Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[C:15](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH:14][C:13]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=2)=[CH:12][N:11]=1.C(=O)(O)[O-].[Na+]>CO>[N:24]1([C:21]2[CH:20]=[CH:19][C:18]([CH:17]=[CH:16][C:15]3[C:10](=[O:9])[NH:11][CH:12]=[C:13]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=4)[CH:14]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CNc1nccc(-c2cnc(OC)c(/C=C/c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CNc1nccc(-c2c[nH]c(=O)c(C=Cc3ccc(N4CCNCC4)cc3)c2)n1
Temperature: 150 °C
Yield: 95.2 %

Procedure:
Pyridine hydrochloride (2 g) was added to tert-butyl 4-(4-((E)-2-(2-methoxy-5-(2-(methylamino)pyrimidin-4-yl)pyridin-3-yl)vinyl)phenyl)piperazine-1-carboxylate (168 mg, 0.33 mmol) and the mixture was heated at 150° C. for 30 min. The reaction mixture was dissolved in MeOH (30 mL) and solid sodium bicarbonate was added until bubbling ceased. The suspension was filtered and the filtrate was concentrated. Purification by column chromatography (DCM/MeOH/aq. NH3 gradient) gave the title compound (122 mg, 94%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.CCN(CC)CC>[C:24]1([S:30]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]([C:15]3[CH:20]=[CH:19][C:18]([O:21][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])=[CH:17][CH:16]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:22])([F:23])[F:1])=[CH:13][CH:12]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C(c2ccc(OS(=O)(=O)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Yield: 89.2 %

Procedure:
An oven-dried 100 ml 3-necked flask is equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, and is charged with 4,4'-(hexafluoroisopropylidene)diphenol (Aldrich) (5.45 grams, 16.2 mmol), 4-dimethylaminopyridine (0.4 gram, 3.3 mmol), and anhydrous Et3N (40 ml). The solution is stirred and treated slowly with benzenesulfonyl chloride (4.7 ml, 36.8 mmol) via syringe. The resulting mixture is heated at reflux for 9 hours. Workup consists of partitioning the reaction mixture between CH2C2 (100 ml) and a mixture of H2 (150 ml) and concentrated HCl (40 ml), washing the organic phase successively with 100 ml portions of H2O, 5 percent NaOH, H2O and saturated brine, drying (MgSO4), filtration and concentration. This gives 10.6 grams of a reddish oily residue. TLC analysis on silica gel shows one main component (Rf =0.54; CH2Cl2). Chromatography on a column packed with flash-grade silica gel (3"×1" i.d.), eluting with CH2Cl2, gives 9.32 grams of a faintly yellowish oil, which solidifies on standing. Recrystallization from EtOAc-MeOH-H2O (20 ml:100 ml:10 ml)affords 8.91 grams (89 percent yield) of the title compound as a white crystalline solid, m.p. 133° C. to 134° C.
Reaction SMILES: [C:1]1(=[O:17])[N:5](CCS(Cl)(=O)=O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.CNC>O1CCCC1>[C:1]1(=[O:17])[NH:5][C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
2-Phthalimidoethanesulfonyl chloride (3.04 g) was dissolved in tetrahydrofuran (40 ml), 50% aqueous dimethylamine (2.5 ml) was added dropwise to the solution at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the resulting residue, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=97:1) to obtain a phthalimide compound (1.60 g). (2) By using the compound obtained in (1) mentioned above (1.58 g) as a starting material, the title compound (840 mg) was obtained in the same manner as that of Reference Example 9, (2).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C:2]2[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1[nH]cccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-aminopyridin-2(1H)-one (99 mg, 0.90 mmol), 2,4,5-trichloropyrimidine (165 mg, 0.90 mmol, 1 equiv.) and NaHCO3 (76 mg, 0.90 mmol, 1 equiv.) in a mixture of MeOH (6 mL) and H2O (3 mL) is stirred at room temperature for 24 h. The resulting precipitate is collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)pyridin-2(1H)-one; ESMS m/z 257.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[CH:17]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:25]([C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:16][CH:17]=3)=[O:26])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Nc1ccc(Oc2cccnc2Cl)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2cccnc2Cl)nc1)c1c[nH]c2ccccc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
The 6-(2-chloropyridine-3-yloxy)-pyridine-3-amine (200 mg, 0.9 mmol) and indole-3-carboxylic acid (150 mg, 0.9 mmol) were dissolved in DMF (5 ml), DCC (200 mg, 0.99 mmol) was added to the solution, and then the mixture was stirred at 70° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (200 mg, 61%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C[O:8][C:9]1C=CC(O)=C[CH:10]=1.C1OC1>[Cr]>[OH:8][CH2:9][CH2:10][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: COc1ccc(O)cc1
Agent: [Cr]
Solvent: C1CO1
Product: C=C(C)C(=O)OCCO
Temperature: 80 °C

Procedure:
Following the procedure according to U.S. Pat. No. 3,875,211, 60 parts by weight of methacrylic acid, 0.16 parts by weight of hydroquinone monomethyl ether (MEHQ), and 0.24 parts by weight of chromium silicylate were placed in an autoclave under nitrogen atmosphere. 36 Parts by weight of ethylene oxide were added in the gas phase. The contents of the autoclave were heated to 80° C. for three hours. Ethylene oxide was removed under vacuum and the reaction mixture cooled to ambient temperature. The reaction mixture was then distilled under vacuum at 60° C. to obtain a 2-hydroxyethylmethacrylate-rich solution with a characteristic composition according to Table 3. There was a clear correlation between the purity of the methacrylic acid used and the optical properties of the hydroxyester as well as the diester content. This is relevant for the further processing of the hydroxyester, for example polymerisation for biomedical products, such as soft, oxygen-permeable contact lenses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2-].[Li+].CS[C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=2[N:17]=1.O>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]2[N:13]=[CH:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=4)[C:19](=[O:32])[N:18]([CH2:33][CH3:34])[C:16]=3[N:17]=2)=[CH:3][CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: Nc1ccncc1
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 50 °C
Yield: 93.6 %

Procedure:
To a 100-mL, three-neck, round bottom flask were added 294.0 mg (3.124 mM) of 4-aminopyridine, 238.8 mg (10.40 mM) of lithium amide, and 15 mL of tetrahydrofuran. The reaction mixture was heated to 50° C. for 1 hour. A solution of 998 mg (2.792 mM) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one in 25 mL of tetrahydrofuran was added in one portion. The reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled to 50° C. and diluted by dropwise addition of 25 mL of water. The solid precipitate was collected by filtration and dried in a vacuum oven at 45° C. for 12 hours to provide 93.6% yield of the filtered compound, mp 305-307° C. Mass Spec (APCI) 403.9 m/z. HPLC established the product was 98.5% pure.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[NH:6][C:7]2[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([C:24]([S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])([CH3:26])[CH3:25])[CH:21]=[C:20]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]2[CH3:39])[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O.CCO>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([NH:4][C:5](=[O:16])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:18]3[N:23]=[C:22]([C:24]([S:27]([CH:30]4[CH2:31][CH2:32]4)(=[O:28])=[O:29])([CH3:26])[CH3:25])[CH:21]=[C:20]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:19]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(Cl)n1
Reactant: O=C(Nc1ccc(B(O)O)cc1)NC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 100 °C

Procedure:
[4-(3-Cyclopropylureido)phenyl]boronic acid, pinacol ester (199 mg, 0.66 mmol), 2-chloro-4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (190 mg, 0.53 mmol), sodium carbonate (1.320 mL, 2.64 mmol) and dichlorobis(triphenylphosphine)palladium(II) (37.1 mg, 0.05 mmol) were suspended in 18% DMF in a DME:Water:EtOH 7:3:2 solution (4 mL) and sealed into a microwave tube. The reaction was heated to 100° C. for 20 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness. The crude product was further purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents, to give the desired material as a white solid (85 mg).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].CNC.Cl.[CH:41]1([C:44]2[CH:45]=[C:46]([CH2:51][NH2:52])[CH:47]=[CH:48][C:49]=2[F:50])[CH2:43][CH2:42]1.C(N(CC)CC)C>C(O)C>[CH:41]1([C:44]2[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=2[F:50])[CH2:51][NH:52][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:36])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:35])[C:18]=2[OH:26])=[O:23])[CH2:42][CH2:43]1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Reactant: NCc1ccc(F)c(C2CC2)c1
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)c(C3CC3)c2)c(O)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A suspension of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.025 g, 0.050 mmol) and dimethylamine (0.050 mL, 0.101 mmol) (2 M in methanol) in ethanol (1 mL) was stirred at 50° C. for 1 h. Added to the mixture were (3-cyclopropyl-4-fluorophenyl)methanamine hydrochloride salt (0.025 g, 0.126 mmol) and triethylamine (0.070 mL, 0.504 mmol) and the mixture stirred at 90° C. for 5 h. The mixture was cooled to room temperature and concentrated. The brown residue was purified by preparative HPLC: Solvent A=10% ACN/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% ACN/10% H2O/0.1% trifluoroacetic acid; Start % B=0; Final % B=100; Gradient time=20 min; Stop time=23 min; Column=Sunfire 19×100 mm, C18, 5 μm. The resulting purple solid was triturated with hot methanol to give the title compound as a white solid (6.0 mg, 21% yield). 1H NMR (500 MHz, CDCl3) δ: 12.03 (1 H, s), 8.56 (1 H, t, J=5.49 Hz), 8.15 (1 H, s), 7.11-7.20 (1 H, m), 6.85-7.01 (2 H, m),4.49 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.97 Hz), 3.28 (3 H, s), 2.91 (3 H, s), 2.42-2.65 (3 H, m), 2.01-2.18 (3 H, m), 1.86-2.00 (2 H, m), 1.71 (2 H, ddd, J=13.28, 6.56, 6.41 Hz), 0.90-1.02 (2 H, m), 0.67-0.80 (2 H, m). LCMS (M+H) calcd for C26H31FN5O5: 512.23; found: 512.24.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[OH:17][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: C#CCCO
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#CCCO)cc1
Yield: 80.2 %

Procedure:
To a solution of methyl 4-bromophenylacetate (229 mg, 1.0 mmole) and 3-butyn-1-ol (151 μL, 2.0 mmole) in triethylamine (4.0 mL) was added cuprous bromide (18 mg, 0.12 mmole) and tetra(triphenylphosphine)palladium (46 mg, 0.04 mmole), and the mixture refluxed under a nitrogen atmosphere for 1 hr 20 min. The mixture was evaporated in vacuo and the residue partitioned with water and ether. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to an oil. Flash chromatography on silica gel in 7:3 hexane:ethyl acetate afforded the title compound (175 mg) as an oil NMR (CDCl3): δ 1.69 (s, 1H); 2.71 (t, 2H); 3.63 (s, 2H); 3.71 (s, 3H); 3.83 (t, 2H); 7.22 (d, 2H); 7.38 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(CC)CC>C(Cl)Cl>[C:37]1([NH:36][C:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[O:11])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To a solution of 1-(ethoxycarbonyl)cyclopropane carboxylic acid (7.4 g, 46.84 mmol) in dry CH2Cl2 (70 mL) was added HATU (35.62 g, 93.67 mmol) at 0° C. After stirring for 10 minutes, a solution of the aniline (8.71 g, 93.67 mmol) and Et3N (9.48 g, 93.67 mmol) in dry CH2Cl2 (30 mL) was then added and the reaction mixture was continued to stir at 40° C. for 24 hrs. The reaction mixture was quenched with water (30 mL) and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:5 (v/v) EtOAc/n-hexane) to afford the title compound as a pale yellow solid (9.7 g, 89%).
Reaction SMILES: Cl.N[OH:3].C[N:5]([CH:7]=[N:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([CH3:17])[CH3:16])[N:12]=[C:11]([NH:19][CH:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)C>CO>[F:18][C:15]([C:13]1[N:12]=[C:11]([NH:19][CH:20]([CH:30]2[CH2:32][CH2:31]2)[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=[C:9]([NH:8][CH:7]=[N:5][OH:3])[N:14]=1)([CH3:17])[CH3:16]
Reactant: NO
Reactant: CN(C)C=Nc1nc(NC(CCCc2ccccc2)C2CC2)nc(C(C)(C)F)n1
Agent: Cl
Solvent: CO
Product: CC(C)(F)c1nc(NC=NO)nc(NC(CCCc2ccccc2)C2CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.69 g (10 mmol) of hydroxylamine hydrochloride are added with stirring at room temperature to a solution of 1.99 g (5 mmol) of 2-dimethylaminomethyleneamino-4-(1-fluoro-1-methylethyl)-6-(1cyclopropyl-4-phenyl-1-butylamino) -1,3,5-triazine in 20 ml of methanol. The reaction mixture is stirred for 2 hours at room temperature. All volatile constituents are carefully distilled off. The crude product is taken up in methylene chloride. The mixture is washed with water, dried over Na2SO4 and evaporated in vacuo. This gives 1.81 g (93.7% of theory) of N-[4-(1-fluoro -1-methylethyl)-6-(1-cyclopropyl-4-phenyl-1-butylamino)-1,3,5-triazin-1-yl]formamide oxime as pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH2:11]2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[NH:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[N:6]=[C:5]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:27]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=2)[CH2:11]1
Reactant: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3cnn(C4CCNCC4)c3)n2)C1

Procedure:
Crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277, 108 mg, 0.19 mmol) was treated with 2:1 DCM/TFA at RT for 1 hour and concentrated in vacuo to get (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide (278) TFA salt. It was dissolved in 10 mL DCE and 2 mL NMP. To it were added DIEA (330 μL, 1.9 mmol) and cyclopentanone (480 mg, 5.7 mmol). The mixture was stirred at RT for 5 hours, and to it were added HOAc (220 μL, 3.8 mmol) and NaBH(OAc)3 (240 mg, 1.14 mmol). The mixture was stirred at RT for overnight. It was diluted with 10 mL MeOH, concentrated in vacuo, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (279) as HCl salt (45 mg, 45%). MS found for C26H40N10O2 as (M+H)+ 525.6, (M−H)− 523.3. UV: λ=254, 270, 297, 331, 374 nm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1>CN(C)C=O.CO>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])=[N:16]2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc2ccccc2n1
Temperature: 4 °C
Yield: 26.8 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 2-quinolinecarboxylic acid (10.4 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (7.2 g). After cooling at 4° C., the crystallized solid is separated by filtration, washed with distilled water (5×50 cc) and air-dried. The product obtained (7.4 g; m.p. 260° C.) is dissolved in a mixture of dimethylformamide (200 cc) and methanol (200 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×15 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)quinoline-2-carboxamide (3.6 g), m.p. 275° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C1(O)C=CC=CC=1.C(=O)(O)[O-].[Na+].Cl>[OH-].[Na+].CCOCC>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:13]=2[CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: Cc1c(N)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: Cc1c(Nc2ncc(Br)cc2C(=O)O)cccc1C(F)(F)F
Temperature: 170 °C

Procedure:
Heat in an oil bath at 170° C. a mixture of 15 g. of 5-bromo-2-chloro-nicotinic acid, 12.2 g. of 2-methyl-3-trifluoromethyl aniline and 60 g. of phenol for three hours. Treat the resulting reaction mixture with ether and 5% sodium bicarbonate solution, concentrate and steam distil to obtain an oily residue. Dissolve the oily residue in dilute sodium hydroxide solution, acidify with dilute hydrochloric acid and filter. Recrystallize the product from methanol to yield 5-bromo-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid, m.p. 222°-224° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:4].Cl>C(O)(=O)C>[F:19][C:16]([F:17])([F:18])[C:12]1[CH:11]=[C:10]([C:9]2[O:8][N:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cnoc1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnoc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A portion of the methyl-5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylate (5.0 g.; 0.018 mol.) in 10 ml. of acetic acid was reacted with 10 ml. of concentrated hydrochloric acid at reflux for six hours. The reaction mixture was cooled to 25° C., and then poured onto 50 g. of ice. The resulting mixture was extracted five times with 25 ml. of methylene chloride. The extracts were combined, dried over magnesium sulfate, filtered, and concentrated to yield a white solid. Recrystallization from ether-hexane yielded 5-(3'-trifluoromethylphenyl)-4-isoxazolecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]([S:12]([CH3:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([S:12]([CH3:14])=[O:13])=[CH:8][N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)C1C=Nc2cc(F)ccc2C1=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21

Procedure:
7-Fluoro-3-methylsulphinyl-4-quinolone (5.0 g.) was dissolved in hot butanone (250 ml.) containing anhydrous potassium carbonate (3.06 g.). The resulting suspension was stirred and treated dropwise with dimethyl sulphate (2.09 ml.). The mixture was stirred and boiled under reflux for 1 hour and filtered while hot. The filtrate was allowed to cool, giving a crystalline product. The product was collected and dried to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p. 226°-8°.