Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]([NH:20][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16](=S)[S:17][CH:18]=1.IC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:20]=[C:21]([OH:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[S:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)Nn1c(-c2c(OC)cc(COC)cc2OC)csc1=S
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1c(O)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Reaction time: 23 h
Yield: 58 %

Procedure:
Acetone (235 mL) was added to ethyl 3-{[4-(2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-thioxo-1,3-thiazole-3(2H)-yl]-amino}-3-oxopropanoate (11.7 g, 27.6 mmol), and then iodomethane (17.1 mL, 276 mmol) was added dropwise at room temperature and the mixture was stirred for 23 hours. The solvent in the filtrate was distilled off under reduced pressure. To the obtained residue were added tert-butanol (235 mL) and potassium tert-butoxide in that order, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the mixture while cooling on ice, and then aqueous 2N hydrochloric acid was added until the pH of the mixture reached approximately 4. The precipitated solid was collected by filtration, and the resulting residue was washed with water and dried under reduced pressure to obtain the title compound (6.3 g, 16 mmol).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][CH2:13][CH:14]=[CH2:15].C1COCC1.[CH:22]1([Mg]Cl)[CH:26]=[CH:25][CH:24]=[CH:23]1.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:12][CH2:13][CH:14]=[CH2:15])=[C:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCC(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=C1C=CC=C1)c1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
First, 6-(2-naphthyl)-6-(3-butenyl)fulvene was prepared from cyclopentadienyl Grignard reagents as follows. A 1 L round bottomed flask was charged with 1-(2-naphthyl)-4-penten-1-one, 97% (21.73 g, 100 mmol), THF (100 mL), and a stir bar, and cooled in an ice bath. Cyclopentadienyl magnesium chloride (150 mL of approximately 1 M solution in THF, 330 mmol) was added dropwise over ½ hour. The yellow solution was stirred for 2 hours in the ice bath. The yellow solution was then refluxed for 2.5 hours, during which time a red color developed. The solution was acidified by first adding 100 mLs of water, and then adding 100 mL of 1 M HCl. The product was extracted with pentane, and the pentane extracts were collected, washed with water, and dried over sodium sulfate. Elution through silica with pentane and concentration under vacuum afforded 20.25 g (73%) of the product 6-(2-naphthyl)-6-(3-butenyl)fulvene as a red oil, which was 93% pure. The major impurity was dicyclopentadiene.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:17])[CH:9]=2)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:17])[CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(OC)c(C)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OC)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 0.20 g (0.60 mmol) 5-methoxy-6-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 4 mL dichloromethane was cooled to 0° C. and 2 mL (3.0 g, 26.1 mmol) trifluoroacetic acid were added. The ice bath was removed and after stirring 1 h at room temperature the solution was evaporated to dryness. The residue was dissolved in dichloromethane, washed with aqueous 1M sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white solid (97%) which was pure enough to be used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C)C(=O)CCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Methyl 4-hydroxybenzoate (Fluka) (1.52 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) in DMF (10 mL) was treated with 2-chloro-N,N-dimethylacetamide (Merck) (1.03 ml, 10 mmol) and the mixture was stirred at RT overnight. The reaction mixture was worked up by partitioning between ethyl acetate and 2M hydrochloric acid, washing with HCl, brine, dried (MgSO4) and evaporating to dryness. The residue was dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and 2-chloro-N,N-dimethylacetamide (Merck) (1.03 ml, 10 mmol). The mixture was stirred at RT over the weekend, and then worked up. Partitioned between ethyl acetate and 2M HCl and the organic solution was washed with HCl (X2), brine (X3), dried (MgSO4), and evaporated to give the title compound (1.62 g, 68%) as a white solid. LCMS (System A) RT=0.73 min, ES+ve m/z 238 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14](O)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:19]C=[N+](C)C>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([Cl:19])[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+](C)=CCl
Reactant: Cc1cc(O)nc(N[C@@H](C)c2ccccc2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)nc(N[C@@H](C)c2ccccc2)n1
Yield: 18.3 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-hydroxy-6-methylpyrimidine (100 mg, 0.436 mmol, 1 eq) in chloroform (2 mL) was added (chloromethylene)dimethylammonium chloride (Vilsmeier reagent) (55.9 mg, 0.436 mmol, 1 eq). After 1 hour the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (eluted with 3:1 hexanes/acetone) to give 19.8 mg of the title compound. Mass spectrum (NH3/CI): 248.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(O[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: OC[C@H]1CCCCN1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(CCN2CCCC[C@@H]2CO)c1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine (288 mg, 2.50 mmol), 3-methoxyphenethyl mesylate (863 mg, 3.75 mmol), sodium carbonate (398 mg, 3.75 mmol) and sodium iodide (30 mg, 0.20 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(3-methoxyphenethyl) piperidine in the form of a light yellow oil (322 mg, 52%).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][O:4]1.C(=O)(O)[O-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(#N)C>[CH2:11]([N:18]1[CH2:5][CH:3]([OH:4])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: OC1CN(Cc2ccccc2)C1

Procedure:
reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine at about 0° C. to about 80° C. in acetonitrile and water to provide 1-benzyl-3-azetidinol, reacting the 1-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 40° C., and isolating 1-benzyl-3-azetidinol (2E/Z)-2-butenedioate;
Reaction SMILES: [OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17].[C:26](OC(=O)C)(=[O:28])[CH3:27].O>CCOCC>[C:26]([O:1][CH:2]([CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(O)CN1CCN(C)CC1
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of 7-[2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxyquinazolin-4-one (1.2 g, 3.3 mmol) and acetic anhydride (670 μl) in ether (2 ml) was stirred 10 minutes at ambient temperature. Ether (2 ml) was further added, followed by acetic anhydride (670 μl). After stirring 1 hour at ambient temperature, water (305 μl) was added and stirring was continued for 1.5 hours. The mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with methylene chloride. The organic layers were combined, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-[2-acetoxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxyquinazolin-4-one (0.93 g, 72%).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1F.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>C(Cl)(Cl)Cl>[Cl:4][C:5]1[C:6]([F:14])=[N:7][C:8]([F:13])=[C:9]([F:12])[C:10]=1[N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1c(F)c(F)nc(F)c1Cl
Temperature: 40 °C
Reaction time: 24 h
Yield: 102.6 %

Procedure:
To a mixed solution of 40 ml dichloromethane and 20 ml N,N-methylformamide were added 18.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine and 20.5 g potassium phthalimide, and the mixture was stirred at 40° C. for one day. After adding 40 ml of chloroform, the mixture was washed twice with 500 ml of distilled water and once with 500 ml of 0.5% aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersed in diisopropylether, and collected by filtration to obtain 32.0 g of the title compound as a colorless powder.
Reaction SMILES: [I:1]Cl.[N:3]1[C:4](=[O:12])[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>C(O)(=O)C>[I:1][C:10]1[CH:9]=[CH:8][C:7]2=[N:3][C:4](=[O:12])[N:5]=[C:6]2[CH:11]=1
Reactant: ClI
Reactant: O=C1N=c2ccccc2=N1
Solvent: CC(=O)O
Product: O=C1N=c2ccc(I)cc2=N1
Temperature: 80 °C

Procedure:
A mixture of iodine monochloride and 2H-benzimidazole-2-one (0.67 g) (Method 59) in glacial acetic acid (8 ml) was heated to 80° C. for 1 hour then cooled. The mixture was partitioned between saturated aqueous sodium sulphite solution and DCM. The organic layer was evaporated to dryness then redissolved in ethyl acetate. The aqueous layer was extracted with ethyl acetate then all ethyl acetate extracts were combined and washed with saturated aqueous sodium hydrogencarbonate solution, water and brine. The organic extracts were passed through a Varian Chem Elut column and washed through with ethyl acetate. Volatile material was removed by evaporation to give the title compound (0.36 g) as a solid which was used without further purification. MS (ESP−): 261 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:6][C:7]1[C:8](=[O:20])[O:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)(=[O:5])[CH3:4]>O.CO.[Pd]>[C:3]([NH:6][C:7]1[C:8](=[O:20])[O:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH2:17])=[CH:12][CH:11]=2)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1cc2cc([N+](=O)[O-])ccc2oc1=O
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc2cc(N)ccc2oc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Palladium 10 wt % on activated carbon (0.322 g, 1/10th the mass of 1) was placed in a 1-L round-bottom flask and the flask was purged with nitrogen. A solution of sodium borohydride (1.21 g, 32.9 mmol) in 22.6 mL water was added drop-wise. A suspension of compound 1 (3.20 g, 12.9 mmol) in methanol (775 mL) was then added over a two hour period and allowed to stir at room temperature an additional 30 min, when the reaction mixture was filtered through Celite and the solvent was removed by rotary evaporation. Water (750 mL) was added to the residue and the solution was cooled to 4° C. for 20 h. The resulting precipitate was filtered and rinsed with cold distilled water. The solid was recrystallized from ethanol to give 2 as a yellow solid (1.59 g, 7.3 mmol) in 57% yield. mp 250-252° C. (lit 252-253° C.). FTIR (KBr) (cm−1): 3410, 3310, 1700, 1650, 1630. 1H-NMR (DMSO-d6): δ (ppm) 9.65 (s, 1H), 8.40 (s, 1H), 7.10 (dd, J=9.1 Hz, J=2.7 Hz, 1H), 6.73 (d, J=9.1 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 5.19 (bs, 2H), 2.14 (s, 3H). 13C-NMR (DMSO-d6): δ (ppm) 171.12, 158.78, 146.92, 142.52, 125.26, 124.98, 120.82, 117.54, 117.15, 110.66, 24.93. HRMS expected, 219.07770; found, 219.07697. Elemental analysis for C11H10N2O3: expected: C, 60.55; H, 4.62; N, 12.84; found: C, 60.15; H, 4.50; N, 12.62.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:38][C:15]2[N:16]=[CH:17][N:18]([CH2:21][C:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([OH:29])[CH2:23][N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)[C:19](=[O:20])[C:14]=2[CH:13]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:22]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[CH2:21][N:18]1[C:19](=[O:20])[C:14]2[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[S:38][C:15]=2[N:16]=[CH:17]1
Reactant: CC(=O)OCCCCCCCc1cc2c(=O)n(CC(O)(Cn3cncn3)c3ccc(F)cc3F)cnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1c2cc(CCCCCCCO)sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
6-(7-Acetoxyheptyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (3.00 g, 5.5 mmol) was dissolved in the mixture of methanol (10 ml) and water (2 ml). Then potassium carbonate (760 mg, 5.5 mmol) was added and the mixture was stirred at RT for 2 hours. Methanol was then removed on rotavapor, water (10 ml) was added to the reaction mixture and extracted with ethyl acetate (2×5 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(7-hydroxyheptyl)-thieno[2,3-d]pyrimidin-4(3H)-one (2.5 gm, 90.57%).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:22][CH2:21][C:8]2=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:10][C:11]([S:12][CH:13]([CH3:15])[CH3:14])=[C:7]2[C:6]1=[O:23])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:13]([S:12][C:11]1[S:10][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]2[CH2:21][CH2:22][C:5]3[N:4]=[C:1]([CH3:2])[O:23][C:6]=3[C:7]=12)([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(NC(C)=O)C2=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCc1nc(C)oc1-2
Yield: 100.1 %

Procedure:
A mixture of ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.00 g), phosphorus oxychloride (1.29 g) and toluene (30 ml) was refluxed under heating for 1.5 hours; the solution obtained was concentrated under reduced pressure, diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4,5-dihydro-8-isopropylthio-2-methylthieno[3,4-g]benzoxazole-6-carboxylate (0.95 g, 100%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 62-63° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg][Cl:7].Cl[CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O1CCCC1.Cl>CCOCC>[ClH:7].[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: CN(C)CCC[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCCC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
The Grignard solution prepared in Step A. is cooled to room temperature and stirred while a solution of 5.05 g. (0.0221 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 25 ml. of dry tetrahydrofuran is added dropwise, external cooling being applied as required to maintain the temperature close to room temperature. When the addition is complete, the mixture is heated to refluxing for 15 minutes. The bulk of the tetrahydrofuran then is distilled under reduced pressure, keeping the water-bath temperature at 50°-60° C. The syrupy mixture is dissolved in 75 ml. of benzene and water, 15 ml., is added dropwise with stirring. The benzene layer is decanted from the gelatinous precipitate which then is re-extracted with three 20 ml. portions of boiling benzene. The combined benzene extracts are washed with water and extracted with three 15 ml. portions of 3N hydrochloric acid. The acid extract is made basic with sodium hydroxide and the yellow oily base that separates is extracted into hexane. After washing the combined extracts with water, the hexane is evaporated and the product obtained as a yellow oil in a yield of 4.61 g. The base is converted to the hydrochloride by dissolving it in a mixture of 15 ml. of absolute alcohol and 15 ml. of absolute ether and adding 1.8 ml. of a 10.28 N solution of dry hydrogen chloride in absolute alcohol. The solution then is diluted to incipient crystallization by the addition of 25 ml. of absolute ether. The yield of 5-(3-dimethylaminopropyl)-5-dibenzo[a,d]cycloheptene hydrochloride, m.p. 186°-190° C. is 4.17 g. Recrystallization from mixtures of absolute alcohol and absolute ether gives the product, m.p. 191°-193° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Oc3ccccc3Cl)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 2-chlorophenol (0.23 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(2-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.59 g, 84%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:20])[CH3:19]>CCOC(C)=O>[CH2:17]([O:21][C:22]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COc1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)COc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
1-[2-(3-Isobutoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-Isobutoxyphenylboronic acid following general procedures as described in these Examples. Silica gel chromatography using 30-100% EtOAc in hexanes as eluant provided 170 mg (94%) of a pale yellow solid. MP 177-178° C., M+H=351.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cn2nc(Oc3ccc(Cl)c(NC(=O)C4CC4)c3)ccc2n1)C1CC1
Yield: 87.1 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.435 mmol), cyclopropanecarbonyl chloride (71.8 mg, 0.652 mmol), triethylamine (132 mg, 1.30 mmol) and tetrahydrofuran (17 mL) as starting materials and in the same manner as in Example 96, the title compound (156 mg, 87%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].C([N-]C(C)C)(C)C.[Li+].CCCCCC.[CH:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[OH:7][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)C(C)(C)C
Reactant: CC(C)(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of pinacolone (10 g, 100 mmol, 1), in anhydrous THF (500 mL), at −78° C. a 2.0 M solution of lithium diisopropylamide (LDA) in hexane (60 mL, 120 mmol) over a period of 30 min. The reaction was stirred at −78° C. for another 30 min. To the resulting white suspension pivalaldehyde (10.9 mL, 100 mmol) was added drop-wise via syringe and the reaction continued for another 12 hrs at room temperature. The reaction was quenched by adding 10 mL of water. Approximately 80% THF was removed and the mixture was then poured into saturated aqueous solution of NH4Cl. The aqueous layer was extracted twice with diethyl ether (200 mL) and the organic layer was washed with plenty of water. The organic layer was then dried over MgSO4 and concentrated to give a crude yellow solid of β-hydroxy ketone (17.2 g, 95%, (2)). The crude product was recrystallized from hexane to give pure white solid with a yield of 81%.