[CH:33][C:34]=2[CH3:35])[CH:27]=1)[C:23]#[N:24]
Reactant: Cc1cc[nH]c(=O)c1Oc1cc(Cl)cc(C#N)c1
Reactant: OCCc1nn(C2CCCCO2)c2ncccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccn(CCc2nn(C3CCCCO3)c3ncccc23)c(=O)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]ethanol (14.6 mg, 0.059 mmol) in CH2Cl2 (400 ul) was added 3-chloro-5-[(4-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy]benzonitrile (15.4 mg, 0.059 mmol), and the resulting mixture was stirred over an ice bath for 5 minutes. The mixture was then treated with triphenylphosphine (30.9 mg, 0.118 mmol) and then diisopropylyazodicarboxylate (13 ul, 0.068 mmol) and stirred over an ice bath for 10 minutes and then at 25° C. for 30 minutes. LC-MS showed the reaction was not complete, and so the mixture was re-cooled over an ice bath and treated with additional diisopropylazodicarboxylate (10 μL, 0.052 mmol). This mixture was stirred over an ice bath for 5 minutes and then stirred at 25° C. for 20 minutes to give a 3:2 mixture of 0 to N alkylation. After this time, the reaction was quenched with MeOH (1 mL) and purified on Gilson LC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) and eluting with a gradient of 5-95% ACN/water (0.5% TFA). The desired fractions were combined and evap in vacuo to give the title compound. LRMS (M+1): 489.9/405.9.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[NH3:17]>CC(C)=O>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([NH2:17])(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(=O)(=O)Cl
Reactant: N
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25.3 g (0.1 mole) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonyl chloride are dissolved in a little acetone and the solution is added dropwise slowly, at room temperature, to 100 ml of concentrated ammonia solution. The mixture is stirred for 30 minutes at room temperature and poured into ice water. After acidification with concentrated hydrochloric acid the product is filtered off with suction. It is recrystallized from isopropanol.
Reaction SMILES: [C-]#N.[K+].Cl.O.COC([CH:10]1[C:14]2([C:24]3=[C:25]4[C:20](=[CH:21][CH:22]=[CH:23]3)[CH2:19][CH2:18][CH2:17][N:16]4[C:15]2=[O:26])[C:13](=[O:27])[NH:12][C:11]1=[O:28])=O>CO>[C:14]12([CH2:10][C:11](=[O:28])[NH:12][C:13]1=[O:27])[C:24]1=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]1)[CH2:19][CH2:18][CH2:17][N:16]3[C:15]2=[O:26]
Reactant: COC(=O)C1C(=O)NC(=O)C12C(=O)N1CCCc3cccc2c31
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1CC2(C(=O)N1)C(=O)N1CCCc3cccc2c31
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a suspension of ethyl α-cyano-5,6-dihydro-2-oxo-Δ1,α -4H-pyrrolo[3,2,1-ij]quinolineacetate (8.47 g, 0.03 mole) in methanol (30 ml) was added potassium cyanide (2.93 g, 0.04 mole) and the mixture was stirred for 3 hours room temperature. The resultant solution was cooled to 0° C., saturated with hydrogen chloride gas and allowed to stand overnight. The mixture was warmed at 50° C. for an hour and refluxed for 4 hours. After cooling, an addition of water (30 ml) gave a viscous tar containing 4-methoxycarbonyl-5',6'-dihydrospiro[pyrrolidine-3,1'-[4H]pyrrolo[3,2,1-ij]quinoline]-2,2',5(1'H)-trione, which was extracted with benzene, washed with water and dried. Evaporation of the benzene afforded yellow oily residue, to which was added 40 ml of acetic acid and refluxed for 10 hours. After evaporation of the solvent, the residue was treated with benzene to give a fine solid. Recrystallization from ethanol yielded 2.92 g (38.0%) of 5',6'-dihydrospiro[pyrrolidine-3,1'-[4H]pyrrolo[3,2,1-ij]quinoline]-2,2',5(1'H)-trione, as colorless needles, mp. 253°-255° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][S@](C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)(C(C)(C)C)(C)C.[ClH:25]>CO.O>[ClH:25].[ClH:25].[NH2:18][C@@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=1)[CH2:9][OH:8]
Reactant: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: O
Solvent: CO
Product: N[C@H](CO)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (16 g, 43 mmol) in methanol (300 mL) was added hydrogen chloride (53 mL, 210 mmol) (4M in dioxanes) and the reaction stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and the material taken up in water (200 mL) and washed with dichloromethane (200 mL) to give (S)-2-amino-2-(5-fluoropyridin-2-yl)ethanol bis-hydrochloride (9.8 g, 43 mmol) as a solution in water. The solution was used crude in the next reaction.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Fc1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccnc1N1CCN(Cc2nc3ccccc3[nH]2)CC1
Reaction time: 1.25 h
Yield: 36.2 %

Procedure:
The product of Example 28B(0.50 g, 2.76 mmol), 2-chloromethyl-1H-benzimidazole (0.48 g, 2.90 mmol), and cesium carbonate (1.8 g, 5.52 mmol) were combined in N,N-dimethylformamide (28 mL) at 23° C. and stirred for 1.25 hours. The mixture was concentrated under reduced pressure and rinsed with 10% methanol/dichloromethane. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was impregnated onto flash silica gel and chromatographed on flash silica gel (10% methanol/dichloromethane) to afford 311 mg (36% yield) of the title compound. mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.00 (m, 1H); MS (APCI) m/e 312 (M+H)+; Anal. calcd for C17H18FN5 0.4 H2O: C, 64.10; H, 5.95; N, 21.98. Found: C, 64.16; H, 5.86; N, 21.95
Reaction SMILES: C[Si](C)(C)C#CCP(=O)(OCC)OCC.[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[CH:33])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[C:33][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: Ic1ccccc1
Agent: CCOP(=O)(CC#C[Si](C)(C)C)OCC
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2ccccc2)CC1

Procedure:
The title compound was obtained as described for the Compound of Example 1, reacting Compound 1c with iodobenzene instead of 2-bromo-6-methylpyridine. Purification by flash chromatography with Petroleum Ether-EtOAc 65:35 afforded the title product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)(=[O:4])=[O:3].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
1-methanesulfonyl-3-trifluoromethylbenzene (220 mg; 1 mmol) was dissolved at 0° C. in 3 mL 98% sulfuric acid and 2 mL of 100% HNO3 were added. The mixture was heated 2 hours at 80° C. and then poured onto ice; a precipitate was isolated: 110 mg (0.40 mmol; 40% yield) of 1-methanesulfonyl-3-nitro-5-trifluoromethylbenzene were obtained as a solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:37])=[C:33](Cl)[N:34]=2)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]1)[CH3:25]>C(#N)C>[CH2:24]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:37])=[C:33]([N:10]3[CH2:11][CH2:12][C:6]4([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]4)[CH2:9]3)[N:34]=2)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]1)[CH3:25]
Reactant: CN1CCC2(CCNC2)C1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCN(C)C4)C3)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 53.3 %

Procedure:
A stirred suspension of 4.40 g (20.7 mmol) of 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 200 ml acetonitrile was treated with 9.42 g (62 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 5.42 g (20 mmol) 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid was added. After stirring 23 hours at room temperature the precipitated product was filtered, washed with acetonitrile and ether, and recrystallized from ethanol to afford 3.99 g of the title compound, mp 252°-254° C. (dec).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20](=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH:5]1([C:11]2[C:12]([CH3:19])=[C:13]([C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)[C:20]([OH:22])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C=O
Reactant: Cc1cc(C)c(C2CCCCC2)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1cc(C2CCCCC2)c(C)c(C(=O)O)c1C

Procedure:
A 350 ml flask is charged with 44.0 g (0.33 mol) of aluminium chloride and 80.9 g (0.40 mol) of 1-cyclohexyl-2,4,5-trimethylbenzene (97.7%; of Example E). With stirring, CO2 gas is passed over the reaction mixture over c. 17 hours at room temperature. The dark brown solution is then diluted with 200 ml of toluene and poured onto ice. The two phases are separated and the organic phase is extracted with 10% sodium hydroxide solution. The basic aqueous phase is acidified with hydrochloric acid and extracted with toluene. The toluene phase is concentrated, giving 12.3 g of crystals. These crystals are recrystallised repeatedly from petroleum ether and then from hexane ethyl acetate. The purified crystals have a melting point of 170°-172° C. 1H-NMR analysis confirms this structure.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CO.[NH2:9][NH2:10].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([O:19][CH3:20])=[CH:14][N:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[N:17]=[C:16]([NH:9][NH2:10])[C:15]([O:19][CH3:20])=[CH:14][N:13]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cnc(Cl)nc1NN
Temperature: 42 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Anhydrous sodium carbonate (5.83 g, 0.055 mole), methanol (60 mL), and 35% aqueous hydrazine (11.0 g, 0.120 mole) were loaded into a 500 mL three necked flask equipped with a thermometer, magnetic stirrer, condenser, and addition funnel. A solution/partial slurry of 2,4-dichloro-5-methoxy-pyrimidine (17.91 g, 0.100 mole) in toluene (30 mL) was added dropwise over 39 min. During the addition, the reaction temperature rose from 15° C. to 39° C. and the solids dissolved to form a clear, pale yellow solution. The reaction mixture was heated to 42° C. for 4.1 h, after which the heat source was removed. Slow, dropwise addition of water (180 mL), caused the product to crystallize out of solution. The resulting slurry was stirred for 2 h at room temperature, then the product was recovered by filtration through Whatman #1 filter paper using a Buchner funnel and aspirator vacuum. After washing the filter cake with water, the product was dried overnight in vacuo at 40° C., to give 15.02 g of white 2-chloro-4-hydrazino-5-methoxypyrimidine (purity 96.2%, yield=82.8%): 1H NMR (300 MHz, DMSO-d6) 3.33 (s, 3H), 3.78 (s, 3H), 4.39 (br s, 2H), 7.59 (s, 1H), 8.73 (br s, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:16])([F:15])[C:6]([C:8]1[C:9](F)=[N:10][CH:11]=[CH:12][CH:13]=1)=O>C(O)C>[F:4][C:5]([F:16])([F:15])[C:6]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:3][N:2]=1
Reactant: O=C(c1cccnc1F)C(F)(F)F
Reactant: NN
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1n[nH]c2ncccc12
Yield: 84.9 %

Procedure:
Hydrazine hydrate (3.06 mL, 63.0 mmol) was added to 2,2,2-trifluoro-1-(2-fluoropyridin-3-yl)ethanone (1.9 g, 9.0 mmol) in absolute ethanol (50 mL), and the mixture was heated to reflux overnight. The cooled reaction mixture was evaporated to afford a solid, which was partitioned between water and ethyl acetate. The aqueous layer was extracted with another portion of ethyl acetate. The combined ethyl acetate extracts were washed twice with brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (1.43 g, 85%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[C:5]([C:11]#[N:12])=[C:4]([OH:13])[C:3]=1[CH3:14].[CH3:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1>CC(O)C.C(OCC)(=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[C:5]([C:11]#[N:12])=[C:4]([OH:13])[C:3]=2[CH3:14])=[CH:22][CH:23]=1)[CH3:15]
Reactant: Cc1c(O)c(C#N)c2ccnn2c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOc1ccc(Nc2c(C)c(O)c(C#N)c3ccnn23)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
The crude product (9.25 mg) of 7-chloro-5-hydroxy-6-methylpyrazolo[1,5-a]pyridine-4-carbonitrile (13) was dissolved in 2-propanol (2.2 mL). To this solution, p-phenetidine (289 μL) was added and the mixture was stirred under reflux with heating for 3 days. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. This solution was washed with a mixture of brine and 1 mol/L hydrochloric acid (1:1) and then with a mixture of brine and saturated aqueous sodium hydrogen carbonate solution (9:1) and dried over sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified with silica-gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (21) (77.8 mg, Yield 56%).
Reaction SMILES: [C:1]1([C:7](=[N:17][O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][CH2:19][O:18][N:17]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.5 %

Procedure:
A mixture of tert-butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methylene]amino]oxy]ethylcarbamate (Example 111) (385.8 mg, 0.94 mmol), trifluoroacetic acid (4 mL) and methylene chloride (2 mL) was stirred at room temperature for 6 h. The solvent was removed in vacuo. The crude material was purified and free based using SCX-2 to give phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone O-(2-aminoethyl)oxime (220 mg, 84%) as an off-white foam: 1H NMR (500 MHz, CD3OD) δ2.97-3.02 (2H, m), 3.20-3.31 (2H, m), 6.75-6.77 (0.6H, m), 7.19 (0.4H, m), 7.40-7.49 (5H, m), 7.91-7.92 (0.6H, m), 8.07-8.20 (1.5H, m), 8.70-8.72 (1H, m); ESI MS m/z 281 [C16H16N4O+H]+; HPLC (Method A) >99% (AUC), Isomeric ratio 58:42, tR=12.5 and 12.2 min.
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[C:7]([CH2:18][OH:19])(C([O-])=O)[N:6]=1)[CH2:2][CH2:3][CH3:4].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:27]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=3)=[N:30][N:29]=[N:28]2)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:39][CH:40]=2)[C:7]([CH2:18][OH:19])=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NC(CO)(C(=O)[O-])C(n2cccc2)=N1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nc(-n2cccc2)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the method described in Example 13, 2-butyl-5-(hydroxymethyl)-4-(1H-pyrrol-1-yl)imidazole-5-carboxylate (Example 29) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:19])([C:15]([F:18])([F:17])[F:16])[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]([NH2:24])[CH2:22][CH3:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:13](=[O:14])[C:12]([OH:11])([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:10]([NH:24][CH2:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C(F)(F)F)OC(=O)N(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: CCCN
Solvent: ClCCl
Product: CCCNC(=O)N(C(=O)C(C)(O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
200 mg of 3-(3,4-dichlorophenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2,4-dione were dissolved in 10 ml of dichloromethane. 55 μl of propylamine were added. The reaction mixture was stirred for 24 hours at room temperature. After evaporation, the residue was purified by chromatography on a silica column (eluent: dichloromethane). 155 mg of 1-(3,4-dichlorophenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)urea were obtained, for a yield of 63%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:38]2[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c(OC)nc(Oc3ccc(F)c(F)c3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (54 mg, 0.1 mmol) as described in Reference Example 17 and 4-methoxy-benzeneboronic acid (Lancaster, 16 mg, 0.11 mmol). HPLC/MS: m/e=488 (M+−1); Rt=4.62 min. 1H-NMR 500 MHz (CDCl3): δ 3.86 (s, 3H), 4.09 (s, 3H), 6.66 (m, 1H), 6.78 (m, 1H), 6.87 (dd, J=6 Hz, J=2 Hz, 2H), 7.08 (dd over m, J=6 Hz, J=2 Hz, 3H), 7.40 (d, J=1 Hz, 2H), 7.45 (d, J=2 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][C:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:24])[CH3:23]
Reactant: CC(C)(N)CCO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(CCO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 3-amino-3-methyl-1-butanol (CAN 42514-50-1; 58.46 mg, 0.51 mmol) as starting materials, and isolated (15 mg, 10.9%) as off white solid; LC-MS (UV peak area, ESI) 100%, 320.4 (M+H).