Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([C:16]#[N:17])[C:3]=1[Br:18].[C:19]1([Cl:25])[C:23](Cl)=[S+:22][S:21][N:20]=1.[Cl-]>ClCCl>[C:11]([O:10][C:9](=[O:15])[NH:8][C:5]1[CH:6]=[CH:7][C:2](/[N:1]=[C:23]2/[C:19]([Cl:25])=[N:20][S:21][S:22]/2)=[C:3]([Br:18])[C:4]=1[C:16]#[N:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: Clc1ns[s+]c1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(Br)c1C#N
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(/N=c2\ssnc2Cl)c(Br)c1C#N

Procedure:
The thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib were prepared following scheme 1: N-Boc Protection of 2-amino-5-nitrobenzonitrile using di-tert-butyl dicarbonate in a suitable solvent, such as dichloromethane, in presence of suitable bases such as triethylamine and 4-(dimethylamino)pyridine and preferably at room temperature, provides tert-butyl (2-cyano-4-nitrophenyl)carbamate I in high yield. Reduction of the nitro intermediate I, for example by treatment with ammonium formate and a catalytic amount of 10% palladium charcoal preferably in ethanol under microwave irradiation for preferably 30 min at 600 W, provides tert-butyl 4-amino-2-cyanophenylcarbamate II in high yield. Treatment of intermediate II by a solution of bromine in dichloromethane in a suitable solvent, such as acetic acid, preferably at room temperature provides tert-butyl 4-amino-3-bromo-2-cyanophenylcarbamate III in a quantitative yield. Intermediate III is reacted with Appel's salt (4,5-dichloro-1,2,3-dithiazolium chloride) (Appel, R. et al., Chem. Ber., 1985, 118, 1632) preferably in dichloromethane at room temperature to afford (Z)-tert-butyl-3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-cyanophenylcarbamate IV. N-Boc deprotection of intermediate IV using di-tert-butyl dicarbonate in a suitable solvent, such acetic acid, preferably under microwave irradiation at 118° C. provides (Z)-6-amino-2-bromo-3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitrile V in a quantitative yield. Cyclization of intermediate V may be accomplished by treatment with copper iodide in a suitable solvent, such as pyridine, preferably under microwave irradiation at 400 W at 130° C. for 20 min to obtain 6-aminobenzo[d]thiazole-2,7-dicarbonitrile VI in good yield (Besson, T. et al., J. Chem. Soc., Perkin Trans. 1, 1998, 3925). Treatment of intermediate VI in a suitable solvent, such as dimethylformamide dimethylacetal, preferably under microwave irradiation at 70° C. (600 W) gives (E)-N′-(2,7-dicyanobenzo[d]thiazol-6-yl)-N,N-dimethylformimidamide VII in good yield. Cyclization of intermediate VII in thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib may be accomplished by a Dimroth rearrangement using the appropriate aniline or primary amine R3NH2 (preferably 1.5 equivalent) in a suitable solvent, such acetic acid and preferably under microwave irradiation at 118° C. (600 W) (Foucourt, A. et al., Tetrahedron, 2010, 66, 4495).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[C:10]([O:29][CH3:30])[CH:9]=1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>CN(C=O)C>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:7][C:4]1[C:3]2[C:8]3[CH:9]=[C:10]([O:29][CH3:30])[C:11]([O:14][CH2:15][CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[CH:12][C:13]=3[C:36]([C:35]3[CH:38]=[CH:39][C:32]([OH:31])=[CH:33][CH:34]=3)=[N:1][C:2]=2[NH:6][N:5]=1
Reactant: COc1cc(-c2c(C)n[nH]c2N)ccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OCC1CCNCC1)c(-c1ccc(O)cc1)nc1[nH]nc(C)c12
Temperature: 75 °C
Yield: 20 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[4-(5-amino-3-methyl-1H-pyrazol-4-yl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (100 mg, 0.24 mmol) and 4-hydroxybenzaldehyde (44 mg, 0.36 mmol) was dissolved in TFA (1 mL) and heated to 75° C. for 15 h. After cooling to rt, the mixture was diluted with DMF and purified by preparative reverse phase HPLC. The fractions containing the desired product were concentrated and lyophilized to yield 4-{1-methyl-8-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrogen trifluoroacetate (26.2 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO): 8.64-8.54 (m, 1H), 8.28-8.18 (m, 1H), 7.64 (s, 1H), 7.57-7.54 (m, 2H), 7.49 (s, 1H), 6.95-6.91 (m, 2H), 4.05 (s, 3H), 3.82 (d, 2H), 3.31 (d, 2H), 2.92 (q, 2H), 2.81 (s, 3H), 2.16-2.04 (m, 1H), 1.94 (d, 2H), 1.53-1.42 (m, 2H); MS (EI) for C24H26N4O3: 419 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:27][CH:26]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: Fc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-fluorobenzyl)-1H-indole and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 386. 1HNMR (300 MHz, DMSO-d6): δ 7.84 (s, 1H), 7.76 (d, 2H, J=8.7 Hz), 7.56 (s, 1H), 7.55 (d, 1H, J=9.7 Hz), 7.41-7.39 (m, 3H), 7.23 (d, 2H, J=8.1 Hz), 7.16 (d, 2H, J=8.7 Hz), 6.55 (d, 1H, J=3.1 Hz), and 5.44 ppm (s, 2H).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][N+:17]([O-])=O)=[C:11]([Cl:20])[CH:10]=1>O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([Cl:20])[CH:10]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1Cl
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 94.1 %

Procedure:
To a stirred suspension of lithium borohydride (0.29 g, 13 mmol) in tetrahydrofuran (20 mL) at ambient temperature was added chlorotrimethylsilane (3.4 mL, 27 mmol), dropwise over 2 minutes. After stirring at ambient temperature for 20 minutes, argon gas was bubbled through the mixture for 2 minutes to remove the remaining trimethylsilane that had formed. A solution of 4-bromo-2-chloro-1-(2-nitrovinyl)benzene (0.88 g, 3.4 mmol) in tetrahydrofuran (15 mL) was added dropwise over 4 minutes with stirring at ambient temperature. The resulting mixture was stirred and heated to reflux for 1 hour. The mixture was cooled in an ice bath and carefully quenched with methanol (20 mL). The solvent was evaporated, and the residue was partitioned between 20% potassium hydroxide (40 mL) and dichloromethane (20 mL). The organic layer was dried over sodium sulfate and concentrated to afford 2-(4-bromo-2-chlorophenyl)ethanamine as a light yellow oil (0.75 g, 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1)([CH3:7])[CH3:6])[CH3:2].[Cl:15]NC(=O)CCC(N)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:8]1[N:9]=[C:10]([NH2:13])[S:11][C:12]=1[Cl:15])([CH3:7])[CH3:6])[CH3:2]
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCOC(=O)C(C)(C)c1csc(N)n1
Solvent: CC#N
Product: CCOC(=O)C(C)(C)c1nc(N)sc1Cl
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-(2-Amino-thiazol-4-yl)-2-methyl-propionic acid ethyl ester (0.3 g, 1.40 mmol) was taken in 10 mL of acetonitrile and N-Chlorosuccinamide (0.224 g, 1.68 mmol) was added the reaction was stirred for 1 hr. at room temperature. After completion of reaction acetonitrile was evaporated under reduced pressure and the residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo. The residue was purified by preparative TLC plate (mobile phase 40% ethyl acetate in hexane) to afford pure compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].C([OH:19])C.[OH-].[Na+]>O>[NH2:1][C:2]1[C:13]([Br:14])=[CH:12][C:11]([C:15](=[O:19])[NH2:16])=[CH:10][C:3]=1[CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: CCN(CC)Cc1cc(C#N)cc(Br)c1N
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)Cc1cc(C(N)=O)cc(Br)c1N

Procedure:
11 gm of 2-amino-3-bromo-5-cyano-N,N-diethyl-benzylamine were refluxed with a mixture of 70 ml of ethanol and 100 ml of 5 N sodium hydroxide. After cooling, the reaction solution was diluted with 100 ml of water and extracted with chloroform. The chloroform extract was dried over sodium sulfate and evaporated, and the residue was recrystallized from isopropanol, yielding 2-amino-3-bromo-5-carbamoyl-N,N-diethyl-benzylamine, m.p. 140-142° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1B(O)O>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1
Reactant: OB(O)c1c(Cl)cccc1Cl
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3c(Cl)cccc3Cl)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 2,6-dichlorophenylboronic acid. LC-MS Method 3, tR=1.317 min, m/z=414. 1H NMR (CDCl3) 1.70 (s, 3H), 2.30-2.40 (m, 1H), 2.48-2.52 (m, 1H), 3.47-3.51 (m, 1H), 4.10-4.15 (m, 1H), 7.10-7.40 (m, 10H), 8.78-8.79 (m, 1H).
Reaction SMILES: [C:1]([O:18][C@H:19]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@@H:21]([CH2:22][CH:23]=[C:24]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@@:25]3([CH2:47][CH3:48])[C@@H:26]([OH:46])[CH2:27][C@@H:28]2[C@H:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[C:1]([O:18][C@H:19]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@@H:21]([CH2:22][CH:23]=[C:24]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@@:25]3([CH2:47][CH3:48])[C:26](=[O:46])[CH2:27][C@@H:28]2[C@H:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)C[C@H](O)[C@@]32CC)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCCCCCCCCCCCCCCC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC=C3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC(=O)[C@@]32CC)C1

Procedure:
Treatment of 3β-hexadecanoyloxy-14α-ethyl-5α-cholest-7-en-15α-ol with pyridinium chlorochromate under the identical conditions described above gave 3β-hexadecanoyloxy-14α-ethyl-5α-cholest-7-en-15-one with the same melting point, infrared spectrum, nuclear magnetic resonance spectrum, mass spectrum, and thin-layer chromatographic behavior as described above for the 15-ketone derived from the 15β-hydroxy compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:20])[CH2:17][N:18]([CH3:19])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNCC(=O)OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(C)C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitro-benzoyl chloride (1.396 g; 7.52 mmol), methylamino-acetic acid methyl ester hydrochloride (1.264 g; 9.06 mmol) and triethyl-amine (2.40 mL; 17.2 mmol) were reacted in DCM (35 mL). After 2 days the r×n was washed with water (1×10 mL), 1 M HCl (2×10 mL), water (1×10 mL) and satd NaHCO3 (2×10 mL). After drying over MgSO4, filtration through silica with a 10:1 DCM:i-PrOH wash and concd, the product was purified by MPLC (silica; 0-->10% i-PrOH in DCM gradient) yielding a pale yellow-orange solid (1.394 g; 73%) as a mix of rotamers. 1H NMR (CDCl3; major rotamer) δ 8.31 (m, 2H), 7.66 (m, 2H), 4.31 (s, 2H), 3.82 (s, 3H), 3.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
1.53 g of 3-hydroxybenzoic acid methyl ester and 1.69 g of imidazole were placed in a 50 ml flask, and a gas in the reaction system was replaced with nitrogen. 5 ml of DMF was added into the flask and stirred at 0° C. The obtained solution was mixed with 1.57 g of t-butyldimethylsilyl chloride, heated up to room temperature, simultaneously stirred overnight, and then mixed with a saturated aqueous solution of ammonium chloride to stop the reaction. The reaction solution was extracted with diethyl ether, and the obtained organic layer was sequentially washed with water, a saturated aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The solvent was distilled away under reduced pressure to obtain 1.69 g of the title compound. Yield: 98%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.Cl.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[C:27]([CH3:38])[CH:26]=1>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:34][CH2:33]2)=[C:27]([CH3:38])[CH:26]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: COc1cc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2cc1OC
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(OC4CCN(C(=O)C5CCCO5)CC4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1′-carbonyldiimidizole (41.38 mg, 0.255 mmol) in N,N-dimethylformamide (1 mL) was added (R)-(+)-tetrahydrofuroic acid (29.6 mg, 0.255 mmol). The reaction was stirred at room temperature for 30 minutes then (6,7-dimethoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride was added. The reaction was stirred at room temperature overnight. The following day, the reaction was filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.51(d, d, J=8.71 Hz, 2H), 7.16(s, 1H), 7.05(d, J=8.4 Hz, 1H), (t, J=13.06 Hz, 7.15 Hz, 1H), 3.95(s, 3H), 3.93(s, 3H), 3.75(m, 4H), 3.44(m, 2H), 2.21(s, 3H), 2.03(m, 4H), 1.85(m, 2H), 1.70(m, 2H), LMRS (M+): 493.5, (M−): 491.5.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].[CH2:10]=[O:11]>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2([CH2:10][OH:11])[CH2:8][OH:9]
Reactant: O=CC1CC2C=CC1C2
Reactant: C=O
Product: OCC1(CO)CC2C=CC1C2

Procedure:
The synthesis of this chemical compound is depicted in Table I. The synthesis consists of the reaction of cyclopentene with acrolein to produce 5-norbornene-2-al. Reaction of 5-norbornene-2-al with formaldehyde results in the formation of 5-norbornene-2,2-dimethanol. Mild oxidation of the latter compound with dibutylstannic oxide yields the 3,9-bis(5'-norbornene-2'yl)-1,5,7,11-tetraoxaspiro[5.5]undecane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([NH2:24])=[O:23])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:8]=3.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:3]=[C:4]([C:22]([NH2:24])=[O:23])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 105 °C

Procedure:
3-Bromo-7-(4-methylpiperazin-1-yl)-9H-carbazole-1-carboxamide (35 mg, 0.090 mmol), phenylboronic acid (22.04 mg, 0.181 mmol), PdCl2(dppf)-CH2Cl2 adduct (7.38 mg, 9.04 μmol), and Na2CO3 (2M) (0.181 mL, 0.362 mmol) were mixed with DME (1 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 105° C. in an oil bath for 1.5 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 385.19 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.08 (s, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 8.02 (d, 1H, J=8.5), 7.87 (d, 2H, J=7.4), 7.50(m, 3H), 7.34 (t, 1H, J=7.3), 7.23 (s, 1H), 6.92 (dd, 1H, J=8.8, 2.1), 3.25-3.15 (m, 8H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(CCC)[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[C:22]([OH:33])[C:21]=3[CH2:34][CH:35]=[CH2:36])=[CH:14][C:7]=2[O:6]1)=[O:4].S(OC)(O[CH3:44])(=O)=O.[OH-].[K+]>C1COCC1>[CH3:44][O:33][C:22]1[C:21]([CH2:34][CH:35]=[CH2:36])=[C:20]([CH:25]=[CH:24][C:23]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[O:19][CH2:18][CH2:17][CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[O:6][C:7]=2[CH:14]=1
Reactant: COS(=O)(=O)OC
Reactant: C=CCc1c(OCCCOc2ccc3c(c2)OC(CCC)(C(=O)OC)CC3)ccc(C(=O)N2CCCC2)c1O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCc1c(OCCCOc2ccc3c(c2)OC(C(=O)OC)CC3)ccc(C(=O)N2CCCC2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 27 (280 mg, 0.51 mmol) dimethyl sulfate (192 mg, 153 mmol) and potassium hydroxide (57 mg, 1 mmol) was added to about 20 ml of THF, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with water and thoroughly extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatography of the crude material on silica gel using 75% ethyl acetate/hexane as eluant gave the product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:11][C:4]=2[NH:3]1.[OH-].[Na+].O.C(O)(=O)C>CCO>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])=[CH:11][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)NC(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)NC(=O)CO2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Ethyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-6-yl)propanoate (63 mg, 0.253 mmol) in 90% aq. EtOH (4.5 mL) was added sodium hydroxide (50 mg, 1.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 50° C. and cooled to room temperature. The mixture was added water (20 mL) and acidified with acetic acid. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO4 and filtered. The filtrate was concentrated in vacuo.
Reaction SMILES: [C:1]([O:6]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:8][CH2:9][CH2:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.COC1C=CC(O)=CC=1>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:8][CH2:9][CH2:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: OCCc1ncc[nH]1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)O

Procedure:
At a temperature of 65° C., methyl methacrylate (MMA) and hydroxyethylimidazole (HEI) in a molar ratio of 5:1 were heated in the presence of 50 ppm pf phenothiazine, 500 ppm of hydroquinone monomethyl ether and 1.25 mol % of a catalyst (based on hydroxyethylimidazole) for 5 h.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C1(O)C=CC=CC=1>C(Cl)Cl>[Si:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of 4-aminobenzyl alcohol (30.0 g, 81.2 mmol), tert-butyldimethylsilyl chloride (12.24 g, 81.2 mmol), imidazole (11.05 g, 162.4 mmol) and anhydrous CH2Cl2 (200 mL) was stirred at room temperature overnight. TLC analysis showed the appearance of a new spot and the disappearance of starting phenol. The solvent was removed in vacuo and then the remaining oily product was loaded onto a silica gel column and purified by chromatography, eluting with 3:1 hexane-ethyl acetate to afford 15.41 g (80%) of the title compound as a pale orange oil: 1H NMR (DMSO-d6) δ6.95 (d, J=8.4, 2H), 6.53 (d, J=8.4, 2H), 4.96 (s, 2H), 4.50 (s, 2H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (DMSO-d6) δ147.65, 128.04, 127.58, 113.57, 64.69, 25.82, 17.97, -5.18; MS (EI, m/z) 237 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O-:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:15]([O-])(O)=O.[Na+]>CO>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)[O-])s1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C)s1
Temperature: 83 °C
Yield: 67 %

Procedure:
5-Methyl-2-thiophene carboxylate (2.0 g, 14.1 mmol, Aldrich, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA) was carefully dissolved in 50 ml methanol and 15 ml conc. sulfuric acid at room temperature under an inert atmosphere. The reaction mixture was refluxed at 83° C. for 5 hours. After the reaction mixture was allowed to cool to room temperature, it was poured into a beaker containing 200 ml of ice. This aqueous mixture was neutralized to pH 7 with solid NaHCO3. This liquid was poured into a separatory funnel and extracted 2×200 ml CH2Cl2. The combined organics were dried over MgSO4, filtered, and stripped to provide the title compound of this Preparation (2.2 g, 67% yield) as a brown oil. 1H NMR (CDCl3): δ 7.61 (1H, d J=4), 6.77 (1H, d, J=4), 3.84 (3H, s), 2.52 (3H, s).