Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=3)[CH2:13]2)[N:4]=1.N1C=CC=CC=1.[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:37](=[O:38])[CH2:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:18]=3)[CH2:13]2)[N:4]=1
Reactant: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of 5c (0.69 g, 1.96 mmol) and pyridine (0.156 g, 2.0 mmol) in dichloromethane (20 ml) was added tert-butylacetyl chloride (0.269 g, 2.0 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.657 g, 1.45 mmol, 72%). 1H NMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J=5.8 Hz, 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([OH:34])=[CH:23][N:22]=3)[C:5]=2[CH3:35])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][CH2:44][N:45]([CH3:47])[CH3:46].CC(=O)CC>CN(C=O)C>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[CH:23][N:22]=3)[C:5]=2[CH3:35])[CH2:3][CH2:2]1
Reactant: CN(C)CCCl
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN(C)C)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 50 °C

Procedure:
80 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol 2-2-1 (0.048 mmol, 1.0 eq) were dissolved in 1.9 mL of dry DMF and 33.5 mg potassium carbonate (0.24 mmol, 5.0 eq) and 10.5 mg 2-chloro-N,N-dimethylethanamine (0.073 mmol, 1.5 eq) were added. The reaction mixture was stirred over night at 50° C. Then butan-2-one was added and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography and HPLC provided 10 mg (0.02 mmol, 37%) of analytically pure target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:11]([N+:22]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCC)(OCC)OCC>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[NH:22]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1-c1ccc(O)cc1
Agent: CCOP(OCC)OCC
Product: Oc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 160 °C
Yield: 50 %

Procedure:
To a pressure resistant vial, was added Compound 7 (2.00 g, 6.22 mmol and Triethyl phosphite (6.53 ml, 37.3 mmol. The mixture was heated to 160° C. overnight. The reaction mixture was concentrated in vacuo. The residue was suspended in chloroform (20 mL), solid precipitate formed and was filtered and washed with ether (10 mL×2) to afford Compound 8 (900 mg, 3.11 mmol, 50.0% yield). 1H-NMR (400 MHz, DMSO) δ: 10.81 (br, 1H), 9.25 (br, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.50-7.33 (m, 5H), 6.95 (s, 1H), 6-78-6.76 (m, 2H), 6.56 (dd, J=8.4, 2.0 Hz 1H), 5.16 (s, 2H); LRMS for C19H15NO2+H+, calc'd: 290.1. found: 290.1 (M+H+).
Reaction SMILES: C([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+]([O-])=O)[CH:8]=[CH:7][CH:6]=2)C.[H-].[Na+].CCCCCC.C(Br)C1C=CC=CC=1>CN(C=O)C.O>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:3]1
Reactant: CCc1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-Ethyl -4-nitro-1H-indole (4.75 g, 25 mmol) was added to a mixture of 1.0 g (25 mmol) of 60% NaH/mineral oil (washed with hexane before adding DMF) in 40 ml DMF. After 45 minutes, 3.0 ml (25 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for four hours, diluted with water, and extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 20% EtOAc/Hexane to give 6.36 g (91%) of 1-Phenylmethyl-2-ethyl-4-nitro]1H-indole as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3ON=C(CC4C=CC(F)=CC=4F)N=3)[C:6](=[O:32])[NH:5][C:4]=2[N:3]=1.ClC1[N:42]([CH2:43][CH:44]=[CH2:45])[C:41]2[C:40](=O)N(CCCC(OCC)=O)[C:38](=[O:55])[NH:37][C:36]=2[N:35]=1>>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:38]3[O:55][N:35]=[C:36]([C:41]4[CH:40]=[CH:45][CH:44]=[CH:43][N:42]=4)[N:37]=3)[C:6](=[O:32])[NH:5][C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCC(=O)OCC)c(=O)c21
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCc3nc(Cc4ccc(F)cc4F)no3)c(=O)c21
Product: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCCc3nc(-c4ccccn4)no3)c(=O)c21

Procedure:
Similarly prepared was 8-chloro-1-(3-{3-[(2,4-difluorophenyl)methyl]-1,2,4-oxadiazol-5-yl}propyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione using ethyl 4-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanoate.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:11]([NH:16][NH2:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(Cl)c(NN)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2,3-Dichloro-6-methoxyquinoxaline (4.2 g., 0.018 mole), the product of Preparation E(b), and 2.7 ml. of hydrazine hydrate in 100 ml. of ethanol were heated under reflux for 4 hours and stirred at room temperature overnight. The precipitate was removed by filtration and washed with ethanol to afford 3.9 g. (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline, m.p. <250° C. Mass spectrum: m/e, 224 (P); m/e 226 (P+2).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10][C:8]=2[N:9]=1)[CH3:2].CC(=CC)C.P([O-])(O)(O)=O.[K+].Cl([O-])=O.[Na+].Cl.[NH4+].O[N:47]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.CC(O)(C)C.O>[CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([C:14]([NH2:47])=[O:15])=[N:10][C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2nc(C=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: On1nnc2ccccc21
Agent: CC=C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2nc(C(N)=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a mixture of 2-(ethylsulfanyl)-4-oxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydropyrido[2,3-d]pyrimidine-7-carbaldehyde (299 mg), 2-methylbut-2-ene (387 mg), potassium dihydrogen phosphate (88 mg) and 2-methyl-2-propanol/water (4/1, 70 ml) was added sodium chlorite (232 mg) by small portions, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added 1M hydrochloric acid and water under ice-cooling, and the mixture was extracted with tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a pale-yellow residue. The residue (117 mg) and 1-hydroxybenzotriazole ammonium (40 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56 mg) was added thereto, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then (NH, ethyl acetate/hexane), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the white title compound (28 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1=[O:13].Cl[CH2:16][CH2:17][S:18][CH3:19]>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:16][CH2:17][S:18][CH3:19])[C:3]1=[O:13]
Reactant: CSCCCl
Reactant: CC1(C)C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CSCCN1C(=O)c2ccccc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
11.4 gm of potassium tert.butylate were added to a solution of 18 gm of 4,4-dimethyl-2H,4H-isoquinoline-1,3-dione in 70 ml of dimethylformamide, and the mixture was stirred for 5 minutes at room temperature. 11.1 gm of 1-chloro-2-methylmercapto-ethane were then added, and the mixture was heated at 80° C. for 2 hours. After distilling off the dimethylformamide in vacuo, the residue was taken up in chloroform and water. The organic phase was separated and evaporated, and the residue was purified on a silicagel column (eluant: chloroform), yielding 23.1 gm (87.7% of theory) of an oily product which was identified to be the compound of the formula ##STR6##
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C1COCC1.C(OCC)(=O)C>[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([NH:4][CH2:3][CH2:1][OH:2])=[O:9]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of ethanolamine (1.10 g, 15.8 mmol) in THF at 0° C. under N2 was added 2,4-difluorobenzoyl chloride (500 mg, 2.83 mmol). The reaction mixture was stirred at 0° C. for 4 h, then diluted with ethyl acetate (100 mL) and washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and saturated NaCl (50 mL). The organic solution was dried over MgSO4 and concentrated in vacuo to yield 2,4-difluoro-N-(2-hydroxyethyl)benzamide as a white solid (495 mg, 87%).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:21])(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:21][C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=2
Reactant: CSc1ccc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc2[nH]c(C)cc2c1
Yield: 71.4 %

Procedure:
To a solution of 1-benzenesulfonyl-2-methyl-5-methylsulfanyl-1H-indole (156 mg, 0.49 mmol) in 10 mL of ethanol was added 10 mL of 10% aqueous sodium hydroxide solution. The mixture was warmed at reflux for 18 hours. The mixture was then diluted with 10 mL of brine and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were washed with two 10 mL portions of 10% aqueous sodium hydroxide solution, two 20 mL portions of saturated aqueous ammonium chloride, two 20 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes (1:99, then 2:98, then 3:97, then 5:96) to afford 62 mg (71.2% yield) of 2-methyl-5-methylsulfanyl-1H-indole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:9][C:5]1[CH:4]=[CH:3][C:2]([C:14]#[C:13][CH2:12][CH2:11][OH:15])=[CH:7][C:6]=1[CH3:8]
Reactant: COc1ccc(Br)cc1C
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C#CCCO)cc1C
Yield: 34.3 %

Procedure:
A stirred solution of 4.6 grams (0.023 mole) of 5-bromo-2-methoxytoluene (commercially available), 3 mL (0.040 mole) of 3-butyn-1-ol, 0.30 gram (0.002 mole) of copper(I) iodide, 14 mL (0.100 mole) of triethylamine, and 0.25 gram (0.0004 mole) of dichlorobis(triphenylphosphine)palladium(II) in 60 mL of DMF was heated at 90° C. for about 18 hours. After this time, the reaction mixture was poured into water and extracted with diethyl ether. The ether extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of hexane and ethyl acetate as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 1.5 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:4]([C:18]([O:20]CC)=[O:19])[CH2:3]1.[OH-].[Na+]>C(O)C>[CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1
Reactant: CCOC(=O)C1C[C@H](C)CCN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 8.95 g (29.3 mmol) of Part (3) compound in 90 mL of absolute ethanol cooled in an ambient water bath was added 90 mL of 1N aq NaOH solution. The reaction mixture was stirred for 16 h then concentrated in vacuo to ~1/2 volume to remove ethanol. The residue was partitioned between 100 mL of 1M aq HCl solution and 100 mL of ether. The aqueous layer was separated and extracted with two-50 mL portions of ether. The ether extracts were combined, dried (magnesium sulfate) and concentrated in vacuo to afford 8.15 g (29.4 mmol, 100%) of title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-butyl-cyclopentane carboxylate (6.42 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 3-methyl-benzoyl chloride (6.00 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, and then using 10% aqueous solution of sodium carbonate for three times, then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 11.99 g of brown liquid. MS: m/e 332(M+′), 287, 213, 196, 167, 119(base), 99.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:52]=[CH:53][C:54]2[O:59][CH2:58][CH2:57][N:56]([NH2:60])[C:55]=2[CH:61]=1>CN(C=O)C>[F:50][C:51]1[CH:52]=[CH:53][C:54]2[O:59][CH2:58][CH2:57][N:56]([NH:60][C:23]([C:20]3[CH:21]=[N:22][C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=4)=[N:18][CH:19]=3)=[O:25])[C:55]=2[CH:61]=1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: NN1CCOc2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCOc2ccc(F)cc21)c1cnc(-c2cccc(F)c2)nc1
Yield: 22 %

Procedure:
DIPEA (174 μL) is added to a mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (218 mg), HATU (380 mg) and 6-fluoro-2,3-dihydro-benzo[1,4]oxazin-4-ylamine (220 mg) in DMF (15 mL) and then heated at 800 C. overnight. The reaction mixture is concentrated in vacuo and the residue is purified by silica gel column chromatography eluting with 30% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (6-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-amide (81 mg). MS: 369 (M+H); 1H NMR (300 MHz, DMSO-D6): δ 11.05 (s, 1H), 9.35 (s, 2H), 8.32 (dd, 1H), 8.18 (dd, 1H), 7.65 (m, 1H), 7.5 (m, 1H), 6.8-6.7 (m, 2H), 6.52-6.45 (m, 1H), 4.36-4.33 (m, 2H), 3.65 (m, 2H). IC50=12 nM.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[K+].CN(C)C=O>O>[CH3:16][C:3]1[C:2]2[O:15][CH2:14][CH2:13][NH:12][C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: Cc1nc2ccccc2c(NCCO)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2c2c1OCCN2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-N-(2-hydroxyethyl)-2-methyl-4-quinolinamine (11.5 g), potassium-tert-butoxide (3.7 g) and 100 ml of dimethylformamide (DMF) was stirred at 80° C. for 3 hours. The mixture was cooled and diluted with 600 ml of water and thereafter kept in a refrigerator for 2 days. The resultant solid was filtered and recrystallized from isopropanol. The yield was 3.3 g, mp 203°-204° C.
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([O:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1)[CH3:10].[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:9]([O:11][C:12]1([NH:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]1)[CH3:10]
Reactant: CCOC1([NH3+])CC1
Reactant: CCCCCC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NC1(OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (2.22 g, 22 mmol) is added dropwise (15 min) with vigorous stirring at 0° to a solution of 1-ethoxycyclopropylammonium chloride (1.37 g, 10 mmol) and caproyl chloride (1.34 g, 10 mmol) in dry tetrahydrofuran (30 ml) and the mixture is stirred at room temperature for 1 hr. The precipitate is filtered off and the filtrate is evaporated in vacuo. The crystalline residue (1.85 g) is dissolved in petroleum ether (20 ml) and the solution is filtered through a short silica-gel column (2 cm × 10 cm). After evaporation the residue (1.30 g) is recrystallised from petroleum ether (at low temperature) yielding pure N-(1-ethoxycyclopropyl)-caproic amide, mp 47°-48.5° (1.0 g, 50%); NMR (60 MHz): δCDCl 3 = 0.7-1.9 (m, 16H), 2.0-2.4 and 2.4-2.8 (2 m, total 2H), 3,57 and 3.63 (2q, J=7.2 Hz, total 2H), 6.7 (br. s, 1H), (two rotamers).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH:14](=O)[CH3:15].C([O-])([O-])=O.[K+].[K+].[BH4-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNCCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
A mixture of (4-amino-butyl)-carbamic acid tert-butyl ester (0.360 g, 1.91 mmol), acetaldehyde (0.085 g, 1.91 mmol) and K2CO3 (0.264 g, 1.91) in MeOH (5 mL) was stirred for 6 h. The mixture was filtered through a celite cake. The filtrate was cooled at 0° C. and NaBH4 (0.106 g, 2.08 mmol) was added. After the reaction mixture was stirred at 0° C. for 45 min water (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×30 mL). The organic extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/MeOH/NH4OH), affording (4-ethylamino-butyl)-carbamic acid tert-butyl ester as a colorless oil (0.215 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:26].[F:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[NH:49][CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:37][CH:36]=1>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][CH:50]([NH:49][C:41]3[N:40]([CH2:39][C:38]4[CH:56]=[CH:57][C:35]([F:34])=[CH:36][CH:37]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:51][CH2:52]2)([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]1=[O:26]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccccc3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccccc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 2.6 using 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (10 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (10 mmol) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][O:24][C:23]([C:18]1([C:20]([O:22][CH2:33][CH2:32][Si:31]([CH3:36])([CH3:35])[CH3:30])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: C[Si](C)(C)CCO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-trimethylsilylethanol according to the procedure of Example 30 as a white foam (HCl salt); 1H NMR (CDCl3) δ 0.03 (s, 18H), 1.06 (t, J=8.6 Hz, 4H), 1.33 (bs, 3H), 1.90 (bs, 1H), 2.80 (bs, 1H), 3.18 (bs, 2H), 3.48 (bs, 2H), 4.37 (t, J=8.6 Hz, 4 H), 5.45 (bs, 1H), 6.80 (m, 3H), 7.26 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1763 cm-1 (C=O); MS (ES) m/z 622 (MH+); [α]D25 -23° (c, 1.0, CHCl3). Anal. Calcd. for C30H44ClNO7Si2 ·HCl: C, 54.70; H, 6.88; N, 2.13; Cl, 10.76; Si, 8.53. Found: C, 53.96; H, 7.05; N, 1.86; Cl, 8.84; Si, 10.33.