Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][CH:23]([C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])=[O:29])C(OC)=O)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.Br>C(O)C>[CH2:37]([O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28](=[O:29])[CH2:23][CH2:22][C:20]1[N:21]=[C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([OH:8])[CH:10]=2)[O:18][CH:19]=1)[CH3:38]
Reactant: CCOc1ccccc1C(=O)C(Cc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1)C(=O)OC
Agent: Br
Solvent: CCO
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1

Procedure:
A 13.4 g quantity of methyl 2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-(2-ethoxyphenyl)-3-oxopropionate obtained in Example 100 was suspended in 67 ml of ethanol, 67 ml of 47% hydrobromic acid was added thereto, and the suspension was heated and refluxed overnight. After standing to cool, the crystals generated were collected by filtration, washed with water and diisopropyl ether, and dried, thereby yielding 8.1 g of white powdery 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1>CO.CC(O)=O.[Pd]>[F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH2:6][CH2:7][C:8]3=[O:35])=[CH:4][CH:3]=1
Reactant: O=C1COc2ccc(N3C[C@@H](CCNCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1COc2ccc(N3C[C@H](CCNCC4CN5C(=O)CCc6ccc(F)c4c65)OC3=O)cc2N1
Yield: 75 %

Procedure:
A solution of the compound of Example 2 (60 mg) in MeOH/AcOH (1:1, 2 mL) was hydrogenated over Pd/C (133 mg) overnight. The catalyst was filtered off and thoroughly washed with MeOH and MeOH/DCM. The filtrate was concentrated under reduced pressure. The residue was taken up in water and 28% aq. NH4OH, filtered, washed with water and TBME and dried under reduced pressure, affording an off-white foam (45 mg; 75% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Cc1ccc(I)cc1
Reactant: Cc1ccc(=O)[nH]c1
Product: Cc1ccc(-n2cc(C)ccc2=O)cc1
Yield: 89 %

Procedure:
The reaction of p-iodotoluene with 5-methyl-2-(1H)-pyridone by the procedure of Example 1, affords 5-Methyl-1-p-tolyl-2-(1H)-pyridone in 89% yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[CH:8]1.[C:16](=O)(O)[O-:17].[Na+]>CN(C=O)C>[CH3:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH:16]=[O:17])=[CH:8]1
Reactant: Cn1ccc2cccnc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cccnc21
Temperature: 0 °C
Yield: 83 %

Procedure:
Phosphoryl chloride (5.15 ml, 55.3 mmol) was added dropwise to DMF (70 ml) under stirring at 0° C. After the reaction mixture was stirred at 0° C. for 10 minutes, a solution of 1-methyl-1H-pyrrolo(2,3-b)pyridine (4.87 g, 36.8 mmol) in DMF (5 ml) was added dropwise at the same temperature. After completion of the dropwise addition, the reaction mixture was stirred at 0° C. for 4 hours and at 60° C. for 3.5 hours. The reaction mixture was poured in ice water—a saturated aqueous solution of sodium bicarbonate to neutralize the mixture therewith, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 1-methyl-1H-pyrrolo(2,3-b)pyridine-3-carbaldehyde (4.87 g, 83%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:58][CH:59]([CH3:61])[CH3:60])[C@@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:57])[CH:38]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:13][O:14][C:15](=[O:31])[C@@H:16]([NH:20]C(OCC2C=CC=CC=2)=O)[CH:17]([CH3:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1COCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:58][CH:59]([CH3:61])[CH3:60])[C@@H:12]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:57])[CH:38]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:13][O:14][C:15](=[O:31])[C@@H:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)NC(C(=O)NCCCC[C@@H](COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)NCCCC[C@@H](COC(=O)[C@@H](N)C(C)C)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Yield: 47 %

Procedure:
To a stirred solution of (2S,2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexyl ester (step C, 120 mg, 0.14 mmol) in anhydrous THF (8 mL), under nitrogen atmosphere, was added palladium 10% wt. on activated carbon (160 mg). The mixture was reacted under hydrogen atmosphere overnight, at room temperature. The solution was filtered and the palladium on carbon was washed with THF (50 mL). The solvent was evaporated and the residue (110 mg) was purified by flash chromatography using ethyl acetate as the eluent. The clear oil was obtained in 47% yield (47 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[CH:5][N:6]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:26][C:23]3[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=3)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cc(OCc2cnc(Cl)s2)ccc1Cl
Reactant: Nc1ccc(S)cc1
Solvent: CCO
Product: Nc1ccc(Sc2ccc(OCc3cnc(Cl)s3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole (from Example 25A) was reacted with 4-aminothiophenol in anhydrous ethanol and at reflux under a nitrogen atmosphere. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation. The residue was taken up in water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration of the solid with 4% ethyl acetate/methylene chloride afforded 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)aniline. A mixture of 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)aniline and di-tert-butyl dicarbonate in 1,4-dioxane was heated at reflux under a nitrogen atmosphere, and then additional Boc anhydride was added and the reaction allowed to reflux. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The resulting solid was triturated with 2.5% ethyl acetate/methylene chloride to obtain tert-butyl 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate. A suspension of 4-(4-((2-chlorothiazol-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate, iron powder, and ammonium chloride in water and ethanol was heated. The reaction was cooled to room temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][NH2:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12](=S)=[S:13].OO.Cl>C(#N)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:12](=[S:13])[NH:11][N:10]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: S=C=S
Reactant: COc1ncc(Cl)c(NN)n1
Agent: Cl
Agent: OO
Solvent: O
Solvent: CC#N
Product: COc1ncc(Cl)c2n[nH]c(=S)n12
Yield: 142 %

Procedure:
5-Chloro-4-hydrazino-2-methoxypyrimidine (17.45 g, 0.10 mol) and 25 g (0.033 mol) of carbon disulfide were combined in 120 mL of acetonitrile and 30 mL of water at ambient temperature with stirring and 11.4 g (0.10 mol) of 30 percent hydrogen peroxide was added to the resulting mixture with stirring over a 2-hour period. The temperature rose from 20° C. to 48° C. Analysis of the mixture by high pressure liquid chromatography (HPLC) indicated that the reaction was complete. A 79.8 g (47.2 percent of the total) portion of the reaction mixture was diluted with 50 mL of water and the mixture was acidified with hydrochloric acid. The solids present were then recovered by vacuum filtration and dried to obtain 10.15 g of a mixture of the title compound and sulfur. The sulfur was then removed by extracting the solids with 45 g of carbon disulfide to obtain 8.08 g (80 percent of theory) of the title compound as a tan powder. This material was 92 percent pure by HPLC analysis; it decomposed on heating.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:12]([O:14]CC)=[O:13])[C:3]1=2.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:12]([OH:14])=[O:13])[C:3]1=2
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)CC(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CC(=O)c2c(C(=O)O)c[nH]c2C1

Procedure:
A stirred mixture of ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (15.7 g, 71 mmol) and ammonium acetate (9.54 g, 124 mmol) in N,N,-dimethylformamide (75 mL) was heated at 100° C. for 2 hours. The reaction mixture was concentrated in vacuo, ice water was added, and the precipitate collected, rinsed with water then diethyl ether and dried to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (5.94 g). To this ester was added aqueous 5N sodium hydroxide (50 mL) and ethyl alcohol (10 mL) and the mixture heated at reflux for 40 minutes. The reaction mixture was cooled in an ice water bath, acidified with aqueous hydrochloric acid, and the precipitate collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (5.2 g). m.p. 210-211° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([NH2:60])=[CH:57][CH:58]=2)[CH:53]=[N:52]1>ClCCCl>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:60][C:56]1[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=1)[N:51]([CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=1)[N:52]=[CH:53]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: C[C@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCCl
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A mixture of (2S)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol), triphenylphosphine (603 mg, 2.3 mmol) and carbon tetrachloride (2.2 ml, 23 mmol) in 1,2-dichloroethane (5 ml) was stirred at 45° C. for 2 hours. 1-(Pyridin-2-ylmethyl)-1H-indazol-5-amine (179 mg, 0.8 mmol) was added and the solvent was evaporated under vacuum. Acetonitrile (5 ml) was added. The mixture was stirred at 75° C. for 2 hours. After cooling, 6N methanolic ammonia (3 ml) was added. The solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 3% to 5% methanol in DCM) to give the title compound as a white foam (208 mg, 58%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum 468.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.O[C:26]1[CH:58]=[CH:57][C:29]([CH2:30][CH:31]2[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:56])=[CH:28][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:4]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[N:11]=[C:3]3[CH2:2][O:1][C:26]3[CH:58]=[CH:57][C:29]([CH2:30][CH:31]4[S:35][C:34](=[O:36])[N:33]([C:37]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]4=[O:56])=[CH:28][CH:27]=3)=[CH:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1nc2cccnc2n1Cc1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl-3-(4-phenylbenzyl)imidazo[5,4-b]pyridine (prepared as described in Preparation 54), 0.738 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.43 ml of tributylphosphine, 0.4 g of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:2 to 1:3 by volume as the eluent, to give 0.95 g of the title compound having Rf=0.44 (on silica gel thin layer chromatography using a 1:3 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][C:3](=O)[CH2:2]1.S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CCO.CC([O-])(C)C.[K+]>COCCOC>[CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([C:23]#[N:24])[CH2:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC2(CCCCC2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCC2(CCCCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of spiro[5.5]undecan-3-one (1.66 g, 10 mmol) and tosylmethylisocyanide (2.54 g, 13 mmol) in DME (50 ml) and abs. EtOH (1 ml) was added KOtBu (2.69 g, 24 mmol) portionwise during 0.5 hr at −10° C. After addition, the reaction mixture was stirred at 0° C. for 1 hr then 2 hr at ambient temperature. Solvent was removed in vacuo and the resulting residue was extracted with diethyl ether (50 ml×3) and the combined organic layer was washed with water (50 ml×3). The organic layer was dried with anhydrous MgSO4, concentrated under reduced pressure and purified by flash column chromatography (50%-100% CH2Cl2/Hexane) to give the nitrile as colorless solid (1.28 g, 72% Yield). 1H-NMR (360 MHz, CDCl3) δ 2.58-2.53 (m, 1H), 1.83-1.70 (m, 4H), 1.63-1.58 (m, 2H), 1.40-1.26 (m, 8H), 1.28-1.20 (m, 4H); 13C-NMR (90 MHz, CDCl3) δ 122.79, 34.41, 31.88, 28.37, 26.88, 24.73, 21.64, 21.55; ESI-MS: Calculated for C12H19N (M+H)+178.3. Found: 178.2.
Reaction SMILES: [CH:1](=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[C:2]1([C@H:1]2[C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC/N=C/c1ccccc1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
To the imine 9A (0.31 g, 1.51 mmol) and triethylamine (0.42 mL, 3.02 mmol) in dichloromethane (15 mL) at 0° C. was added titanium chloride (1.51 mL, 1.0 M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 3 h and then quenched with saturated potassium carbonate. The mixture was filtered through celite and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by preparative HPLC equipped with a YMC ODS S5 (30×100 mm) column. The separation was performed using a linear gradient (solvent A: 10% acetonitrile-90% water-0.1% TFA; solvent B: 90% acetonitrile-90% water-0.1% TFA; 0 to 100% B in 12 min with a flow rate of 40 mL/min to give 0.095 g of 9B as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.50 (m, 2H) 3.42 (s, 3H) 3.55 (m, 1H) 3.72 (m, 2H) 4.98 (d, J=7.09 Hz, 1H) 7.36 (m, 2H) 7.44 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[BH4-].[Na+].O>>[O:2]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7])[CH3:1]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cc(CO)cc(OC)c1OC
Temperature: 40 °C
Yield: 92.72 %

Procedure:
Adding 3,4,5-trimethoxybenzaldehyde (15 g, 76.45 mmol) and anhydrous alcohol (200 ml) in the three-necked bottle (250 ml), heating to 40° C. to dissolve, adding sodium borohydride (1.48 g, 38.23 mmol), heating to reflux for 45 minutes, and monitored by TLC. When the reaction is completed, cooling it to room temperature, adding deionized water (10 ml, 555.8 mol), to quench the reaction and suction filtering, washing the filter residue by anhydrous alcohol (20 ml), conflating the filtrate, concentrating in rotarory evaporater to dry, adding dichlormethane (100 ml) to dissolve, washing with sodium hydroxide solution (50 ml) twice and with deionized water (50 ml) twice, adding proper amount of anhydrous magnesium sulfate to dry overnight, filtering, washing the filter residue with dichlormethane (20 ml), conflating the filtrate, concentrating in rotarory evaporater to dry to get 3,4,5-trimethoxyl benzyl alcohol, 14.05 g of colorless oily product), the yield: 92.72%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])[CH3:2].P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][C:12]1[N:11]=[C:10]2[S:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[C:15]2=[CH:14][CH:13]=1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1c(C(=O)OC)sc2nc(Cl)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate 7-oxide (245.4 mg) and toluene (7.9 mL) was added phosphoryl chloride (0.367 mL). The mixture was stirred at 80° C. for 3 h. After cooling, the mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (147 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH2:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:27][CH3:26])=[O:15])=[C:12]([CH3:17])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Reactant: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)-2-methylnicotinic acid (180 mg, 0.678 mmol) in DCM (5 mL) and DMF (0.2 mL) at 0° C., was added oxalyl chloride (0.178 mL, 2.033 mmol). The reaction mixture was stirred for 3 h at RT then diluted with DCM (5 mL) and treated with a solution of methylamine hydrochloride (457 mg, 6.78 mmol) in DCM (5 mL) cooled to 0° C. The mixture was stirred for another 1 h at RT. The solution was extracted with DCM (20 mL), washed with saturated NaHCO3 (2×10 mL) and water (20 mL); dried over Na2SO4 and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N,2-dimethylnicotinamide (50 mg, 0.179 mmol, 27% yield) as a brown gum. LC/MS, (ESI) m/z 279.2 [(M+H)+, calcd for C14H13ClFN2O 279.1]; LC/MS retention time (method D): tR=0.62 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (800 mg, 2.49 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.031 g, 7.47 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (510 mg, 2.74 mmol) in DMF (25 ml) was stirred at 80° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate removed in vacuo. The residue was purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product recrystallised from ethanol to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(2-morpholinoethoxy)quinazoline (510 mg, 47%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>N1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
In 40 ml of pyridine were dissolved 5.2 g of 5-fluorouracil. The solution was ice cooled and 0.8 g of titanium tetrachloride was added thereto. Then, 6 ml of 2,3-dihydrofuran in 20 ml of pyridine were added to the mixture in 1.5 hours while stirring it at 80° C. The reaction was continued for 4 hours. After completion of the reaction, pyridine was removed from the reaction liquid by distillation and 500 ml of chloroform and 5 g of silica gel were added to the residue. The mixture was decolored and filtered and the filtrate was concentrated to obtain 5.5 g of 1-(2-tetrahydrofuryl)-5-fluorouracil in a yield of 69%.