Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N)(=[O:39])C>C1COCC1.O.[Pd](Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]=2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[O:10])[CH:6]=[CH:7][CH:8]=1)(=[O:39])[NH2:2]
Reactant: CC(N)=O
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C#N)c1
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C(N)=O)c1
Temperature: 23 °C
Yield: 87.9 %

Procedure:
A solution of methyl 3-{3-[(3-cyanophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (125 mg, 0.257 mmol), palladium(II) chloride (9.1 mg, 0.051 mmol), and acetamide (152 mg, 2.57 mmol) in THF (1.5 mL) and water (0.5 mL) is heated at 50° C. for 3 h then cooled to 23° C. and partitioned between water and Et2O. The organics are washed with water, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 75% EtOAc in hexanes) gives methyl 3-{3-[(3-carbamoylphenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (114 mg, 88%).
Reaction SMILES: [CH3:1][N:2]([C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][N:2]([C@H:15]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16]1)[C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: BrCCc1ccccc1
Reactant: CN(C(=O)C12CC3CC(CC(C3)C1)C2)[C@H]1CCNC1
Product: CN(C(=O)C12CC3CC(CC(C3)C1)C2)[C@H]1CCN(CCc2ccccc2)C1

Procedure:
(S)-N-Methyl-N-(pyrrolidin-3-yl)-1-adamantanecarboxamide and (2-bromoethyl)benzene were reacted under the same conditions as in Example 1 to give (S)-N-methyl-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: CC(O)C.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].Cl>>[CH3:22][CH:21]([OH:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.8 %

Procedure:
2-Propanol (1.53 ml, 20 mmol) was added to 9.9 ml (10 mmol) of a toluene solution of DIBAH (1.02 M) at room temperature and the mixture was stirred at room temperature for 1 hour. Thereto was added 0.601 g of acetophenone, and the resultant mixture was stirred at room temperature for 6 hours, followed by hydrolysis with 1 N hydrochloric acid with ice cooling. Extraction with ethyl acetate and concentration gave 1.001 g of α-phenethyl alcohol as an oil. Conversion 55%, yield 47.7%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[O:5][C:6]=1[Br:7].Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:8]([C:4]1[O:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9]
Reactant: O=C(Cl)c1cc(Br)c(Br)o1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A solution of the product of Step 1 (0.1 mol) in dichloromethane (300 ml) was cooled to 0° C. and treated with N,O-dimethylhydroxylamine hydrochloride (11.7 g, 0.12 mol) followed by triethylamine (36 ml, 0.36 mol). The mixture was allowed to warm to room temperature and stirred for 30 minutes The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. After separation of the layers, the organic phase was washed sequentially with 2M hydrochloric acid, water and brine, dried and concentrated in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1:1) to give the title compound (30.1 g, 96%); 1H NMR (CDCl3) 7.12 (1H, s), 3.78 (3H, s), 3.31 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[CH2:28][CH2:29][O:30][CH2:31][CH:32]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:27]3[CH2:32][CH2:31][O:30][CH2:29][CH:28]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-iodo-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example 35(d)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 314.0 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [NH2:1][C:2]([CH2:21][OH:22])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1[O:22][CH2:21][C:2]([CH2:3][OH:4])([CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=2)[N:1]=1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CCC2(CO)COC(C)=N2)cc1
Yield: 88.5 %

Procedure:
A solution of 450 mg (1.5 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol, 0.32 mL (1.75 mmol) of triethylorthoacetate and 0.56 mL (3.2 mmol) of DIEA in 6 mL of DMF was stirred at 75° C. for 2 h. The mixture was cooled, partitioned between 40 mL of 3:1 v/v ether/EtOAc and water and the layers were separated. The organic layer was washed with water and dried. Flash chromatography on silica gel using 4:1 v/v CH2Cl2/EtOAc as the eluant afforded 440 mg (91%) of the title compound: Mass spectrum (NH3—CI) 332 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[CH:33]1([Mg]Br)[CH2:35][CH2:34]1>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:33]1([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][C:6]([CH2:19][N:20]4[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]4)=[CH:7][CH:8]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: Br[Mg]C1CC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C4CC4)nc3c2)nn1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (100 mg, 0.22 mmol) in THF (3 mL) was added Ni(dppp)Cl2 (12 mg, 0.02 mmol) and cyclopropylmagnesium bromide (0.5M, 1.3 mL, 0.66 mmol). The mixture was stirred at 60° C. for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound MS (+ESI): 471 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[N:2]1
Reactant: NCCCNc1nsc2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCNc1nsc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-(Benzo[d]isothiazol-3-yl)propane-1,3-diamine (100 mg, 0.48 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (92 μL, 0.53 mmol). The solution was cooled on an ice-water bath and then a solution of 4-chlorobenzoyl chloride (68 μL, 0.53 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2 h while warming to room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 20% ethyl acetate in hexanes and selected fractions were combined and concentrated under reduced pressure to yield N-(3-(benzo[d]isothiazol-3-ylamino)propyl)-4-chlorobenzamide as a white solid, (73 mg). 1H NMR (300 MHz, DMSO-d6): 8.6 (broad s, 1H), 8.1 (d, 1H), 7.8 (m, 3H), 7.4 (m, 5H), 3.5 (m, 2H), 3.3 (m, 2H), 1.9 ppm (m, 2H). MW=346 confirmed by LC-MS, tr=3.97 min (Method B) MH+=347.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.NC1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:12]
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Scheme I describes a method to prepare quinolinone compounds such as Structure 5, nitro-quinolinone compounds such as Structure 6, and amino-2-quinolinone compounds such as Structure 3 through modified Knorr reactions. Thermal condensation of a 4-aminoacetanilide (Structure 1) with a 3-ketoester, for example, ethyl 4,4,4-trifluoroacetoacetate in nitrobenzene affords a bis-amide such as Structure 2. When a bis-amide compound of Structure 2 is treated with concentrated sulfuric acid at 60-100° C., aminoquinolinone compounds of Structure 3 are produced. An alternate process of preparing 6-aminoquinolinone compounds such as Structure 3 starts with a similar Knorr reaction. The synthesis begins with reaction of an aniline such as Structure 4 and a 3-ketoester in refluxing toluene followed by treatment of a Lewis acid such as p-toluenesulfonic acid to produce a 2-quinolinone such as Structure 5. Classic nitration of the 2-quinolinone (e.g., Structure 5) selectively provides a 6-nitroquinolinone compound (e.g., Structure 6). Reduction of the nitroquinolinone such as Structure 6 under standard reduction conditions (e.g., metal catalyzed hydrogenation or tin chloride reduction) affords aminoquinolinone compounds such as Structure 3.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[CH2:10]([C:15]12[CH2:22][CH2:21][C:18]([C:23]([OH:25])=O)([CH2:19][CH2:20]1)[CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][CH3:14].Cl.CN>C(Cl)Cl>[CH3:1][NH:4][C:23]([C:18]12[CH2:21][CH2:22][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:20][CH2:19]1)[CH2:16][CH2:17]2)=[O:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCCCCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (1.44 mL, 11.1 mmol) was added to a mixture of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (3-A) (1.09 g, 4.45 mmol) and methylamine hydrochloride (1.5 g, 22.3 mmol) in methylene chloride (10 mL) was added and the mixture stirred at room temperature for 18 h. After diluting with methylene chloride, the mixture was washed with water, brine, dried (MgSO4) and concentrated in vacuo to give N-methyl-4-pentylbicyclo[2.2.2]octane-1-carboxamide (3-C). 1H NMR (500 MHz, CDCl3): δ 0.91 (t, 3H); 1.22 (m, 8H); 1.43 (m, 6H); 1.77 (m, 6H); 2.82 (d, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:12]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[C:8]([Cl:12])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1c(O)ccc(Cl)c1F
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1c(O)c(Cl)cc(Cl)c1F
Temperature: 60 °C
Yield: 85.3 %

Procedure:
To 20 g (114.6 mmole) of 3-chloro-2-fluoro-6-hydroxybenzaldehyde in 250 mL of glacial acetic acid was added 27.8 g of Cl2 gas over a period of 30 min. The mixture was stirred and heated to 60° C. for 2 hrs and allowed to stir at rt overnight. The reaction mixture was diluted with 1L of water and extracted four times with diethyl ether. Combined extracts were washed with water and sat. brine and concd in vacuo to afford a slurry. Addition of 250 mL of water afforded a solid which was collected by filtration and allowed to air dry for 8 hrs to afford 20.42 g (85%) of a yellow solid: mp 58-62° C.; 1H NMR (CDCl3/400 MHz) 7.65 (d, 1H, J=7.5 Hz), 10.26 (s, 1H), 11.88 (s, 1H); 13C NMR (CDCl3/100 MHz) 111.2 (d, J=12.0 Hz), 118.2 (d, J=4.6 Hz), 127.8, 137.6 (C—H, d, J=2.1 Hz), 156.8 (d, J=3.0 Hz), 158.3 (d, J=260.8 Hz), 191.4 (CHO, d, J=8.8 Hz); 19F NMR (CDCl3/400 MHz) −124.7 (d, 1F, J=7.7 Hz); MS (EI) 208 (M+, 100); 207 (91); HRMS (EI) m/z calcd for (C7H3O2Cl2F) 207.9494, found 207.9470.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:36]3[S:32][C:33](=[O:38])[NH:34][C:35]3=[O:37])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 81.5 %

Procedure:
To a stirred suspension of 16 (1.81 g, 4.3 mmol) in anhydrous toluene (25 mL), 2,4-thiazolidinedione (0.56 g, 4.74 mmol), benzoic acid (0.68 g, 5.60 mmol) and piperidine (0.60 mL, 6.03 mmol) was added sequentially and heated at reflux temperature with continuous removal of water using a Dean-Stark apparatus for 2 h. Solvent was evaporated to dryness under reduced pressure. The residue obtained was purified by silica gel chromatography, eluted with hexane-ethyl acetate (1:1) to yield 17 (1.82 g, 81%): mp 104-106° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (br s, 1H), 7.76 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 7.07 (d, J=4.8 Hz, 2H), 7.03 (d, J=4.8 Hz, 2H), 6.33-6.28 (m, 3H), 4.01 (t, J=7.5 Hz, 1 Hz), 3.66 (s, 6H), 3.56 (s, 3H), 3.22 (dd, J=13.8 and 8.4 Hz, 1H), 2.90 (dd, J=13.5 and 7.2 Hz, 1H); MS (EI) m/z 520[M]+; Anal. (C28H25NO7S) C: calculated, 64.73; found, 65.89; H: calculated, 4.85; found, 5.08, N: calculated, 2.70; found, 2.56.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([OH:22])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)C>[OH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([NH:15][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:17]1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N[C@@H]1CCC[C@H](O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (4.38 g, 18.82 mmol) and (1S,3R)-3-aminocyclohexanol (2.276 g, 19.76 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) were dissolved in ethanol (75 mL) before adding DIEA (4.93 ml, 28.2 mmol) and heating to 60° C. After 2 hrs, LCMS showed the desired product mass was the dominant peak formed. The reaction was removed from heat and concentrated. The crude material was purified on a 340G SNAP Biotage column (20-100% ethyl acetate in hexane) to give ethyl 4-((1R,3S)-3-hydroxy-cyclohexylamino)-2-(methylthio)pyrimidine-5-carboxylate (5 g, 16.06 mmol, 85% yield) as a white foam; MS (ESI) m/z 312.1 [M+1]+
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:28]=2[Cl:35])=[O:26])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[I-].[Li+].N1C=CC=CC=1>O>[Cl:35][C:28]1[CH:29]=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:27]=1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@@H:4]([C:3]([OH:36])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:19][CH:20]=1)=[O:26]
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3cc(C#N)ccc3Cl)cc2)C(=O)OC)CCCC1
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3cc(C#N)ccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a mixture of 4-[(2-chloro-5-cyanophenylcarbonyl)amino]-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.1 mmol, 51 mg) and lithium iodide (1.0 mmol, 133 mg) was added pyridine (2 mL) at room temperature. The solution was refluxed for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the mixture was cooled to room temperature and diluted with water (15 mL) and the bulk of the pyridine was removed under reduced pressure. Then it was extracted with ether (2×15 mL) to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated white solid was collected by filtration and washed with 20 mL of water and 20 mL of hexane. After air-drying, the crude product was crystallized from acetonitrile to afford 20 mg (40%) of a white solid: mp 169-172° C. HR MS (C26H26ClN3O5): Obs mass, 498.1802. Calcd mass, 498.1795, M+H).
Reaction SMILES: NC1C=C2NC(C3C=C(N[C:19](C4OC(F)=CC=4)=[O:20])C=CC=3Cl)=NC2=NC=1.C(Cl)(=O)OC(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]2[O:45][C:46](F)=[CH:47][CH:48]=2)=[O:43])=[CH:37][C:36]=1[C:50]1[N:51](C(OC(C)C)=O)[C:52]2[C:53]([N:65]=1)=[N:54][CH:55]=[C:56]([NH:58][C:59]([O:61][CH:62]([CH3:64])[CH3:63])=[O:60])[CH:57]=2.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:62]([O:61][C:59](=[O:60])[NH:58][C:56]1[CH:57]=[C:52]2[NH:51][C:50]([C:36]3[CH:37]=[C:38]([NH:41][C:42]([C:44]4[O:45][C:46]([O:20][CH3:19])=[CH:47][CH:48]=4)=[O:43])[CH:39]=[CH:40][C:35]=3[Cl:34])=[N:65][C:53]2=[N:54][CH:55]=1)([CH3:64])[CH3:63]
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)[nH]c2c1
Reactant: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)n(C(=O)OC(C)C)c2c1
Agent: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(-c3nc4ncc(NC(=O)OC(C)C)cc4[nH]3)c2)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)-5-fluorofuran-2-carboxamide (1-9) (60 mg, 0.161 mmol) in pyridine (2 mL), and the isopropyl carbonochloridate (1M solution, 0.241 mmols, 1.5 eq) was added. The brown reaction mixture was stirred at room temperature for 12 hrs. Checked via LCMS for the desired peak and found M+H (544) which seemed to be isopropyl 2-(2-chloro-5-(5-fluorofuran-2-carboxamido)phenyl)-6-((isopropoxycarbonyl)amino)-1H-imidazo[4,5-b]pyridine-1-carboxylate. Removed all solvents under vacuo and the reaction mixture was redissolved in MeOH (2 mL), and added potassium carbonate (55 mg, 0.402 mmols, 2.5 eq). The reaction mixture was heated at 60 C for 1 hr, checked via LCMS once more and found the M+H=470 as the only peak. The reaction mixture was filtered and the methanolic solution was then injected into the mass triggered HPLC to isolate the desired compound, treated with carbonate based resin and isolated the free base of Compound 39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][OH:59])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH2:57][CH2:58][OH:59])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(Cc1cccc(Br)c1)N1CCN(CCO)CC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CC(=O)N4CCN(CCO)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(3-bromo-phenyl)-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanone (143 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-186) as a yellow powder (56 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1ccncc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccncc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 293 (M+, 100), 92 (40), 65 (39).
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: Nc1ccc[nH]c1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
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+).