Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[C:20]([CH3:32])[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]=2[N:4]=1.[CH3:33][N:34]([CH2:36][C:37]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH2:48])[CH:46]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35].[OH-].[NH4+:52]>FC(F)(F)CO.C(OCC)(=O)C>[CH3:35][N:34]([CH3:33])[CH2:36][C:37]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH:48][C:3]3[N:16]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH2:52])=[O:17])[C:6]4[CH:19]=[C:20]([CH3:32])[N:21]([S:22]([C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)(=[O:24])=[O:23])[C:5]=4[N:4]=3)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)cc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3cc(C)n(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a flask containing 5-chloro-8-fluoro,2-methyl-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (423 mg, 0.86 mmol) in 2,2,2-trifluoroethanol (10 mL) was added 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (254 mg, 1.02 mmol). The resulting slurry was stirred at 80° C. for 6 h. Solvents were removed under reduced pressure to afford a yellow solid. One third of this material (˜200 mg) was suspended in THE (5 mL) and excess aqueous ammonium hydroxide (27%) (˜12 mL) was added. The reaction was let stir at rt for 5 h, at which time the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid that was purified via chromatography on SiO2 to afford 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (117 mg, 0.17 mmol) as a yellow solid. ESIMS (M+H)+=688.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[NH:10][N:9]=2)[CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28].C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:9]=2)[CH:3]=1
Reactant: Brc1ccnc(-c2n[nH]c(-c3cocn3)n2)c1
Reactant: Fc1ccccc1CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cocn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1 %

Procedure:
To a stirring solution of 4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole (1 eq) in DMF was added sodium hydride (2.1 eq). After 10 minutes, 1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction was stirred overnight at room temperature. Brine was used to quench the reaction. Methylene chloride was used to extract the aqueous layer. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. SiO2 chromatography yielded 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole as a solid in 1% yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:23][CH2:22]1
Reactant: NCC1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CN)CC3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 634.5 %

Procedure:
A mixture of 0.52 g (0.19 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 150 ml acetonitrile, and 0.66 g (5.76 mmole) 4-aminomethylpiperidine [J. Med. Chem., 9 441 (1966)] were stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in 500 ml of aqueous ammonium hydroxide at pH 10.5. The solution was filtered and the solvent was removed at reduced pressure. The precipitate was washed with 5 ml of water, then ether until dry to give 0.42 g of 7-[4-(aminomethy)-1-piperidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, mp 203°-206° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1.CON(C)[C:28](=[O:30])[CH3:29].O>O1CCCC1>[C:28]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
n-Butyllithium (2.5 Min hexane, 2.31 mL, 5.8 mmol) was added to a solution of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.56 g, 4.76 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at −78° C. for one hour. A solution of N-methoxy-N-methylacetamide (0.97 g, 9.4 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture dropwise then warmed to room temperature and stirred for an additional hour. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with water, then brine solution (80 mL each), dried over sodium sulfate, filtered, concentrated to give 1,1-dimethylethyl 7-acetyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.34 g, 97% yield); MS (EI) for C16H21NO4: 292 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:14])[CH2:10][NH:11]C=O.[ClH:15].C(OCC)(=O)C.C(OCC)(=O)C>CO>[ClH:15].[NH2:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[OH:14]
Reactant: O=CNCC(O)c1ccc(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCC(O)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
N-[2-(2,4-difluorophenyl)-2-hydroxy-ethyl]-formamide (1.0 g) was dissolved in methanol (2 mL), 4N hydrochloric acid/ethyl acetate (60 mL) was added. After stirring at 60° C. for 3 hours, the solution was allowed to cooled down to room temperature, and the solid that were generated by adding ethyl acetate (50 mL) was collected by filtration, washed with ethyl acetate, and the title compound (770 mg) was obtained as a colorless solid.
Reaction SMILES: [CH:1]1([N:4]([CH3:20])[C:5]2[C:6]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:7]=3[N:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH2:3][CH2:2]1.O[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=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>C1COCC1>[CH:1]1([N:4]([CH3:20])[C:5]2[C:6]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:7]=3[N:8]=[C:9]([CH2:11][O:12][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:10]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccnc1
Reactant: CN(c1nc(CO)nc2sc3c(c12)CCCC3)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(c1nc(COc2cccnc2)nc2sc3c(c12)CCCC3)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.1 %

Procedure:
To a mixture of [4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-methanol (0.25 g, 0.00086 mol), 3-hydroxypyridine (0.090 g, 0.00095 mol) & triphenylphosphine (0.24 g, 0.00095 mol) in THF (20 ml) was added DIAD (0.19 g, 0.00095 mol) in THF (5 ml), and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the resulting crude material was purified by preparative HPLC to give cyclopropyl-methyl-[2-(pyridine-3-yloxymethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine (35 mg, 11%) as a brown residue. 1H NMR (400 MHz, CDCl3): δ 0.35-0.42 (m, 2H), 0.62-0.68 (m, 2H), 1.72-1.78 (m, 2H), 1.88-1.97 (m, 2H), 2.80-2.90 (m, 5H), 3.00 (s, 3H), 5.24 (s, 2H), 7.16 (dd, 1H), 7.30 (dd, 1H), 8.17 (dd, 1H), 8.42 (d, 1H); LC-MS: [M+H]=367.3 m/z.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([CH3:13])[CH:6]=1.O>C(O)C.O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[C:7]([CH3:13])[CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)ccc1CC#N
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
After carbon tetrabromide (6.7 g, 20 mmol) and triphenylphosphine (5.2 g, 20 mmol) were added to a solution of (4-bromo-2-methylphenyl)methanol (3.7 g, 18.4 mmol) which was synthesized according to the method described in literature (Dawson, M. I., et al., J. Med. Chem., 1984, vol. 27, pp. 1516-1531) under ice-cooling, the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture and the insolubles were removed by filtration. After the obtained filtrate was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/0-10/1) to give a crudely purified 4-bromo-1-(bromomethyl)-2-methylbenzene. Potassium cyanide (1.3 g, 20 mmol) was added to a solution of crude 4-bromo-1-(bromomethyl)-2-methylbenzene obtained in the above in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=6/1-3/1) to give (4-bromo-2-methylphenyl)acetonitrile as a pale orange solid (2.4 g, two-step total yield: 63%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[O:13]=[C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][N:10]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O=C1NCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of 1-benzylimidazolidin-2-one (3.5 g, 19.9 mmol) in DMF (50 ml) at 0° C. were added lithium tert-butoxide (1.9 g, 23.8 mmol) and tert-butyl bromoacetate (3.2 ml, 21.8 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crystalline residue was washed with n-hexane, and dried to give tert-butyl 2-(2-oxo-3-benzylimidazolidinyl)acetate (5.08 g).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:44]>CCCCO>[ClH:44].[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:20])[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:4]=23)[CH2:23]1
Reactant: ClCCl
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)cc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide (0.24 g, 0.67 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.40 g, 2.01 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 20-80% CH3CN/water gradient; 30 CV) to give a solid. The solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide hydrochloride (0.14 g, 41% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.94 (s, 1H), 9.95 (s, 1H), 8.26 (s, 1H), 8.17-8.-9 (m, 6H), 7.65 (br s, 1H), 7.42 (t, 2H), 3.43-3.35 (m, 2H), 3.25-3.15 (m, 2H), 3.10-3.04 (m, 1H), 1.92-1.85 (m, 1H), 1.66-1.59 (m, 1H), 1.46-1.28 (m, 2H); LCMS (APCI+) m/z 432 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[C:12]([O:15][C:16]1[C:17]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:18][C:19]2[O:23][C:22]([CH2:25][CH2:26]/[CH:27]=[C:28](\[CH3:31])/[CH2:29]O)([CH3:24])[CH2:21][C:20]=2[C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][C:16]1[C:17]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:18][C:19]2[O:23][C:22]([CH2:25][CH2:26]/[CH:27]=[C:28](\[CH3:31])/[CH2:29][Cl:1])([CH3:24])[CH2:21][C:20]=2[C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CO)O2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CCl)O2
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
N-Chlorosuccinimide (150 mg) was suspended in dichloromethane (4 ml). After adding dimethyl sulfide (0.1 ml) dropwise at -5° C., the suspension was stirred for 15 min. Subsequently, a solution of 5-acetoxy-4,6-di-tert-butyl-2-(5-hydroxy-4-methyl-3(E)-pentenyl)-2-methyl-2,3-dihydrobenzofuran (0.4 g) in dichloromethane (1 ml) was added dropwise and the resulting mixture was stirred at -5° C. for 90 min. After the end of the reaction, dichloromethane was distilled off under reduced pressure and the concentrate was purified by silica gel chromatography (25% ethyl acetate in n-hexane) to afford 5-acetoxy-2-(5-chloro-4-methyl-3(E)-pentenyl)-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran [0.3 g (yield, 70%)] as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4]>C(Cl)Cl.C(N(CC)CC)C.C(Cl)(=O)C>[C:3]([O:4][CH2:3][C:2]([NH:1][C:11](=[O:16])[CH3:10])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][CH3:7])(=[O:4])[CH3:2]
Reactant: CCCC(N)(CO)CCc1ccccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCCC(CCc1ccccc1OCc1ccccc1)(COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 129 %

Procedure:
To a solution of 2-amino-2-(2-(2-benzyloxyphenyl)ethyl)pentanol (1.1 g) in methylene chloride (35 ml), triethylamine (1.2 ml) and acetyl chloride (0.5 ml) were added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=1:1) to give the subject compound (0.90 g).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C@@H:9]([C:18]([OH:20])=[O:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:23][O:19][C:18](=[O:20])[C@H:9]([CH2:8][C:7]1[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
To suspesion of of 4-nitro-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine (226.2 mmol, 70.2 g) and sodium carbonate (1.13 mol, 95 g) in DMF (500 mL) was added methyl iodide (1.13 mol, 70.4 InL) at room temperature. The suspesion was stirred for 15 h at room temperature at this time TLC analysis of the mixture indicated the absence of starting acid and the excess methyl iodide and some DMF were removed under high vacuum. The residue was poured into water (2 L) and stirred at room temperature as a precipitate formed slowly over 72 h. The precipitated solids were collected by filtration and washed with water (2 L). After air and vacuum drying, 72 g (98%) of a light yellow solid, mp 95-96° C. were obtained. 1H-NMR, (DMSO-d6) (400 MHz) δ 8.16 (d, 2H, J=20 Hz), 7.53 (d, 2H, J=20 Hz), 7.39 (d, 1H, J=22 Hz), 4.26-4.28 (m, 1H), 3.6 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H). 13C NMR, CDCl3 (100 Mhz) δ 172.04, 155.29, 146.27, 145.96, 130.48, 123.18, 78.36, 54.44, 51.9, 36.1, 27.99. HR MS: Obs. mass, 325.1404. Calcd. mass, 325.1400 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:9][O:10][C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH2:23][CH2:24][C:25]3=[O:30])[CH2:8][O:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1([CH2:9][O:10][C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH2:23][CH2:24][C:25]3=[O:30])[CH2:6][O:7][CH2:8]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN=[N+]=[N-])COC2)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-(2-((3-(azidomethyl)oxetan-3-yl)methoxy)-3,4-dimethoxyphenyl)-indan-1-one (3 g, 7.57 mmol) in in tetrahydrofuran (30 mL), were added triphenylphosphine (7.6 g, 29.28 mmol) and the reaction mixture was stirred at RT for 2 h. Water (3 mL) was added to the above reaction mixture and the resultant reaction mixture was heated to 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the obtained residue was acidified with 1N hydrochloric acid solution. Then extracted with ethyl acetate (3×) and the aq layer was basified with sodium bicarbonate solution and extracted with ethyl acetate and the combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as a liquid.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([Cl:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C>ClCCl>[ClH:24].[CH2:16]([N:13]1[CH:14]=[CH:15][C:10](=[N:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=[CH:12]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCNc1ccncc1
Reactant: CCCCCCCCCl
Solvent: ClCCl
Product: CCCCCCCCN=c1ccn(CCCCCCCC)cc1
Product: Cl
Temperature: 180 °C
Yield: 187.4 %

Procedure:
A mixture of 4-octylaminopyridine (25 g., 0.121 mole) and octyl chloride (20.5 ml., 0.121 mole) was heated at 180° C. for 1 hr. More octyl chloride (0.5 ml.) was added and the mixture was again heated at 180° C. for 1 hr., then dissolved in dichloromethane. The dichloromethane solution was treated with charcoal, filtered, and stripped of solvent under vacuum. The solid residue was slurried in ether (1.5 kg.), collected by filtration, washed with ether (500 g.), isolated in a dry bag, and dried (50°-80° C., 0.1 mm.). The procedure was repeated using the same amounts of starting materials and the product were combined, affording N-(1-octyl-4(1H)-pyridinylidene)octanamine monohydrochloride (80.5 g., 93% yield, m.r. 120°-125° C.), which is the monohydrochloride salt of the compound of Formula I wherein R and R' are both octyl.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27].CCN(CC)CC>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: NC(CO)CO
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Yield: 42 %

Procedure:
A solution of 4-chloro-2-methylsulfinyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (0.75 mmol) in dichloromethane (30 mL) was mixed with a solution of serinol (0.075 g, 0.82 mmol) and Et3N (0.21 mL, 1.5 mmol) in DMF (0.75 mL). The resultant mixture was stirred at room temperature for about 1 hour, then concentrated under vacuum. Flash chromatography (EtOAc:Hexane, 3:1) provided the title compound 4-chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxy-methyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (42%): LC-MS m/z 383 (M+H)+; 1H-NMR (CDCl3) δ 1.95 (s, br, 2H), 3.90 (m, br, 5H), 6.05 (m, br, 1H), 6.56 (d, J=9.6 Hz, 1H), 7.10 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.94 (d, J=9.6 Hz, 1H).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: CC(C)(C)OC(=O)CCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.0 eq.) in THF at −78° C., was added dropwise over 10 min a solution of BuLi (1.6 N in hexane, 1.0 eq.) and stirring was continued at −78° C. for 45 min. A pre-cooled solution of tert-butyl 6-iodohexanoate (1.0 eq.) in THF was then added by cannula over 5 min and the reaction stirred overnight, slowly warming to RT. The reaction was then left to stir at RT for a further hour and was quenched by the addition of aqueous NH4Cl solution. The THF layer was decanted off and concentrated under reduced pressure, meanwhile and the aqueous mixture was extracted with EtOAc (3×). The EtOAc extracts were used to redissolve the oily THF residue and this solution was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was used directly in the next step without further purification (I1).