Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[CH:27]2[N:21]([C:22]3[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=3[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=32)[CH2:20][CH2:19][NH:18]1>CC(=O)CC.C1C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:19][CH2:20][N:21]2[C:22]3[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=3[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH:27]2[CH2:17]1)[CH3:10]
Reactant: CCOC(=O)CCCCBr
Reactant: c1ccc2c(c1)Oc1ccccc1N1CCNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCCN1CCN2c3ccccc3Oc3ccccc3C2C1
Yield: 97 %

Procedure:
Ethyl 5-bromopentanoate (1.66 g, 0.0079 mol) and potassium carbonate (1.75 g, 0.0127 mol) were added to a solution of 1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]-oxazepine (1.6 g, 0.0063 mol prepared similarly as described in Neth. Appl. 6709520, Chem. Abs. 70, 115192 (1969)) in 2-butanone (45 ml) and the reaction mixture was heated at 70-80° C. for 17 h. The mixture was diluted with benzene (50 ml), the solid was filtered off, washed with benzene (2×10 ml) and the filtrate was evaporated in vacuo. The residue (3.2 g) was purified by column chromatography on silica gel (100 g) using benzene and a mixture of benzene and chloroform (1:1) as eluents to afford 2.35 g (97%) crude 5-(1,3,4,14b-tetrahydro-2H-dibenzo[b,f]-pyrazino[1,2-d][1,4]oxazepin -2-yl)pentanoic acid ethyl ester.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[N:19]=[N:20][CH:21]=[CH:22][CH:23]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[N:19]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cccnn1
Agent: [I-]
Product: c1cnnc(N=C2SC[C@@H]3Cc4ccccc4CN23)c1
Yield: 65.7 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 3-aminopyridazine (9.5 g) as the starting materials, (S)-3-(pyridazin-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (9.3 g) is obtained in the form of light beige crystals, m.p.=140°-142° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH2:14][O:15][CH:16]([F:18])[F:17])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:19][O:20][C:21](Cl)=[O:22]>ClCCl>[F:18][CH:16]([F:17])[O:15][CH2:14][CH2:13][C@H:2]([NH:1][C:21]([O:20][CH3:19])=[O:22])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)Cl
Reactant: N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
(S)-Benzyl 2-amino-4-(difluoromethoxy)butanoate (116 mg, 0.448 mmol) was dissolved in anhydrous dichloromethane (2.5 mL) and cooled down to 0° C. and TEA (181 mg, 1.79 mmol) and methylchloroformate (51 mg, 0.538 mmol) were added respectively. The mixture was stirred for 30 minutes and then it was stirred at room temperature overnight. The resulting product mixture was quenched with saturated NaHCO3 and extracted with dichloromethane. The organic layer was washed with saturated NH4Cl solution and brine and dried over Na2SO4. The volatiles were removed in vacuo to afford 56 mg (40%) of desired product after column purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH2:23][CH3:24].[C:25](O)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][CH2:23][CH3:24])[N:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1OCCCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCOn1c(CCCC)nc2c(N)nc3ccccc3c21

Procedure:
The 1-(4-aminobutoxy)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine was dissolved in dichloromethane (20 mL) and methanol (5 mL). Stearic acid (0.71 g) was added and the reaction was stirred to dissolve the stearic acid. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl (EDC, 0.45 g) was added and the reaction was stirred at ambient temperature for 16 hours. An additional portion of EDC was added (0.23 g) and the reaction was stirred for an additional 24 hours. Final portions of stearic acid (0.22 g) and EDC (0.37 g) were added to drive the reaction to completion and the reaction was stirred at ambient temperature for another 24 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography using a Biotage chromatography system (Si40+M2358-1 SiGel column, 85:15 dichloromethane/methanol isocratic elution). The semi-pure product was purified by flash column chromatography two more times using a 90:10 dichloromethane/methanol isocratic elution, followed by a 95:5 dichloromethane/methanol isocratic elution The fractions containing product were concentrated to yield 1.12 g of N-(4-{[4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]oxy}butyl)octadecanamide as an off white waxy solid. 1H-NMR (CDCl3): δ 0.89 (t, 3H), 1.01 (t, 3H), 1.14-1.42 (m, 28H), 1.50 (m, 2H), 1.65 (m, 2H), 1.74-1.94 (m, 4H), 2.02 (m, 2H), 2.20 (t, 2H), 2.95 (t, 2H), 3.40 (q, 2H), 4.33 (t, 2H), 5.59 (t, 1H), 6.10 (broad s, 2H), 7.39 (m, 1H), δ 7.57 (m, 1H), 7.83 (d, 1H), 8.07 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCCCC.O>C1COCC1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[B:14]([OH:15])[OH:13])#[N:5]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1ccccc1Br
Agent: [Li]CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Dissolve 2-bromobenzonitrile (melt in water bath at 65° C. before use, 6.733 kg, 37.0 mol, 1 eq) in THF (52.5 L) in a cryogenic reactor and cool to −78° C. Add triisopropylborate (13.96 kg, 74 mol, 2 eq). Allow the mixture to cool to −78° C. again. Add hexyllithium (2.5M in hexane, 15.38 kg, 55.5 mol, 1.5 eq) over a period of 2 h (max internal temp=69° C.). After the addition, stir for 1 h at −75° C. Add the mixture (−74° C.) to water (48 L, 5° C.) over a period of 15 min with stirring to give a slightly yellow emulsion (−1° C.). Warm the mixture to 23° C. and stir at this temperature for 90 min. Separate the layers. Extract the aqueous layer with isopropyl acetate (24 L). Combine the organic layers and re-extract with brine (22 L). Combine the aqueous layers and acidify to pH 1 with 1M sulfuric acid (31 L). Extract the product twice with isopropyl acetate (41 L and 39 L). Combine the organic layers and stir overnight with brine (21 L) at 2° C. Collect the organic solution (90 L) and distill under reduced pressure at 50-60° C. to reduce the volume to 10 L. Strip the suspension with isopropyl acetate (11 L). Add methylcyclohexane (20 L) at 25° C. Cool the suspension to -7° C. Collect the precipitated product by filtration. Wash the filter cake with a mixture of isopropyl acetate (2 L) and methylcyclohexane (4 L). Dry the filter cake on the rotovap at reduced pressure at 50° C. to obtain 2.997 kg of title compound as a white powder; 55% yield (poor yield due to some material sticking to the reactor wall). 1H NMR (solvent-dx): § 7.53 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.62 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.73 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([O:15][CH3:30])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1CNC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 3,4-bis((tert-butoxycarbonylamino)methyl)benzoic acid (380 mg, 1 mmol) in THF (5 mL) was added NaH (200 mg, 60%). After stirring at room temperature for 20 min, MeI (4 eq) was added and the resultant solution stirred at room temperature overnight. Water was added and the aqueous phase extracted with EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to afford methyl 3,4-bis((tert-butoxycarbonylamino)methyl)benzoate (368 mg). The ester was hydrolyzed following the procedure described in step 1e of Example 14 to afford 3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid (300 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1([S:14](Cl)(=[O:16])=[O:15])[NH:12][C:11]([Cl:13])=[CH:10][S:9]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[S:14]([C:8]1[S:9][CH:10]=[C:11]([Cl:13])[N:12]=1)(=[O:16])=[O:15]
Reactant: COCCCN
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Solvent: C1CCOC1
Product: COCCCNN(CCCOC)S(=O)(=O)c1nc(Cl)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
40 g of 3-methoxy-n-propylamine were added dropwise at room temperature to a solution of 25.25 g (0 1 mol) of 2,4-dichlorothiazole-sulphonyl chloride from Example 1 in 600 ml of THF, and the mixture was subsequently stirred for 30 minutes at room temperature. After concentrating under a waterpump vacuum, the mixture was stirred with 400 ml of water, the aqueous phase was extracted twice using methylene chloride, and the combined organic phases were dried over magnesium sulphate. After removing the solvent under a waterpump vacuum, 31.3 g of a brown oil were obtained which was chromatographed on silica gel using toluene/ethanol (5:1) as the eluent. 29.3 g (79%) of product were obtained, m.p 55° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:31])=[C:6]([CH2:28][CH2:29][CH3:30])[C:7]2[O:12][C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:27]=1)(=[O:3])[CH3:2].[C:32]1([O:42][CH2:43][CH2:44][CH2:45]Br)[C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:4]1[C:5]([O:31][CH2:45][CH2:44][CH2:43][O:42][C:32]2[C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[CH:35]=[CH:34][CH:33]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:7]2[O:12][C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:27]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Reactant: BrCCCOc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c2c(cc(C(C)=O)c1OCCCOc1cccc3c1CCCC3)CCC(CCC(=O)OCC)(CCC(=O)OCC)O2
Reaction time: 6 h

Procedure:
A mixture of 204 mg (0.469 mmol) of the title product of Example 81, 378 mg (1.41 mmol) of the title product of Example 12, and 136 mg (0.985 mmol) of anhydrous potassium carbonate in 4 ml of dimethylformamide was stirred at 80° for six hours. A further 136 mg of potassium carbonate was added, and the mixture was heated for another six hours. The mixture was permitted to cool and was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfite, filtered, and the solvent removed under reduced pressure. Chromotography of the residue over silica gel using 15% ethyl acetate/toluene as eluent gave the title compound, 114 mg.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[N:2]1.[H-].C([Al+]C(C)(C)C)(C)(C)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[N:2]1
Reactant: O=C(O)CCCc1nsc2ccccc12
Agent: CC(C)(C)[Al+]C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCCCCc1nsc2ccccc12
Temperature: -10 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
4-(1,2-Benzisothiazol-3-yl)butyric acid (C. Branca et al, Phytochemistry 14, 1975, 2545) (17 g) was dissolved in dry toluene (500 ml) and cooled to -10° C. Di-tertbutyl aluminium hydride (120 ml of an 1M solution in toluene) was added dropwise at -10° C. followed by stirring for 2 h at room temperature. Dilute sulfuric acid (2M, 300 ml) was added, the phases separated, the aqueous phase extracted with ether, and the combined organic phases dried over magnesium sulfate. Removal of solvents in vacuo left a viscous oil which was purified by column chromatography (silica gel, eluent:ether). 4-(1,2-Benzisothiazol-3-yl)-1-butanol (5.2 g) was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Br[C:12]1[CH:13]=[CH:14][C:15]([N+:25]([O-:27])=[O:26])=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:13]=[CH:14][C:15]([N+:25]([O-:27])=[O:26])=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCOCC1
Reactant: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Product: COC(=O)C1(c2ccc([N+](=O)[O-])c(N3CCC(C)CC3)c2)CCOCC1

Procedure:
The title compound is prepared by the procedure of Example 16, step (a) using tetrahydro-pyran-4-carboxylic acid methyl ester and 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (US 2005131022 A1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][OH:22]>CCO.C(#N)C>[OH:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ncccc12
Reactant: OCCCl
Solvent: CCO
Solvent: CC#N
Product: O=c1cc(-c2ccc(OCCO)cc2)oc2ncccc12
Temperature: 25 °C
Yield: 32.1 %

Procedure:
In a 100 mL dry round bottom flask with reflux condenser and magnetic stirrer was placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.0 g, 4.18 mmol) in EtOH (10 mL) and acetonitrile (50 mL). 2-Chloroethanol (2.05 g, 25.0 mmol) was added slowly and the reaction mixture was refluxed for 48 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified by column chromatography, using 2% MeOH in dichloromethane to afford 2-(4-(2-hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one (380 mg, 32% yield). MS (ES) m/z: 284.94 (M+1), 283.95 (M); Mp. 157-159° C.
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1[S:21][CH2:22][C:23]([OH:25])=[O:24].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](/[N:36]=[C:37]2\[CH:38]=[C:39](Cl)[C:40](=[O:47])[C:41]3[C:46]\2=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([OH:47])=[C:39]([S:21][CH2:22][C:23]([OH:25])=[O:24])[CH:38]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc21
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(O)CSc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c2ccccc2c1O

Procedure:
5.2.58 2-(4-(4-chlorophenylsulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid (14p) was prepared according to the procedure of procedure B for 10a except using (E)-4-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)-benzene sulfonamide (12e), which afforded the title compound 57.7 mg (68.4%) as a white solid, m.p.: 158-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:20](O)=[O:21])=[C:11]2[C:10]([C:28]([O:30][CH3:31])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:23]1([C@@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]=[C:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]=23)[C:20]([NH:46][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45]2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C3CCCC3)c12
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C3CCCC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopentylacetic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C27H38N4O5, 499; found, 499.6.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:2]1.ClN1C(=[O:21])CCC1=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]2=[O:21])=[CH:2]1
Reactant: c1ccc2c(c1)ccn2-c1ccsc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=C1Cc2ccccc2N1c1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 1-(3-thienyl)indole (9.14 g, 0.0459 M) in 350 ml of dry methylene chloride under a nitrogen atmosphere was added 6.44 g (0.0482 M) of N-chlorosuccinimide (NCS) at room temperature. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo. The resulting foamy residue was immediately dissolved in 190 ml of glacial acetic acid. The resulting mixture was heated to 70° C. followed by the addition of 49.5 ml of 85% H3PO4 and heating of the reaction mixture to reflux for one hour. The mixture was then cooled to room temperature, poured onto ice water, basified to pH ~11-12 with Na2CO3 and extracted with ethyl acetate (3×500 ml). The combined ethyl acetate extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo leaving dark brown-black oil. Purification of the crude product on a silica gel column (elution with CH2Cl2, followed by elution with 90% CH2Cl2 --10% CH3OH) gave a total of 7.2 grams (72.8%) of brown crystalline solid; m.p. 62°-67° C. MS: M+= 215. IR(KBr) 5.9 μ(s) c=O. NMR(CDCl3)delta: 3.6 (s, 2H), 6.7-7.4 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-amino-6-chloropyridin-3-yl)-(5-fluoro-2-methoxyphenyl)methanone (Example 19) and 1-methanesulfonylpiperidin-4-ylamine (Step A. Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 423.1502, Calcd for (M+H)+: 423.1497. Ki for cdk4=0.040 μM, cdk2=0.098 μM, and IC50 for HCT116 cell line=9 μM.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1.[CH3:21][N:22]=[C:23]=[O:24].O>N1C=CC=CC=1>[CH3:21][NH:22][C:23](=[O:24])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:6]=1
Reactant: CN=C=O
Reactant: Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of 10 g (0.033 mole) of 2-amino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole, and 2.3 g (0.04 mole) of methyl isocyanate in 50 ml of pyridine was heated at 50° for 3 hours. The reaction solution was mixed with 400 ml of water and allowed to stand overnight in the refrigerator. On the following morning, the crystalline solid was collected and dried in the oven. There was obtained 10 g of the desired product, m.p. 200°14 203°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.7-2.8 (CH3, doublet), 6.8 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=O).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4c(C(F)(F)F)cccc34)c2c1
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of 2,5-dimethylindole (765 mg) and 4-chloro-8-trifluoromethylquinoline (1.22 g) in NMP (1.5 ml) and 4M HCl in dioxane (0.2 ml) was heated at 140° C. for 1 h. After cooling the mixture was triturated with ether and filtered to give the sub-title compound (1.33 g) as a dark red solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([OH:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>CC#N>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([O:12][C:33]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:34])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1O
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OC(=O)N1CCCC1
Reaction time: 3 h
Yield: 52 %

Procedure:
tert-Butyl 3-amino-5-hydroxy-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate, prepared in example 1C, Step C, (40 mg, 0.14 mmol) in CH3CN (1 mL) was combined with Et3N (52 mg, 0.52 mmol) and pyrrolidine-1-carbonyl chloride (51 mg, 0.39 mmol) at room temperature. After stirring for 3 h, the mixture was evaporated under reduced pressure, water was added and extracted with ethyl acetate (3 mL), washed with water (3 mL×3), brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide tert-butyl 3-amino-4,6-dimethyl-5-(pyrrolidine-1-carbonyloxy)-thieno[2,3-b]pyridine-2-carboxylate (41 mg, 52%).