Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].Cl.[CH3:10]O>>[CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: CC(C)(CO)C(=O)O
Agent: Cl
Product: COC(=O)C(C)(C)CO
Reaction time: 8 h

Procedure:
A mixture of 2,2-dimethyl-3-hydroxypropionic acid (CXXXII, 11.54 g, 97.7 mmol), methanol (150 ml) and methanol (25 mi) saturated with hydrochloric acid gas is stirred overnight at 20-25°. The mixture is then concentrated under reduced pressure, ether is added, and again the mixture is concentrated. The residue is dissolved in ether and poured cautiously into a small amount of saturated sodium bicarbonate. The phases are separated and the aqueous phase is washed several times with ether. The combined organic phases are backwashed with saline, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 2,2-dimethyl-3-hydroxypropionate (CXXXII), NMR (CDCl3) 1.20, 2.48, 3.56 and 3.71 δ.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1>C(Cl)Cl.O=[Mn]=O>[N:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[CH:12]=[O:13])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: OCc1cccc(-n2ccnn2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc(-n2ccnn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3-(1H-1,2,3-triazol-1-yl)phenyl)methanol (55 mg; 0.31 mmol) in anh. DCM (1 ml) was treated with MnO2 (411 mg; 4.73 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 2 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with DCM. The filtrate was concentrated to dryness under reduced pressure giving 3-(1H-1,2,3-triazol-1-yl)benzaldehyde as a colorless solid. LC-MS (conditions A): tR=0.45 min.; [M+H]+: 174.09 g/mol.
Reaction SMILES: C(OCC([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19](N2C(=O)CCC2CI)[C:18]([I:30])=[C:17]([C:31]([NH:33]C(COC(=O)C)COC(=O)C)=[O:32])[C:16]=1[I:45])=[O:14])COC(=O)C)(=O)C.C([O-])(=O)C.C([N+](CC)(CC)CC)C>C(#N)C>[I:45][C:16]1[C:17]([C:31]([NH2:33])=[O:32])=[C:18]([I:30])[CH:19]=[C:20]([I:21])[C:15]=1[C:13]([NH2:12])=[O:14]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2C(=O)CCC2CI)c1I
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Product: NC(=O)c1c(I)cc(I)c(C(N)=O)c1I
Reaction time: 18 h
Yield: 15.8 %

Procedure:
To a solution of N,N'-bis[2-(acetyloxy)-1[(acetyloxy)methyl]ethyl]-5-[2-(iodomethyl)-5-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (12.00 g, 110 mmol) in acetonitrile (150 ml) was added tetraethylammonium acetate (5.74 g, 22 mmol) and the mixture stirred at 50° for 18 hours. Acetonitrile was removed in vacuo at 60°, the residue dissolved in ethyl acetate (200 ml), and the resulting solution washed with brine (2×100 ml) and with water (100 ml). The ethyl acetate layer was dried and removal of the solvent afforded the crude product as a colorless glassy solid. This material was purified by column chromatography over silica gel, using 20% hexane in ethyl acetate as eluent, to obtain N,N-bis [2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[2-(acetyloxy)methyl)-5-oxo-1-pyrrolidinyl]2,4,6-triiodo-1,3-benzenedicarboxamide as a colorless solid (9.4 g, 83.6% yield).
Reaction SMILES: Br[C:2]1[N:3]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=2.Cl.[OH-:25].[Na+]>C(O)CCC>[NH2:11][C:8]1[N:7]=[C:6]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[O:25])[N:3]2[CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CC(C)COc1nc(N)c2nc(Br)n(CC3CCOCC3)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)COc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1

Procedure:
8-Bromo-2-[(2-methylpropyl)oxy]-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (100 mg) in n-butanol (2 mL) was refluxed with concentrated hydrochloric acid (2 mL) at 100° C. (external temperature) for 3 hours. The reaction mixture was evaporated under reduced pressure to dryness. To the reaction mixture was then added a small volume of water and an equivalent volume of methanol to give a suspension, which was then neutralised to by the addition of 2M sodium hydroxide (from pH ˜3 to 7). This was then evaporated under reduced pressure to give a beige solid which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This gave the title compound (13 mg) as white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([OH:18])=O)=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:18])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)O)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1e from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and pyrrolidine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][S:20]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1)(=[O:22])=[O:21]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:27][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][N:25]=2)[CH2:29][CH2:30]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 43 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 43%). MS (m/e): 488.1 (M+H+, 100%), 505.0 (M+NH4+, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:26][O:27][C@H:28]([CH3:32])[C:29](O)=[O:30].CN(C)C=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][O:27][C@H:28]([CH3:32])[C:29]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([NH:18][C:15]2[N:14]=[CH:13][C:12]3=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:17]3[N:16]=2)[CH:20]=1)=[O:30]
Reactant: CO[C@H](C)C(=O)O
Reactant: COc1ccc(-c2ccc3cnc(Nc4cccc(N)c4)nn23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cnc(Nc4cccc(NC(=O)[C@@H](C)OC)c4)nn23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
N-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-benzene-1,3-diamine (50.0 mg, 0.150 mmol), (R)-(+)-2-Methoxypropionic acid (18.8 mg, 0.180 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34.6 mg, 0.180 mmol) and N,N-Dimethylformamide (0.999 mL, 12.9 mmol) were combined in a vial and stirred at rt for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with sat'd NaHCO3 and filtered off resulting ppt. Took ppt up in CH2Cl2 and purified by ISCO silica gel chromatography (0-100%) EtOAc in hexanes to afford title compound (12 mg, 15%) LCMS=419.0 (M+H), HPLC rt=2.935 min, purity=99%. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.74 (d, J=2.1 Hz, 1H), 8.72 (s, 1H), 8.48 (dd, J=2.6 Hz, 8.9H, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.38-7.36 (m, 1H), 7.32-7.29 (m, 2H), 6.95-6.92 (m, 2H), 6.89 (d, J=8.6 Hz, 1H), 6.85 (d, J=4.5 Hz, 1H), 4.01 (s, 3H), 3.90-3.85 (m, 1H), 3.45 (s, 3H), 1.48 (d, J=7.1 Hz, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.39 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/heptane) to yield the title compound as a light brown solid (0.054 g, 11%). MS (ISP) 476.0 [(M+H)+]; mp 238° C.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([NH:6][CH:7]1[C:11](=[O:12])[S:10][CH2:9][CH2:8]1)=[O:5]>Cl>[C:4]([NH:6][C@H:7]([C:11]([OH:12])=[O:1])[CH2:8][CH2:9][SH:10])(=[O:5])[CH3:3]
Reactant: [OH-]
Reactant: CC(=O)NC1CCSC1=O
Agent: Cl
Agent: [Na+]
Product: CC(=O)N[C@@H](CCS)C(=O)O
Temperature: 50 °C
Yield: 90 %

Procedure:
NaOH (1 M deoxygenated aqueous solution, 100 mL) was dropwise added to DL-N-acetylhomocysteine thiolactone (4.00 g, 25.124 mmol). Addition time: 15 min. The reaction mixture was warmed up to 50° C. and allowed to react for 30 min. The reaction was cooled down to 0° C., acidified with HCl (10% aqueous solution, 30 mL) and the product was extracted with nBuOH (4×70 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was slurred with Et2O/hexanes (1:3, 150 mL) to furnish 4.00 g of DL-N-acetylhomocysteine (white solid, yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:30]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:29])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:21])[CH2:24][CH2:25]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)c2ccccc2)CC1

Procedure:
1-(1-Benzoyl-piperidin-4-yl)-3-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl methyl)-urea was prepared starting from intermediate N and benzoyl chloride. MS calcd. for C29H28ClN4O3 [(M+H)+] 515.2, obsd. 515.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[CH3:19][S:20]([CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:22])=[O:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][CH:26]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnccc1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(NC(=O)/C=C/c2cnccc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.1 %

Procedure:
A mixture of (2E)-3-[4-(4-fluorophenyl)pyridin-3-yl]prop-2-enoic acid (0.24 g), 4-[(methylsulfonyl)methyl]aniline (0.19 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g), 1-hydroxy-1H-1,2,3-benzotriazole (0.20 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give a solid. The obtained solid was recrystallized from acetone/hexane to give the title compound (0.28 g).
Reaction SMILES: [C:1]1(=O)O[CH2:4][CH2:3][CH2:2]1.[C:7]1(OC)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:4]1[CH:8]2[CH:7]3[CH:3]4[CH2:4][CH:3]1[CH2:2][CH:1]1[CH:2]4[CH2:1][CH:11]([CH2:10][CH:9]12)[CH2:12]3
Reactant: COc1ccccc1
Reactant: O=C1CCCO1
Product: C1C2CC3C4CC5CC(C14)C(C2)C3C5

Procedure:
1.0 g of the polymer (A-12) produced in Production Example 1 was dissolved under heat in a mixed solvent of 5.0 ml of gamma-butyrolactone and 5.0 ml of anisole to prepare a coating solution. The ratio of all carbon atoms of the cage structure (diamantane) to all carbon atoms of the total solid content of the insulating film-forming coating solution was about 36%. The solution was filtered through a 0.1-micron tetrafluoroethylene filter, and then applied onto a silicon wafer in a mode of spin coating. The coating film was heated on a hot plate in a nitrogen stream atmosphere at 180° C. for 60 seconds, and then further on a hot plate at 300° C. for 10 minutes. The specific dielectric constant of the thus-formed insulating film having a thickness of 0.5 microns was 2.57. The Young's modulus of the film was 6.0 GPa. 3σ of the film thickness was calculated, and it was 2.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][N:16]=4)=[CH:30][CH:29]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCc1ccc(-c2ccnc(F)c2)nc1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
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(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-fluoro-[2,4′-bipyridin]-5-yl)methanamine 24-2 (15 mg, 0.074 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (18 mg, 0.09 mmol), and HATU (36 mg, 0.095 mmol) were added N,N-diisopropylethylamine (DIEA, 26 μL, 0.15 mmol) and DMF (0.6 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-((2′-fluoro-[2,4′-bipyridin]-5-yl)methyl)-4-(pyrazin-2-yl)benzamide 24 as a solid. MS m/z 386.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])OC(=O)[O:9][C:4]=2[CH:3]=1.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>CN1C(=O)CCC1>[NH2:20][C:16]1[CH:15]=[C:14]([NH:21][C:6](=[O:11])[C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=2[OH:9])[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(N)c1
Reactant: O=c1oc(=O)c2ccc(Cl)cc2o1
Solvent: CN1CCCC1=O
Product: Nc1cccc(NC(=O)c2ccc(Cl)cc2O)c1
Temperature: 110 °C

Procedure:
7-Chloro-benzo[1,3]dioxine-2,4-dione (91) (0.090 g, 0.455 mmol) and benzene-1,3-diamine (397) (0.17 g, 1.57 mmol) were combined and dissolved in NMP (6 mL). The mixture was heated to 110° C. for 2 h. TLC was inconclusive, it was later determined that the desired product had same Rf as the aniline (397). LC-MS indicated complete reaction. The mixture was diluted with MeOH (2 mL) and LiOH (aqueous, 2.0 M, 4 mL). The mixture was stirred for 10 minutes. The solution was diluted with EtOAc (25 mL), washed with water (2×15 mL), saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc in hexane) gave the desired product (398) as an off-white solid upon concentration (0.091 g, 0.347 mmol, 76% yield). LC-MS (ESI): (exact mass: 262.05) m/e=263.0 [M+1]+ (100%), 525.3 [2M+1]+ (10%).
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]/[CH:4]([OH:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].CCOCC.N1C=CN=C1.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>O1CCCC1>[Br:1]/[CH:2]=[CH:3]/[CH:4]([O:14][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(c1ccccc1)C(O)/C=C/Br
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(c1ccccc1)C(/C=C/Br)O[Si](C)(C)C

Procedure:
A solution of 7.8 g. of 1-bromo-4-methyl-4-phenyl-trans-1-pentene-3-ol in a mixture of 45 ml. of ether and 15 ml. of tetrahydrofuran was treated with 4.2 g. of imidazol under N2. After imidazol dissolved completely, the solution was treated at 0° with 5 ml. of trimethylsilyl chloride and stirred for one hour. The solvents were evaporated at 25° and the residue was diluted with n-pentane. After passing through an alumina column, the n-pentane filtrate was evaporated at 25° to afford 9.0 g. of the title product as a colorless liquid, λmaxfilm 3.45, 6.15, 6.65, 6.90, 7.20, 7.30, 7.98, 8.90, 9.10, 9.22, 10.60, 11.30, 11.85, 13.14 and 14.25 μ.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:11]=[CH:10][C:9]3[NH:8][CH:7]=[C:6]4[C:12](=[O:21])[N:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:14]=[C:5]4[C:4]=3[CH:3]=2)[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCNCC1
Reactant: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1
Product: CC(C)N1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3c2)CC1
Yield: 84 %

Procedure:
23a was stirred with excess of N-isopropylpiperazine at 175° C. for 72 hours. The precipitates were collected by filtration and washed with ethyl acetate and purified using column chromatography to obtain title compound in 84% yield. 1H-NMR (DMSO-d6) δ (ppm): 1.01 (6H, d, J=6.03 Hz), 2.63 (4H, br), 2.70 (1H, m), 3.22 (4H, br), 7.13 (2H, brt, J=7.32 Hz), 7.42 (3H, m), 7.58 (1H, d, J=9.32 Hz), 8.23 (2H, d, J=8.54 Hz), 8.54 (1H, s). m/z 388.5 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][C:6]1=[O:14].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)(=[O:25])=[O:24])[C:6]1=[O:14]
Reactant: CN(C)CCn1c(=O)[nH]c2cccnc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2cccc(F)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(2-dimethylaminoethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (20 mg, 0.10 mmol) in THF at room temperature is treated with 3-fluorophenyl-sulfonyl chloride (26 mg, 0.12 mmol), followed by diisopropylethylamine (25 μL, 0.20 mmol) and DMAP (5 mg), stirred at room temperature for 12 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson preparative HPLC1 to give the title compound, [M+H] 365, retention time (RT) 2.54 minutes. 1HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formic acid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH2:5][OH:6].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: OCc1cc(O)cc(O)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc(O)cc(CO)c1

Procedure:
the subtitle compound was prepared from 3,5-dihydroxybenzyl alcohol (5 g) and ethyl bromoacetate (5.96 g) by the method of example 21 step (ii). Purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 1.6 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[C:19]([Cl:35])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.O>CN(C)C=O>[Cl:35][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)=[C:7]([O:36][CH3:37])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=[O:25]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 59 mg), potassium carbonate (138 mg), and 1-methylpiperazine (0.055 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 58 mg (yield 95%) of the title compound.
Reaction SMILES: CC(C)=[O:3].[CH2:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[C:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)(=[O:3])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: NC(=O)C1CCc2ccc(Cc3ccccc3)cc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21
Reaction time: 8 h

Procedure:
To 150 ml. of acetone is added 12.5 g. of 6-benzylindan-1-carboxamide, followed by the dropwise addition of a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid. After the addition has been completed, the mixture is stirred overnight. Then 200 ml. of water is added and the acetone is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed with water and dried, followed by removal of the solvent by distillation under reduced pressure. The residue is purified by column chromatography (500 g. of silica gel; eluted with a 7:3 solvent mixture of chloroform and acetone) and the resultant crude crystals are recrystallized from benzene. The procedure gives 6-benzoylindan-1-carboxamide as crystals melting at 195°-197° C.