Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][C:8]([NH:12][C:13](=[O:19])[C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:20][CH2:21][CH2:22][N:3]12.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[CH:23](=[C:20]1[C:4]2=[N:5][C:6]3[CH:7]=[C:8]([NH:12][C:13](=[O:19])[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][C:11]=3[C:2](=[O:1])[N:3]2[CH2:22][CH2:21]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(=O)Nc1ccc2c(=O)n3c(nc2c1)CCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Temperature: 60 °C
Reaction time: 6 h

Procedure:
N-(9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-amino-oxoacetic acid, ethyl ester, m.p. 198°-200° C. (1.2 g) was reacted with benzaldehyde (0.84 g) in methanol (20 ml), in the presence of sodium methoxide (0.86 g) under stirring at 60° C. for 6 hours. After cooling the reaction mixture was concentrated in vacuo and diluted with ethyl ether: the precipitate was filtered, washed with ether and dissolved in water. Acidification with acetic acid gave a precipitate which was filtered and washed with water: crystallization from formic acid gave 0.4 g of N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-amino-oxoacetic acid, m.p. 220°-225° C.
Reaction SMILES: [OH:1][CH:2]([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[S:4]([O-:7])(=[O:6])=[O:5].[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:39]([O:1][CH:2]([C:10]([F:13])([F:11])[F:12])[C:3]([F:8])([F:9])[S:4]([O-:7])(=[O:6])=[O:5])(=[O:41])[CH3:40].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Yield: 70 %

Procedure:
In 28 g of methylene chloride were dissolved 3.0 g of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate synthesized in Synthesis Example.11 and 0.7 g of pyridine. While stirring under ice cooling, 0.8 g of acetic anhydride was added to the solution. Thereafter, 0.7 g of triethylamine and 0.04 g of 4-(N,N-dimethylamino)pyridine were added to the solution, which was stirred for 4 hours. Water, 20 g, was added to quench the reaction. The organic layer was separated and washed with 20 g of water three times. The organic layer was then concentrated, obtaining triphenylsulfonium 2-acetoxy-1,1,3,3,3-pentafluoropropane-1-sulfonate. Colorless oily matter, 2.2 g (yield 70%).
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][C:4](N)=[O:5].[Br:9][CH:10](Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][C:4]1=[O:5]
Reactant: NC(=O)CCC(N)=O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1CCC(=O)N1CCBr

Procedure:
49.5 g of succinamide was dissolved in 750 ml of 2-butanone under heating. 187.9 g of dibromoethane and 138 g of anhydrous potassium carbonate were added to the solution and the mixture was heated under reflux for 9.5 h.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH3:44])[CH2:38]1.O>CS(C)=O>[OH2:22].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:36][CH:37]4[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH3:44])[CH2:38]4)=[O:23])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=C(O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CS(C)=O
Product: CCN1CCCC(NC(=O)Cc2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7.0 Grams (0.02 mole) of 2-[4-(7-chloro-4-quinolylamino)phenyl]acetic acid hydrochloride were dissolved in 150 milliliters of dimethyl sulphoxide by heating the stirred mixture to 100° C. under nitrogen. The solution was cooled to room temperature, 6.48 grams (0.04 mole) of carbonyl di-imidazole were added and the mixture was stirred for 21/2 hours under nitrogen. 7.68 Grams (0.06 mole) of 3-amino-1-ethylpiperidine were added, the solution was stirred for another 21/2 hours and poured into 500 milliliters of water. The mixture was refrigerated overnight and the resulting solid was broken up, stirred with water, collected and dried. The solid was dissolved in chloroform and chromatographed on an alumina column made up in chloroform. Elution with chloroform/methanol (4:1) gave 8.15 grams (92.5% yield) of 2-[4-(7-chloro-4-quinolylamino)phenyl]-N-(1-ethyl-3-piperidyl)acetamide monohydrate, melting point 160°-162° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([OH:13])(=[O:12])=O)[CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.[CH2:25]([NH2:27])[CH3:26]>O>[CH2:25]([NH:27][S:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:12])=[O:13])[CH3:26]
Reactant: CCN
Reactant: O=[N+]([O-])c1cncc(S(=O)(=O)O)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCNS(=O)(=O)c1cncc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 0.5g. of 5-nitro-3-pyridinesulfonic acid, 0.5g. of phosphorous pentachloride and 15 ml. of phosphorous oxychloride was heated under reflux for 6 hours. After removing the solvent by evaporation, dry chloroform was added to give a powdery crystal. After adding the crystal to 2.5 ml. of 20% ethyl amine under cooling, the mixture was stirred for 1 at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate. The extact was washed with water and dried. After removing the solvent by evaporation and purification by chromatography, 0.2g. of the desired compound was obtained. m.p. 117°-118° C. Similarly, the following compounds were synthesized.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2>CN(C=O)C>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 34.5 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 260 mg of 4-chloroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 82 mg of the target compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10](=[CH2:17])[C:11]([O:13][CH2:14][CH2:15][NH2:16])=[O:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[F:32][C:33]([F:39])([F:38])[S:34](F)(=[O:36])=[O:35]>C(#N)C>[CH3:17][C:10](=[CH2:9])[C:11]([O:13][CH2:14][CH2:15][NH:16][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])=[O:12]
Reactant: O=S(=O)(F)C(F)(F)F
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: -30 °C

Procedure:
In a 1-liter three-neck flask equipped with a thermometer, a reflex condenser and a calcium chloride tube were placed 350 g of acetonitrile, 70.7 g (0.699 mol) of triethylamine, 33.1 g (0.200 mol) of 2-aminoethyl 2-methylacrylate hydrochloride and 0.2 g of phenothiazine as a polymerization inhibitor, followed by cooling to −30° C. with stirring. After the inside temperature of the flask reached −30° C. C, 36.5 g (0.240 mol) of trifluoromethanesulfonyl fluoride was introduced as a gas into the slurry over 1 hour. Upon completion of the gas introduction, the reaction solution was stirred for 1 hour and then warmed to room temperature. The solvent (acetonitrile) and the unreacted reaction substrate (trifluoromethanesulfonyl fluoride) were evaporated from the reaction solution under a reduced pressure. To the solution was added 1 liter of diisopropyl ether. The resulting slurry was subjected to filtration to filter out precipitates of triethylamine hydrochloride and triethylamine hydrofluoride. The filtrate was washed with 200 ml of 18% aqueous calcium chloride solution and subjected to two-phase separation. The organic phase was further washed three times with 200 g of 10% aqueous sodium chloride solution, and then, dried with 40 g of magnesium sulfate. The magnesium sulfate was removed by filtration. After that, 0.2 g of phenothiazine was added to the organic phase. The solvent was evaporated to obtain 44.2 g of a crude reaction product. The crude reaction product was subjected to distillation under a reduced pressure, thereby yielding 36.0 g of target 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate as an organic fraction at 105-115° C./13Pa. The purity of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate in the organic fraction was determined by gas chromatography to be 97.0%. The organic fraction was dissolved into a mixed solvent of diisopropyl ether and n-hexane under heating. The solution was cooled, thereby collecting 32.4 g of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate as a white crystal. The purity of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate in the crystal was determined by gas chromatography to be 99.0%. The yield of the 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-me thylacrylate was 61%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:11])[NH:8]2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C.[Cl-].[Na+].O.C(Cl)Cl>[CH2:26]([N:8]1[C:7]([I:11])=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: Clc1nc(N2CCOCC2)c2nc(I)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 50 °C
Yield: 118.3 %

Procedure:
4-(2-chloro-8-iodo-9H-purin-6-yl)morpholine (500 mg, 1.0 mmol) was stirred together with cesium carbonate (890 mg, 2.7 mmol) in DMF (4.2 mL) at ambient temperature for 10 minutes. Allyl bromide (0.36 mL, 4.1 mmol) was introduced and the reaction mixture was heated at 50° C. for 2 hr. The mixture was cooled to ambient temperature and diluted with brine and DCM and the layers separated. The aqueous phase was extracted into DCM (3×), dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(9-allyl-2-chloro-8-iodo-9H-purin-6-yl)morpholine as a white foam (480 mg, 90%). 1H NMR (500 MHz, DMSO) δ 5.94 (d, J=10.6 Hz, 2H), 5.76 (s, 1H), 5.19 (d, J=10.3 Hz, 2H), 4.79 (d, J=16.9 Hz, 2H), 4.69 (s, 2H), 3.73 (s, 4H). LC/MS (ESI+): m/z 406 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][CH:23]=1)=O.C([BH3-])#N.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][CH2:20][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1ccc2c(N[C@H]3CC[C@@H](NCc4ccc5cc[nH]c5c4)CC3)ccnc2c1

Procedure:
A mixture of example 23A (30 mg, 0.11 mmol), 6-formylindole (19.2 mg, 0.132 mmol) and solid supported cyanoborohydride (0.22 mmol) was shaken in 1:1 mixture tetrahydrofuran and acetic acid for 15 hours, filtered and concentrated. The residue was purified with a high throughput HPLC system to provide the desired compound as its bis TRIFLUOROACETIC ACID salt. MS (ESI(+)Q1MS m/z 405 (M+H)+); 1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H), 8.74 (d, 1 H), 8.49-8.79 (m, 2 H), 7.96 (d, 1 H), 7.85 (dd, 1 H), 7.62 (d, 1 H), 7.56 (s, 1 H), 7.45 (t, 1 H), 7.13 (d, 1 H), 6.94 (d, 1 H), 6.47 (t, 1 H), 4.28 (br.s, 1 H), 4.08 (br.s, 1 H), 2.27 (s, 2 H), 1.73-2.13 (m, 9 H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[CH:12]=2)=[CH:7][CH:6]=1.Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>C1COCC1>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][O:18][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[CH:16]=[CH:15][C:14]=1[CH3:17]
Reactant: COC(CBr)OC
Reactant: COc1ccc(-c2ccc(C)c(O)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C)c(OCC(OC)OC)c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To NaH (357 mg (600 mg 60% in mineral oil, hexane washed 3×), 14.86 mmol) was added dry THF (100 ml), 4′-methoxy-4-methyl-biphenyl-3-ol (1.59 g, 7.43 mmol), and 2-bromo-1,1-dimethoxy ethane (1.76 g, 10.40 mmol). The reaction was stirred at 60° C. overnight, cooled, passed through a silica plug and concentrated to 1.66 g (74%) of product as a white solid: mp 3940° C.; 1H NMR (300 MHz, DMSO-d6): δ 2.17 (3H, s), 3.38 (6H, s), 3.79 (3H, s), 4.09 (2H, d, J=5.2 Hz), 4.73 (1H, t, J=5.2 Hz), 7.00 (2H, d, J=8.8 Hz), 7.09 (1H, dd, J=7.7 Hz, 1.5 Hz), 7.15 (1H, d, J=1.2 Hz), 7.18 (1H, d, J=7.8 Hz), 7.62 (2H, d, J=8.8 Hz); MS (ESI) m/z 303 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O.C(OCC)C>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:10]([C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 5 h
Yield: 42.3 %

Procedure:
4-Phenylbenzoyl chloride (2.00 g, 9.23 mmol) was added to a mixed solution of 4-aminocinnamic acid (1.51 g, 9.23 mmol) and sodium hydrogen carbonate (2.33 g, 27.7 mmol) in water and diethyl ether under ice-cooling, which was stirred for 5 hours. After the reaction mixture was separated, 5N hydrochloric acid was added to water layer, and the precipitated crude product was washed with water and ethyl acetate, to give the titled compound (1.34 g).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.C[OH:23]>C(O)(=O)C.[C].[Pd]>[C:18]([OH:17])(=[O:23])[CH3:21].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N)CC1
Yield: 57 %

Procedure:
In methanol (2 ml) and acetic acid (30 ml), 4-benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) was dissolved, followed by the addition of 10% palladium carbon (water content: about 50%, 3.06 g). The resulting mixture was subjected to catalytic reduction overnight under medium pressure (3 atmospheric pressure). After the removal of the catalyst by filtration, the filtrate was distilled off under reduced pressure. The residue was solidified in ethyl acetate, whereby the title compound (2.23 g, 57%) was obtained.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7]C)=[O:6].[NH2:9][C:10]([NH2:12])=[S:11].C(=O)(O)[O-].[Na+].[OH-].[Na+].[ClH:20]>CO.CC(C)=O>[ClH:20].[NH2:12][C:10]1[S:11][CH2:2][CH:3]([CH2:4][C:5]([OH:7])=[O:6])[N:9]=1
Reactant: COC(=O)/C=C/CBr
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: NC1=NC(CC(=O)O)CS1
Yield: 40 %

Procedure:
A solution of 9.3 g. (0.05 mole) methyl 4-bromocrotonate, 3.9 g. (0.05 mole) thiourea and 8.4 g. (0.10 mole) sodium bicarbonate in 200 ml. acetone was heated at reflux for two hours. The resulting mixture was filtered and the filtrate evaporated at reduced pressure to yield 10.0 g. of crude methyl 2-amino-(2-thiazoline)-4-acetate. The methyl ester was dissolved in 60 ml. of 20% (w/w) aqueous methanol, heated with 2.3 g. (0.05 mole) sodium hydroxide and stirred at room temperature for 18 hours. The resulting solution was acidified (pH 1.0) with 6N hydrochloric acid and evaporated to dryness. The solid residue was dissolved in water and washed with methylene chloride. The aqueous layer was separated and evaporated in vacuo to afford a residual oil which solidified upon trituration with acetone to yield 4.5 g (56%). The solid was taken up in methanol, treated with activated carbon, filtered and the filtrate evaporated to give 3.2 g. (40 %) of the title compound, M.P. 177°-179° C. Infrared (KBr) cm-1 : 1610, 1660, 1720, 3100-2600; 1H-NMR (D6 -dimethylsulfoxide) ppm (delta): 2.70 (d, 2H), 3.45 (m, 3H), 3.70 (m, 1H), 4.48 (m, 1H); Mass spectrum (m/e): 159.9 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:24])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[CH:28]([Mg]Br)=[CH2:29].[Cl-].[NH4+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:24])[CH:28]=[CH2:29])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: -78 °C
Yield: 39.6 %

Procedure:
To a 50 mL round bottom flask equipped with a stir bar was added 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (0.415 g, 1.03 mmol) and THF (12 mL). The reaction mixture was cooled to −78° C. To the stirred suspension was added vinylmagnesium bromide (5 mL, 1M in THF, 5 mmol) in one portion. The solution was allowed to gradually warm to −30° C. over 1 h. Additional vinylmagnesium bromide (3 mL, 1M in THF, 3 mmol) was added and the reaction mixture was further warmed to 0° C. over 1.5 h. The cold reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3×50 mL). The organic fractions were collected, washed with brine (3×25 mL) and concentrated. The resulting solid was further purified by flash chromatography, eluting with EtOAc:Hexane (0-100%) to give 2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (0.175 g, 40%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.43 (s, 1H), 7.77-7.75 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 6.06-5.98 (m, 1H) 5.42 (app d, 1H, J=5.5 Hz), 5.32 (app d, 1H, J=17.2 Hz), 5.16 (app d, 1H, J=10.2 Hz), 4.26 (s, 3H), 2.27 (s, 3H); ESMS (m/z): found, 429.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:13]([O:12][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1cccc(COC(C)=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOc1cccc(CO)n1
Yield: 108.1 %

Procedure:
To a solution of 4.89 g (21.9 mmol) of 2-acetoxymethyl-6-butoxypyridine dissolved in 20 ml of ethanol was added 20 ml of an 8% sodium hydroxide solution, and the mixture was refluxed for one hour. After removal of the ethanol under a reduced pressure, the residue was extracted with ether and separated by silica gel chromatography (ethyl acetate:hexane=1:3) to obtain 4.29 g of the desired product (yield 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]([NH:14][C:15](=[O:17])[CH3:16])[CH2:11]CCC1=2.S([O-])([O-])(=O)=O.[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(C)C>[O:3]=[C:2]1[C:4]2[S:5][CH:9]=[CH:8][C:7]=2[CH:10]([NH:14][C:15](=[O:17])[CH3:16])[CH2:11][CH2:1]1
Reactant: CC(=O)NC1CCCc2sccc21
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)NC1CCC(=O)c2sccc21
Temperature: 10 °C
Yield: 73.6 %

Procedure:
Acetone (200 ml), N-(4,5,6,7-tetrahydrobenzo[b]-thien-4-yl) acetamide (9.75 g, 0.05 mol) and magnesium sulfate (21.0 g, 0.17 mol) are mixed, stirred and cooled to 10° C. Next, 150 ml of an aqueous potassium permanganate solution (prepared from 21.0 g, 0.133 mol of potassium permanganate and 200 ml of water) is added over 15 minutes to the above mixture, and the whole stirred for 3 hours. After 3 hours reaction time, analysis of the mixture by high pressure liquid chromatography (HPLC) indicates the reaction to be incomplete. The remainder of the above potassium permanganate solution (~50 ml) is added and the reaction mixture stirred for two more hours. Isopropanol (20 ml) is then added, the reaction mixture stirred overnight, and filtered. HPLC analysis of the filtered solution indicates a 73.6% yield of title product, and also the presence of 2% of starting material.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(=O)C)[C:14]4=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:26]=1)(=O)C.C1C(=O)N([Cl:34])C(=O)C1>CN(C=O)C>[Cl:34][C:15]1[C:14]2=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=[C:13]2[C:12]2[O:11][CH2:10][C:9]3[CH:26]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=3[C:17]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Oc1ccc2c(c1)COc1c-2ccc2c(OC(C)=O)cccc12
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)COc1c-2cc(Cl)c2c(O)cccc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by reacting 1-(Acetyloxy)-6H-dibenzo[c,h]chromen-8-yl acetate(360 mg, 1.03 mmol) with NCS (210 mg, 1.57 mmol) and anhydrous DMF (20 ml) according to method B for 2.0 h at room temperature, followed by heating to 100° C. for 1 h. The reaction was concentrated under reduced pressureAnd the solids were dissolved in MeOH (30 ml). NH3 was bubbled in for 0.5 h while acetate removal was monitored by LC-MS. The reaction was concentrated to a dark sludge, dissolved in EtOAc and passed through a silica plug to produce 200 mg (65%) foam. An analytical sample was produced by silica chromatography (1:1 EtOAc:hexanes). mp ˜185° C. dec.; 1H NMR (400 MHz, DMSO-d6) δ 5.23 (2H, s), 6.72 (1H, d, J=2.3 Hz), 6.81 (1H, dd, J=8.6 Hz, 2.6 Hz), 6.92 (1H, dd, J=7.5 Hz, 1.0 Hz), 7.33 (1H, appt), 7.62 (1H, dd, J=8.5 Hz, 1.0 Hz), 7.69 (1H, d, J=8.6 Hz), 7.79 (1H, s), 9.78 (1H, s), 10.11 (1H, s); MS m/z297/399 (Cl pattern) (M−H+).