Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.[C:20]1([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na]>CN(C)C=O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:33]3[CH2:32][CH2:31][C:30]4([N:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:27][NH:28][C:29]4=[O:36])[CH2:35][CH2:34]3)[C:10](=[O:19])[NH:11][C:12]=2[CH:17]=1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cc(Cl)ccc31)CC2
Yield: 25 %

Procedure:
A mixture of 4.9 parts of 5-chloro-1,3-dihydro-2-oxo-2H-benzimidazole-1-propanol methanesulfonate, 3.7 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.4 parts of sodium crbonate and 90 parts of N,N-dimethylformamide is stirred and heated for 1 hour at 50°-60° C. The N,N-dimethylformamide is distilled off and the residue is taken up in water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The product is filtered off and crystallized twice: first from 2-propanol and then from a mixture of N,N-dimethylformamide and water, yielding 1.8 parts (25%) of 8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 233.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[C:16](OC(=O)C)(=O)[CH3:17].Cl>C(O)C>[CH3:16][C:17]1[NH:1][C:2]2=[CH:3][C:4]3[C:5]([CH3:15])([CH3:14])[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[C:11]2[N:12]=1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3

Procedure:
3.1 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one and 2.8 ml. acetic anhydride were stirred in 50 ml. ethanol for 30 minutes at ambient temperature. 20 ml. concentrated hydrochloric acid were then added thereto and the reaction mixture refluxed for 18 hours. The solvent was removed in a vacuum and the residue was dissolved in water, rendered alkaline with ammonia, filtered off with suction and washed with water. After recrystallization from ethyl acetate, there were obtained 2.4 g. of the title compound; m.p. 290°-294° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([NH:12][C:13]1[CH:19]=[CH:18][C:17](=[O:20])[C:16]([NH2:21])=[CH:15][CH:14]=1)=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([NH:12][C:13]1[CH:19]=[CH:18][C:17](=[O:20])[C:16]([NH:21][C:23](=[O:25])[CH3:24])=[CH:15][CH:14]=1)=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)C=C(Nc1ccc(N)c(=O)cc1)C(=O)OCC
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)C=C(Nc1ccc(NC(C)=O)c(=O)cc1)C(=O)OCC

Procedure:
A solution of 2-(4-amino-5-oxo-1,3,6-cycloheptatrien-1-ylamino)-2-butenedioic acid diethyl ester (1.7 g, described in Example 1) in acetic anhydride (17 ml) is stirred at room temperature for 16 hr. The solution is evaporated and the residue is dissolved in ethyl acetate. The solution is washed with 1N potassium hydroxide and water, dried over sodium sulfate and evaporated to give a residue of 2-(4-acetylamino-5-oxo-1,3,6-cycloheptatrien-1-ylamino)-2-butenedioic acid diethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][CH2:21][NH:22][CH3:23])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[C:25]([OH:28])(=O)[CH3:26]>>[OH:24][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:20][CH2:21][N:22]([CH3:23])[C:25](=[O:28])[CH3:26])[N:12]=[CH:11][N:10]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)O
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Yield: 100 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using acetic acid and 2-methyl-4-({5-[2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol (obtained as described in Example 3, preparation of starting materials) to give N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide as a light brown solid in 100% yield; NMR spectrum (DMSO-d6) 1.90 (s, 3H), 2.16 (s, 3H), 3.02 (s, 3H), 3.85 (t, 2H), 4.45 (t, 2H), 6.82 (d, 1H), 7.18 (dd, 1H), 7.25 (d, 1H), 7.34 (m, 2H), 7.92 (t, 1H), 8.65 (s, 1H), 9.45 (s, 1H), 10.52 (s, 1H); Mass spectrum MH+ 367.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl.[NH2:18][OH:19]>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:18][OH:19])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(CN2CCC(=O)CC2)cc1
Agent: Cl
Product: COc1ccc(CN2CCC(=NO)CC2)cc1

Procedure:
1-(4-Methoxybenzyl)-4-piperidone oxime is prepared from 1-(4-methoxybenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:21][CH3:22])[C:19]=1[CH3:20])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][O:21][C:18]1[CH:17]=[C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:19]=1[CH3:20]
Reactant: COc1ccccc1NC(=O)c1cc(OC)c(C)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3ccccc3o2)cc(OC)c1C
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethoxy-N-(2-methoxyphenyl)-4-methylbenzamide (1.29 g, 4.49 mmol), toluene (22 mL), p-toluenesulfonic acid monohydrate (5.9 g, 31 mmol) and molecular sieves was refluxed until no starting material was observed by TLC. Cooled mixture to rt and filtered, washing with warm chloroform. Removal of solvent from filtrate afforded a yellow solid. Purification of crude solid by flash chromatography on silica gel using 1:3 EtOAc:hexanes gave the desired intermediate, 2-(3,5-dimethoxy-4-methylphenyl)-1,3-benzoxazole, as a colorless solid.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[N+](=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[N-]>C(Cl)Cl>[C:20]1([C:18]2[O:19][C:12]([CH2:11][C:10]#[N:14])=[N:13][CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CCC#N
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: N#CCc1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
BF3.Et2O (1.1 mL, 8.5 mmol) was added dropwise to a solution of malononitrile (2.26 g, 34.2 mmol) in dry CH2Cl2 (20 mL) at 0° C., followed by addition of 2-diazo-1-phenylethanone (0.5 g, 3.4 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h and then quenched with aqueous 10% NaOH solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 2-(5-phenyloxazol-2-yl)acetonitrile (200 mg, yield 32%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.47-7.38 (m, 3H), 7.32 (s, 1H), 4.02 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2O: 184.06. found: 185.2 (M+H)+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH2:13]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH2:21])=[O:20])[CH2:14][CH3:15]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:13]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](=[NH:21])[O:20][CH2:6][CH3:7])[CH2:14][CH3:15]
Reactant: CC[O+](CC)CC
Reactant: CCCOc1ccccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1ccccc1C(=N)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
A solution of triethyloxonium fluoroborate (33.0 g., 0.175 mole) in methylene chloride (75 ml.) was added during 10 minutes to a stirred solution of 2-n-propoxybenzamide (31.3 g., 0.175 mole) in methylene chloride (150 ml.). The solution was stirred for an additional 18 hours at room temperature. The solution was concentrated to about one-fifth volume and was diluted with diethyl ether to precipitate the ethyl 2-n-propoxybenzimidate fluoroborate (44.0 g., 85% yield), m.p. 108°-112°.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>C(OCC)C>[P:1]([O:8][Si:17]([CH3:19])([CH3:18])[CH3:16])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOP(OCC)O[Si](C)(C)C
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a mixture of diethyl phosphite (2.8 mL, 0.0217 mol) and triethylamine (9 mL, 0.065 mol, 3.0 eq) in dry diethyl ether (250 mL) at 0° C. was slowly added freshly distilled trimethylsilyl chloride (3.3 mL, 0.0260 mol, 1.2 eq) via syringe. The resulting slurry was allowed to slowly warm to room temperature, and was then warmed to 45° C. for 14 h. Volatiles were removed by distillation using a 55° C. oil bath. The resulting mixture was diluted with pentane (150 mL), filtered to remove triethylammonium salts, and concentrated at atmospheric pressure using a 55° C. oil bath. Distillation of the resulting oil gave diethyl trimethylsilyl phosphite as a colorless oil (3.64 g, 80%). BP 60° C. (5 mmHg). ##STR309## Step 2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C@@H:33]([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: C[C@H](N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@@H](C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 240 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and (S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 230 for 10 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as an off-white amorphous solid. mp 96-101°, LC MS m/z=441 (MH+). Retention time=2.04 min.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(=O)([O-])[O-].[Ag+2].C1C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[N:7]=[C:6]([N:8]3[C:12](=[O:13])[C:11]4[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=4[C:9]3=[O:18])[CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)n1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(OCc2ccc(Cl)cc2)n1
Reaction time: 72 h

Procedure:
A mixture of N-(6-hydroxy-2-pyridyl)-3,4,5,6-tetrahydrophthalimide (3.9 g), silver carbonate (2.2 g), p-chlorobenzyl chloride (2.6 g) and benzene (75 ml) is stirred, in the dark, at 45° for about 72 hours. Then, the reaction is cooled and filtered. The filtrate is washed with 10% sodium bicarbonate and water, dried and stripped to give N-[6-(4-chlorobenzyloxy)-2-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: C(OC([N:8]([C:16]1[O:17][CH2:18][C:19]2([C:32]3([CH2:35][O:34][CH2:33]3)[C:28]3([CH2:31][CH2:30][CH2:29]3)[O:27][C:26]3[C:21]2=[CH:22][C:23]([C:36]2[CH:37]=[N:38][CH:39]=[C:40](Br)[CH:41]=2)=[CH:24][CH:25]=3)[N:20]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[C:43]([CH:45]1[CH2:47][CH2:46]1)#[CH:44]>CCN(CC)CC.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:45]1([C:43]#[C:44][C:40]2[CH:41]=[C:36]([C:23]3[CH:22]=[C:21]4[C:19]5([CH2:18][O:17][C:16]([NH2:8])=[N:20]5)[C:32]5([CH2:33][O:34][CH2:35]5)[C:28]5([CH2:31][CH2:30][CH2:29]5)[O:27][C:26]4=[CH:25][CH:24]=3)[CH:37]=[N:38][CH:39]=2)[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(-c3cncc(Br)c3)ccc1OC1(CCC1)C21COC1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC1=NC2(CO1)c1cc(-c3cncc(C#CC4CC4)c3)ccc1OC1(CCC1)C21COC1
Reaction time: 1 h
Yield: 15.6 %

Procedure:
To a stirred solution of di-tert-butyl[6′-(5-bromopyridin-3-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl]imidodicarbonate (48 mg, 0.075 mmol) in Et3N (0.67 ml) were added ethynylcyclopropane (0.063 mL, 0.75 mmol), PdCl2(PPh3)2 (10 mg, 0.015 mmol) and CuI (5.7 mg, 0.030 mmol) at room temperature and the mixture was sealed and irradiated with microwave at 150° C. for 1 hour. To this mixture was added activated carbon (ca. 100 mg) and the mixture was stirred for 1 hour to remove palladium residues. The mixture was passed through a pad of Celite. The filtrate was evaporated to give a residue. To the solution of the residue in toluene (3 ml) was added silica gel (500 mg) and the mixture was refluxed for 2 hours. The mixture was passed through a pad of Celite and the filtrate was evaporated to give a crude product, which was purified with column chromatography (MeOH in CHCl3=0 to 10%) to give 6′-[5-(cyclopropylethynyl)pyridin-3-yl]trispiro[cyclobutane-1,2′chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (5 mg).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:23].[Na+].OO>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](/[CH:13]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH:20]([O:23][C:1](=[O:9])[CH3:2])[CH3:21])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC(C)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 160.9 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.2 g (17 mmol) of 5-octyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-acetoxy-1-heptenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.0 g (yield 78%) of 5-octyloxy-2-{4-(6-acetoxy-1-trans-heptenyl)-phenyl}-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([S:16]([Cl:15])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]1=2
Reactant: O=S(=O)(O)Cl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 60 °C

Procedure:
94.0 g (0.5 mol) of 1,2,3,4-tetrahydro-1,1,4,4tetramethylnaphthalene were stirred into 100 ml of chlorosulfonic acid at 20° C. within 30 min. The reaction solution was maintained at 60° C. for 1 hour, cooled to room temperature and then poured into 1.5 1 of ice and extracted with ether. The organic phase was washed to neutrality with brine and water, dried over magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yielded 55.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-sulfonyl chloride of melting point 71°-74° C.
Reaction SMILES: C([N:3]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:15][C:7]=2[N:6]2[C:16](Cl)=[C:17]([C:19]([O-:21])=[O:20])[N:18]=[C:5]2[C:4]1=[O:23])C.[ClH:24]>>[Cl:24][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C:7]3[N:6]4[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=[C:5]4[C:4](=[O:23])[NH:3][C:8]=3[C:9]=2[CH:10]=1
Reactant: Cl
Reactant: CCn1c2c(n3c(Cl)c(C(=O)[O-])nc3c1=O)Cc1ccccc1-2
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1cc(Cl)ccc1C3

Procedure:
0.58 g of ethyl-chloro-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in suspension in 10 ml of 6N hydrochloric acid is heated to reflux for 24 hours. After cooling to a temperature close to 20° C., the insoluble matter is filtered off, washed with water and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. 0.38 g of 7-chloro-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-2-carboxylic acid is thus obtained in the form of a beige powder whose melting point is higher than 260° C. (analysis C14H10ClN3 O4 ; % calculated C: 52.60, H: 3.15, Cl: 11.09, N: 13.14; % found C: 52.9, H: 3.3, Cl: 10.8, N: 12.9); 1H spectrum in DMSO, T=300K, δ in ppm (300 MHz): 4.02 (2H, s, CH2), 7.37 (1H, d, J=7 Hz, CH arom.), 7.60 (1H, d, J=7 Hz, CH arom.), 7.92 (1H, s, CH arom.), 8.52 (1H, s, CH arom.), 12.45 (1H, s, NH)).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:5]=[CH:4]1.[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:22]([O:28][CH2:29][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:5]=[CH:4]1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(OCc1ccccc1)c1cccc2cc[nH]c12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2cccc(C(=O)OCc3ccccc3)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
To a suspension of sodium hydride (174 mg) in tetrahydrofuran (8.0 ml) was added dropwise a solution of benzyl indole-7-carboxylate (700 mg) in tetrahydrofuran (7.0 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. Chloromethyl pivalate (461 mg) was added to the mixture and the solution was stirred at ambient temperature for 3 hours. The reaction was quenched with 1 N hydrochloric acid and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded benzyl 1-pivaloyloxymethylindole-7-carboxylate (1.08 g) as a yellow oil.
Reaction SMILES: [I-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:26]3[C:25](=[N:27]O)[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]=2[CH3:35])=[CH:13][CH:12]=1>C1(C)C(C)=CC=CC=1.C(O)(=O)C>[C:3]([NH:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[C:19]([CH3:35])[N:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 97 °C
Reaction time: 2 h

Procedure:
In flask 1, a mixture of sodium iodide (171.6 mg, 1.14 mmol) in xylene (12.5 mL), acetic acid (12.5 ml) and acetic anhydride (4.2 mL, 44.54 mmoles) was heated to 97° C. In flask 2, acetic anhydride (4.2 mL, 44.5 mmol) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (10 g, 22.3 mmol corrected for assay) in xylene (12.5 mL) and acetic acid (12.5 ml) at ambient temperature. The mixture in flask 2 was added to the mixture in flask 1 over 2-3 hours maintaining the temperature at 97° C. The reaction was held at this temperature for a further 2 hours following the end of the addition. The reaction was cooled to 60° C. and split into 2 equal size portions. One of these portions was cooled to r.t. and propan-1-ol (25 mL) was added, following by water (25 mL), added over 15 minutes, effecting a precipitation. After stirring for 1 h, the solid product was collected by filtration, washed with propan-1-ol (2×10 mL) and dried in vacuo at 40° C. to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid; 4.32 g (91% based on work up of half of the reaction mixture). Purity by HPLC 97.15 area %.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:19][C:30](=[O:31])[CH2:29][Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1NC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)CCl)c1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cool solution of (2-amino-6-methoxyphenyl)carbamic acid benzyl ester (9.5 g; 34.9 mmol) and triethylamine (5.8 ml; 42 mmol) in anhydrous THF (90 ml), chloroacetylchloride (3.3 ml; 42 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hours, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous HCl and diluted aqueous Na2 CO3 then it was dried and evaporated. The crude residue was crystallized with n-hexane to give the title compound as a white solid. 10.8 g.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH3:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[CH3:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Cc1cccc(N)c1C
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: Cc1cccc(Nc2c(Nc3ccccc3O)c(=O)c2=O)c1C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2,3-dimethylaniline (0.026 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 309 (M+).