Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:41]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.41 mmol) in DMF (1 mL) was added chloromethyl pivalate (35 μL, 0.25 mmol) at rt. The reaction was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 1/1) to afford (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl pivalate (30 mg, 23%) and (N-(3-(5-(4-chlorophenyl)-1-((pivaloyloxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propylsulfonamido) methyl pivalate (20 mg, 13.3%) as white solids. The title compounds were characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [BH4-].[Na+].[O:3]([C:21]1[CH:28]=[C:27]([O:29][CH3:30])[C:24]([CH:25]=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1)[Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>O1CCCC1>[O:3]([C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([CH2:25][OH:26])=[C:27]([O:29][CH3:30])[CH:28]=1)[Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
Sodium borohydride (519.0 mg, 13.73 mmol) was added to an ice-cold solution of 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzaldehyde (3.85 g, 9.15 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours and 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzyl alcohol as a colorless crystalline powder (melting point: 127.5-129.0° C.) (4.01 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:69][NH:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:70]([CH:71]2[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]2)[CH3:69])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CNC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-methylcyclohexylamine (0.027 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.036 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([NH:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14].P(Cl)(Cl)(Cl)=O>CN(C=O)C>[C:26]1([CH2:25][C@H:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[C:13]2[O:14][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CNC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)c1ncc(-c2ccccc2)o1
Yield: 41 %

Procedure:
The product from Example 48 Part A (412 mg, 1 mmol) was dissolved in DMF and treated with phosphorous oxychloride (460 mg, 3 mmol) at 90° C. according to the procedure described by Robert Dow et al. (J. Org. Chem., 1990, 55, 386) to yield 160 mg (41% yield) of the product. MS 395.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=1.B([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][C@@H:28]([C:30]([OH:32])=[O:31])[NH2:29])=[CH:25][CH:24]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:29][CH:28]([CH2:27][C:26]1[CH:33]=[CH:34][C:23]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[C:30]([OH:32])=[O:31]
Reactant: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(Cc1ccc(-c2cc(OC(c3ccccc3)C(F)(F)F)ncn2)cc1)C(=O)O
Temperature: 120 °C
Yield: 11500.3 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with 4-chloro-6-(2,2,2-trifluoro-1-phenyl-ethoxy)-pyrimidine (30 mg, 0.1 μmol), 4-borono-L-phenylalanine (32 mg, 0.16 mmol), 1 ml of acetonitrile and 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, 1M) was added to above solution followed by 10 mol percent of POPd2 (dihydrogen di-μ-chlorodichlorobis(di-tert-butylphosphinito-κP)dipalladate. The reaction vessel was sealed and heated to 120° C. for 30 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 4.8 mg of 2-amino-3-{4-[6-(2,2,2-trifluoro-1phenyl-ethoxy)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 11%. 1H-NMR (400 MHz, CD3OD): δ 3.20 (m, 1H), 3.40 (m, 1H), 4.25 (t, 1H), 6.82 (dd, 1H), 7.43 (m, 5H), 7.57 (s, 1H), 7.60 (m, 2H), 8.10 (d, 2H), 8.75 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[C:7]([CH3:22])=[CH:6][C:5]1([CH3:24])[CH3:23])(=[O:3])[CH3:2].[Al+3].[Cl-:26].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]([CH3:22])[CH:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)[C:5]1([CH3:23])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CC(=O)N1c2ccc(N)cc2C(C)C(c2ccc(Cl)cc2)C1(C)C
Reaction time: 1 h

Procedure:
A mixture of 1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (25 mg) and AlCl3 (35 mg) in chlorobenzene (2 ml) was stirred for 1 h. The reaction mixture was quenched with water and in addition a solution of 2 M NaOH and ethyl acetate were added. The organic layer was separated, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:16])=O>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][CH:4]=1)[CH3:12]
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
In a round bottom flask fitted with a reflux condenser is placed 4 g of p-dimethylaminobenzoic acid and 8 ml of oxalylchloride. The evolution of gas starts immediately and the spontaneous reaction is run at room temperature for 15 minutes. 8 ml of toluene is added and and the mixture is heated to gentle reflux for one hour. The reaction mixture is then distilled to dryness under reduced pressure to produce a blue-green solid which is washed with ether and dried on a watch glass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]=[C:12]([CH3:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28]I.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:26][C:27]([F:31])([F:30])[CH2:28][N:10]1[C:9](=[O:25])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:12]([CH3:24])=[N:11]1
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC(F)(F)F)c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 48.7 %

Procedure:
The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (3 mL) and treated with 1,1,1-trifluoro-2-iodoethane (27.5 mL, 280 mmol) in presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50-60° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 48%). 1HNMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 3.10 (s, 3H), 4.85 (q, J=9 Hz, 2H), 6.90 (m, 2H), 7.10 (dd, J=6 Hz, J=9 Hz, 2H), 7.25 (m, 2H), 7.95 (d, J=9 Hz, 2H). MS (DCI/NH3) 458 (M+NH4)+Anal. calc. for C20H16N2F4SO3: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.41; H, 3.56; N, 6.35.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][N+:8]([O-])=O)[CH2:3][C:4](=[O:6])[CH3:5].[N+](CC(=O)CCC)([O-])=O.N(C(OCC)=O)=NC(OCC)=O.C(P(CCCC)CCCC)CCC>>[CH3:1][C:2]([CH3:11])([CH2:3][C:4](=[O:6])[CH3:5])[C:7]#[N:8]
Reactant: CC(=O)CC(C)(C)C[N+](=O)[O-]
Agent: CCCC(=O)C[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Product: CC(=O)CC(C)(C)C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-5-nitropentan-2-one was made according to the literature procedure; see Kloetzel, M. C. J. Am. Chem. Soc., 69, pp.2271-2275 (1947). Under a nitrogen atmosphere, a solution of nitropentanone (9.55 g, 60.0 mmol) was cooled to 0° C. Diethyl azodicarboxylate (11.5 g, 66 mmol) and tributylphosphine (26.71 g, 132 mmol) were sequentially added. The reaction was stirred for one hour at 0° C. and then for one hour at room temperature. The solvent was removed under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with dichloromethane). The resulting oil was treated with hexane; a precipitate formed and was removed by fitration. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with 45% to 55% ethyl acetate in hexane) to provide 5.17 g of 2,2-dimethyl4-oxopentanenitrile as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:34])[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3ccncc3)c3ccccc23)cc(OC)c1OC
Yield: 25.6 %

Procedure:
Substantially the same procedure as in Example 59 was repeated using Compound 1 (1.43 g) obtained in Example 1 and isonicotinoyl chloride hydrochloride (1.51 g) to give Compound 61 (0.48 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:40][CH:41]([CH2:43][C@H:44]([OH:48])[C:45](O)=[O:46])[CH3:42]>C(Cl)Cl>[OH:48][C@@H:44]([CH2:43][CH:41]([CH3:42])[CH3:40])[C:45]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:46]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of L-leucine methyl ester hydrochloride (1.97 g) dissolved in DCM (32 mL) was added NMM (1.9 mL) and the mixture was stirred for 5 minutes before being cooled to 0° C. HOBt (4.0 g), EDAC (3.8 g) and L-α-hydroxyisocaproic acid (1.35 g) were then added sequentially to the reaction mixture. After 30 minutes at 0° C., the reaction was allowed to warm to room temperature and continued stirring overnight. The reaction mixture was concentrated and the resulting crude product was dissolved in EtOAc and washed 2×1.2N HCl, 2× saturated NaHCO3, brine, dried (MgSO4) and concentrated to yield the desired product (2.32 g, 82%). 1H NMR (300 MHz, CDCl3) δ 0.93-0.96 (m, 12H), 1.50-1.67 (m, 5H), 1.82-1.93 (m, 1H), 3.73 (s, 3H), 3.83 (bs, 1H), 4.11-4.18 (m, 1H), 4.57-4.64 (m, 1H), 7.07 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.327 mmol) in pyridine (4.0 mL) was added 2-chloro-2-oxoethyl acetate (56 μL, 0.523 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in methanol (10 mL), potassium carbonate (45 mg, 0.327 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1% aqueous citric acid solution, and extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (73.6 mg, 44%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([NH2:9])[N:3]=1
Reactant: C1CNCCNC1
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: CCO
Product: Nc1cc(N2CCCNCC2)nc(N)n1

Procedure:
The analogous 1-(2,6-diamino-4-pyrimidinyl)homopiperazine was prepared by reaction of 2,6-diamino-4-chloropyrimidine with unprotected homopiperazine (5 mol equivalents) in ethanol in a sealed tube, following the procedure of Example 19. Yield of the obtained base: 91.3%, mp. 62°-72° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)N.N[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>O>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Agent: NS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Temperature: 150 °C

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (3.0 g) from Example 1, sulfamic acid (1.9 g), and 1-(3-aminopropyl)-4-methylpiperazine (15 mL) was heated to approximately 150° C. for 24 hours. After cooling, the residue was dissolved in water. The aqueous solution was made alkaline with a solution of saturated sodium bicarbonate and extracted with dichloromethane several times. The dichloromethane layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethyl acetate to give 2.0 g of 6-(2,6-dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 474=M+ +C2H5, 446=M+ +H (Base); mp 208°-211° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20]#[N:21].[Cl:22][C:23]1[C:29]([O:30][CH3:31])=[CH:28][C:26]([NH2:27])=[C:25]([CH3:32])[CH:24]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[C:29]([O:30][CH3:31])=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:20]#[N:21])=[C:25]([CH3:32])[CH:24]=1
Reactant: COc1cc(N)c(C)cc1Cl
Reactant: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 125 °C
Yield: 81.8 %

Procedure:
Following the procedure of Example 11, a mixture of 75.8 mg (0.25 mmol) of 4-chloro-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile, 51.5 mg (0.30 mmol) of 4-chloro-5-methoxy-2-methylaniline and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at 120-130° C. for 2 hours to yield the crude product. Purification of the crude product on preparative TLC (developing solvent: 95:5 methylene chloride/methanol) yields 88.7 mg (82.1%) of the pure product as a yellow solid, mp 171-173° C.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:20][O-:21].[Na+]>O1CCCC1>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([O:21][CH3:20])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cncc(Nc2ccc(I)cc2F)c1C(N)=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
140 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.340 mmol, 1 eq.) were dissolved in 3 mL of tetrahydrofurane and cooled to −75° C. bath temperature upon which 18 mg sodium methoxide (0.340 mmol, 1 eq.) were added and the mixture allowed to come to room temperature. Then the mixture was stirred at 80° C. bath temperature for 3 days. Since the reaction was not completed another 18 mg sodium methoxide (0.340 mmol, 1 eq.) were added and the mixture stirred at 80° C. bath temperature for 1 more day. The reaction mixture was concentrated in vacuo and the residue was partitioned between 20 ml each of water and dichloromethane. The aqueouse layer was separated and reextracted twice with dichloromethane (20 ml each). The combined organic layers were washed with brine (30 ml), dried over a silicone filter and concentrated. The residue was purified by flash chromatography to afford 67 mg (0.17 mmol, 51%) of the analytically pure target compound.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[Br:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: Oc1cccc(Br)c1
Reactant: COC(=O)c1ccc([C@@H](C)O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)Oc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of (R)-methyl 4-(1-hydroxyethyl)benzoate (1.8 g, 10 mmol), 3-bromophenol (1.9 g, 11 mmol) in 30 mL of anhydrous tetrahydrofuran was added Triphenyl phosphine (2.9 g, 11 mmol). The reaction mixture was stirred at room temperature for 0.5 hour under nitrogen atmosphere. Then diisopropylazodicarboxylate (2.4 g, 12 mmol) was added dropwise at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, it was quenched with water, and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give (S)-methyl 4-(1-(3-bromophenoxy)ethyl)benzoate (2.2 g, 66%)
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:13]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with the ethyl 4-iodobenzoate (10 g, 36 mmol) and THF (45 mL). Solution cooled down to 0° C. Turbo Grignard 1.3 M in THF (30.6 mL, 39.8 mmol) was then added in one portion and the reaction stirred for 30 minutes at 0° C. Pivaloyl chloride (5.35 mL, 43.5 mmol) was then charged in a second flask in THF (10 mL) and the preformed anion transferred via canula to the acyl chloride. The reaction was then slowly warmed to room temperature and stirred overnight. The reaction was quenched with ammonium chloride solution (sat. aq.) and extracted with ethyl acetate (2×), washed with brine (1×), dried over sodium sulfate, filtered and concentrated to provide ethyl 4-pivaloylbenzoate as a crude yellow gum (8.50 g). Used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.30-1.36 (m, 9H) 1.42 (t, J=7.04 Hz, 3H) 4.40 (q, J=7.24 Hz, 2H) 7.61-7.69 (m, 2H) 8.04-8.12 (m, 2H); MS (M): 234.