Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](/[CH:4]=[N:5]\[C:6](=O)[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:15]=[N:16][C:17]3[NH:22][CH2:21][C:20](=[O:23])[N:19]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([O:31][CH3:32])[CH2:27][CH2:26]4)[C:18]=3[N:33]=2)=[CH:9][N:8]=1)C.C(O)(=O)C.[NH2:39]N>O>[CH3:32][O:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([CH2:24][N:19]2[C:18]3=[N:33][C:14]([C:10]4[CH:9]=[N:8][C:7]([C:6]5[N:5]=[CH:4][NH:2][N:39]=5)=[CH:12][C:11]=4[CH3:13])=[CH:15][N:16]=[C:17]3[NH:22][CH2:21][C:20]2=[O:23])[CH2:26][CH2:27]1
Reactant: NN
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(=O)/N=C\N(C)C)cc4C)nc32)CC1
Solvent: O
Solvent: CC(=O)O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 0 °C

Procedure:
(Z)—N-((Dimethylamino)methylene)-5-(8-(((trans)-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide (0.467 g, 1.00 mmol) was added to acetic acid (6 mL). The reaction was cooled to 0° C. and hydrazine (1.00 mL, 32 mmol) was added dropwise. The reaction was allowed to stir and warm to 25° C. over 10 min. Reaction was concentrated under a stream of nitrogen placed in reaction vessel. Water (5 mL) was added and the product was collected by filtration and purified using reverse-phase semi-preparatory HPLC (20-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.046 g, 0.106 mmol, 11% yield). 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 8.72 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 4.30 (s, 2H), 3.99 (d, J=7.03 Hz, 2H), 3.32 (s, 3H), 3.08-3.17 (m, 1H), 2.71-2.76 (m, 3H), 2.06 (br. s., 2H), 1.80-1.89 (m, 1H), 1.74 (br. s., 2H), 1.09 (d, J=11.32 Hz, 4H); MS (ESI) m/z 435.5 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]([NH2:17])(=[S:16])[CH3:15]>C(O)(=O)C>[CH3:15][C:14]1[S:16][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[N:17]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Cc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Yield: 84.7 %

Procedure:
A mixture of 2-bromo-3'-nitroacetophenone (5 g, 20.5 mmol) and thioacetamide (1.4 g, 18.6 mmol). in glacial acetic acid (50 ml) is heated to reflux over night. After cooling the precipitate is filtered off, washed with water and dried to yield 2-methyl-4-(3-nitrophenyl)thiazole (3.47 g, 85%). Mp 87-88° C. This product is hydrogenated as described in Example 4 to yield 2n quantitatively. Mp 80-81° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 15 g (0.10 mole) of 2-chloro-3-nitro pyridine and 9.3 g (0.10 mole) of aniline were heated by means of an oil bath at about 120° C. for 30 min. The mass spectra of a sample taken at 15 min indicated presence mainly of the title compound. The product was partitioned between chloroform and aqueous basic solution (sodium hydroxide). The aqueous solution was washed twice more with chloroform. The chloroform extracts were washed once with a sodium chloride-sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated to give 21.9 g of black oil which solidified on standing. The solid was triturated in 30-60 pet-ether for 1 hr. The remaining solid was filtered off and washed with the same solvent and air dried to give 18.7 g (87%). The solid was recrystallized from cyclohexane. Nuclear magnetic resonance confirmed the title compound, m.p. 172°-174° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl.[OH-].[Na+]>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2
Reactant: Fc1cccc2[nH]ccc12
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: Fc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To a stirred suspension of sodium borohydride (560 mg) in diethyl ether (6 ml) was added dropwise zinc chloride (1.0 M solution in diethyl ether, 7.4 ml). The mixture was stirred at room temperature under argon atmosphere for 1 day. To the resultant mixture was added dropwise a solution of 4-fluoroindole (500 mg) in diethyl ether (5 ml). After being stirred at room temperature under argon atmosphere for 12 days, thereto was added a cold 0.5 N aqueous hydrochloric acid solution (30 ml) at 0° C. After that, the mixture was basified with a cold 2 N aqueous sodium hydroxide solution at 0° C., and extracted with ethyl acetate 3 times. The combined organic layer was dried over magnesium sulfate, and the insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the titled compound (351 mg) as pale yellow oil. APCI-Mass m/Z 138 (M+H). 1H-NMR (DMSO-d6) δ 2.93 (t, J=8.6 Hz, 2H), 3.46 (t, J=8.6 Hz, 2H), 5.78 (br-s, 1H), 6.24-6.31 (m, 2H), 6.87-6.94 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:37])(C)C>CC(CC)=O>[ClH:37].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][CH2:28][S:29][CH3:30])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: CSCC[C@@H]1NC2(CCN(C(=O)c3ccc(F)cc3)CC2)N(Cc2ccccc2)C1=O
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1-benzyl-8-(4-fluorobenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (223 mg, 0.5 mmol) was dissolved in ethyl methyl ketone (1.8 mL), water (5 μL) and TMSCl (70 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1-benzyl-8-(4-fluorobenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 227 mg (94%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:6]([O:8]C)=[O:7].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CN(C)C(=O)C.O>[C:14]([O:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:6]([OH:8])=[O:7])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cc(Cl)nc(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1cc(C(=O)O)cc(Cl)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-(bromomethyl)-6-chloroisonicotinate and sodium acetate in N,N-dimethylacetamide is stirred at 120° C. for 2 hours. The mixture is cooled to room temperature and diluted with water (50 mL). The mixture is washed with ethyl acetate/toluene (2:1, 80 mL×2). Water layer is acidified (to pH 4) by the addition of 2M hydrochloric acid, extracted with ethyl acetate (80 mL×2), dried over sodium sulfate. The organic solvent is removed under reduced pressure to give the title compound as a crude product (590 mg, clear brown oil, include N,N-dimethylacetamide). This is used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]C)=[O:21]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:10][CH2:19][C:20]([OH:22])=[O:21])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(Cl)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Cl)cc(C=O)c1OCC(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 5-chloro-2-hydroxy-3-methylbenzaldehyde (5.86 mmol) in acetonitrile (30 mL) was treated with potassium carbonate (17.59 mmol). The reaction mixture was stirred for 30 min and was then treated with methyl bromoacetate (7.03 mmol). The resulting mixture was stirred at room temperature overnight. Analysis by LCMS indicated the formation of the desired intermediate ester, and the reaction mixture was concentrated to dryness in vacuo. The crude material was dissolved in a 3:1 methanol:water mixture (20 mL) and was heated to 50° C. with stirring. The reaction was then cooled to room temperature and was acidified to pH˜3 using 1N aq HCl. The methanol was removed in vacuo and the resulting aqueous suspension was diluted with water (100 mL) and was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting beige solid was used without further purification (1.07 grams, 80% yield). MS(ES)+ m/e 229.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:18](=O)[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:18][CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclobutylamino)-2-methylbenzoate (0.70 g, 2.73 mmol) and acetaldehyde (0.36 g, 8.20 mmol) in dichloroethane (15 mL), acetic acid (0.98 g, 16.4 mmol) was added and the reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (1.7 g, 8.2 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure to give title compound (0.71 g, 91%).
Reaction SMILES: CO.CC(OC[C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12](N)[C:13](=[O:14])N2[C:9]=1C(O)=O)=O.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=[O:23]>O1CCOCC1>[S:16]1[CH:17]=[CH:8][CH:9]=[C:11]1[CH2:12][C:13]([OH:14])=[O:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)Cc1cccs1

Procedure:
A solution of 15 mM of 7 ACA and 400 mM of thienylactic acid in 50% dioxane/50% acetate 50 mM is prepared at a ph 6. The column is thermostatized at 25° C., the flow and volume of the derivative are the same as in example 1. The moveable phase that we use for HPLC is 30% methanol/70% phosphate, 0.067M at a pH of 4.7, the rest of the conditions are maintained like those in example 1. After attaining the balance, the degree of conversion of 7-ACA into cephalothin is above 95%.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[CH3:7])C.[OH-].[Na+]>>[CH3:7][N:6]1[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CN(C)Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Product: CN1CC(=O)Nc2ccccc2C1
Temperature: 150 °C

Procedure:
2.0 g N-(o-aminobenzyl)sarcosine ethyl ester was dissolved in 40 g polyphosphoric acid and the mixture was heated to 150° C. for two hours, then cooled and charged with 300 ml icewater.pH was adjusted to 8 with 50% NaOH and the mixture was extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:21]([CH2:22]Br)=[CH:20][S:19][CH:18]=1>CN(C)C=O>[CH:18]1[S:19][CH:20]=[C:21]2[CH2:22][N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:16][C:17]=12
Reactant: CCOC(=O)CN
Reactant: BrCc1cscc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2cscc2C1
Temperature: 5 °C
Reaction time: 67 h
Yield: 22.2 %

Procedure:
13.18 g (0.0945 mol) of ethyl aminoacetate hydrochloride, 33.8 g (0.245 mol) of potassium carbonate and 60 ml of dimethylformamide are introduced, under argon, into a 250 ml round-bottomed flask. The mixture is cooled to 5° C. and 8.5 g (0.0315 mol) of 3,4bis(bromomethyl)thiophene in solution in 30 ml of dimethylformamide are added over 25 minutes. This mixture is stirred at room temperature for 67 h. The mixture is poured into 500 ml of ice-cold water and extracted 3 times with ether. The organic phases are washed 3 times with water, combined, dried, filtered and then concentrated under reduced pressure. There are obtained 1.57 g (0.007 mol) of product (yield 24%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH:14][C:15]1[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=1>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:14][C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CCCOc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCOc1ccc(C(=O)Oc2cc[nH]c(=O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A 2.14 g quantity of 4-n-propoxybenzoyl chloride was added to a suspension of 1.00 g of 4-hydroxy-2-pyridone in 30 ml of pyridine, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 1.98 g of the title compound in a yield of 81%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[C:5]([F:28])=[CH:4][N:3]=1.[C:29](=[NH:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:10]([CH2:9][NH:8][C:6]1[C:5]([F:28])=[CH:4][N:3]=[C:2]([N:42]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:7]=1)=[CH:19]2
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Fc1cnc(N=C(c2ccccc2)c2ccccc2)nc1NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Temperature: 80 °C
Reaction time: 19.5 h

Procedure:
A Schlenk tube was charged with 2-chloro-N-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)-5-fluoropyrimidin-4-amine (0.1027 g, 0.2368 mmol), benzophenone imine (0.04751 ml, 0.2842 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.05421 g, 0.05920 mmol), rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.1106 g, 0.1776 mmol), sodium tert-butoxide (0.03186 g, 0.3315 mmol), and 2 ml of toluene, and the mixture was purged with argon and stirred at 80° C. After 19.5 hr, the mixture was cooled to room temperature and diluted with Et2O (40 ml), filtered, rinsed with Et2O (40 ml), and concentrated under reduced pressure to give N4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-N2-(diphenylmethylene)-5-fluoropyrimidine-2,4-diamine as an orange syrup: LC-MS m/z 578.0 and 580.1 [M+H]+. The orange syrup was carried on crude without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(OC([N:37]([CH2:45][CH3:46])[C:38]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:42]([C:38]4([NH:37][CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)C1(C(=O)O)CCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), 1-(tert-butoxycarbonyl(ethyl)amino)cyclobutanecarboxylic acid (29.2 mg, 0.12 mmol), HATU (45.8 mg, 0.12 mmol) and di-isopropylethylamine (20 μL, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA and was then stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(ethylamino)cyclobutyl)methanone; ESMS m/z 541.3 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH3:12])[C@H:9]([CH3:13])[O:8][C@@H:7]([O:14][C:15](=[O:42])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)[C@@H:6]1[O:43][CH3:44])[CH2:2][CH3:3].I[CH2:46][CH3:47]>>[CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH3:12])[C@H:9]([CH3:13])[O:8][C@@H:7]([O:14][C:15](=[O:42])[N:16]([CH2:46][CH3:47])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:37])[F:39])=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)[C@@H:6]1[O:43][CH3:44])[CH2:2][CH3:3]
Reactant: CCCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Reactant: CCI
Product: CCCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)N(CC)c2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC

Procedure:
Compound 207 was N-ethylated as in Example 82, using iodoethane instead of iodomethane, to give Compound 253. 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.22 (d, J=68 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.17 (s, 1H), 3.8 (q, J=7.5 Hz, 2H), 3.60-3.30 (m, 11H), 3.10 (br s, 1H), 1.38 (d, J=6.0 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H); MS 659.12 ([M+H]+).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:9]=[C:10]([OH:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH:32]([CH3:34])[CH3:33]>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:9]=[C:10]([O:11][CH:32]([CH3:34])[CH3:33])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(O)c21
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC(C)C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a mixture of ethyl 2-(1,4-dihydroxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (320 mg, 0.95 mmol) and anhydrous K2CO3 (480 mg, 3.48 mmol) in DMF (10 mL) at 0° C. under N2 atmosphere was added 2-bromopropane (400 mg, 3.30 mmol). The reaction mixture was stirred at room temperature overnight and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (110 mg. Yield: 30.6%)
Reaction SMILES: C1COCC1.[Si]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][C:23]([NH:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([F:29])[CH:25]=2)[N:20]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:19]=1)(C(C)(C)C)(C)C>O>[CH:31]1([NH:30][C:23]2[CH:22]=[C:21]3[C:26]([C:27](=[O:28])[C:18]([O:17][CH2:16][CH2:15][CH2:14][OH:13])=[CH:19][N:20]3[CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:25][C:24]=2[F:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(OCCCO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 2 h
Yield: 46 %

Procedure:
To a 15 ml THF solution of 762 mg of 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-7-(cyclohexylamino)-1-cyclopentyl-6-fluoroquinoline-4(1H)-one was added 1.5 ml of a 1 M tetrabutylammonium fluoride THF solution at room temperature, followed by stirring for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, evaporation was carried out under a reduced pressure. By purifying the residue by silica gel column chromatography, 273 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(3-hydroxypropoxy)quinolin-4(1H)-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1.N1C=CC=CC=1C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I.O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: Clc1cccc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccn1
Solvent: O
Product: Nc1ncccc1-c1ccc(Oc2cccc(Cl)c2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a mixture of 4-(2-aminopyridin-3-yl)phenol (400 mg), 1-chloro-3-iodobenzene (615 mg), picoline acid (52.9 mg) and tripotassium phosphate (1368 mg) in DMSO (6 mL) was added copper (I) iodide (82.0 mg). The reaction mixture was stirred under a nitrogen atmosphere at 120° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and concentrated under reduced pressure to give the title compound (307 mg) as a yellow solid.