Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 56 %

Procedure:
Upon boiling a solution of 7.6 g 2-nitrobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for two hours, 2,6-diamino-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 142° C (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:17][CH:18]([CH2:20]O)O>>[CH2:9]([C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:20][CH:18]=[CH:17]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCC(O)CO
Reactant: Nc1ccc(Cc2ccccc2)cc1Br
Product: Brc1cc(Cc2ccccc2)cc2cccnc12

Procedure:
2-bromo-4-benzylaniline and glycerol can be combined to form 6-benzyl-8-bromoquinoline,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[NH:12][C:11]([C@@H:13]4[CH2:17][CH2:16][CH2:15][N:14]4[C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[N:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(Cl)cc3)cc2)[nH]1
Temperature: 75 °C
Yield: 85.4 %

Procedure:
A mixture of (S)-benzyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.7 g, 11.0 mmol), 4-chlorophenylboronic acid (2.0 g, 12.1 mmol), tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol), 2M aqueous potassium carbonate solution (22 mL, 44 mmol), and dimethylformamide (100 mL) was degassed under a stream of argon for 15 minutes. The reaction was heated to 75° C. for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(4′-chlorobiphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.3 g, 85%).
Reaction SMILES: CSC.B.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C@H:13]1[C:24](O)=[O:25])=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][C@H:13]1[CH2:24][OH:25])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 124.3 %

Procedure:
Borane-dimethyl sulfide (1.55 ml, 15.5 mmol) was added to a solution of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylic acid (2.39 g, 7.76 mmol) in THF (50 ml) under stirring at 0° C. The reaction mixture was stirred at the same temperature for 10 minutes and then at 50° C. for 2 hours. After cooling the reaction mixture to 0° C., water (30 ml) was added thereto, followed by extraction with ethyl acetate. 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 (silica gel: 60 g), whereby from chloroform/methanol (50/1) eluate fractions, the title compound (2.83 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[C:11]([Cl:18])=[C:12]([CH2:16][OH:17])[N:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[K+].Cl[O-:23].[Na+].Cl>CC(C)=O.C(=O)(O)[O-].[Na+].O.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[C:11]([Cl:18])=[C:12]([C:16]([OH:23])=[O:17])[N:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-]Cl
Reactant: Cn1cc(OCc2ccccc2)c(=O)c(Cl)c1CO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(OCc2ccccc2)c(=O)c(Cl)c1C(=O)O
Reaction time: 2 h
Yield: 56 %

Procedure:
To a mixture of 5-(benzyloxy)-3-chloro-2-(hydroxymethyl)-1-methylpyridin-4(1H)-one (4.90 g, 17.5 mmol), TEMPO (120 mg, 0.77 mmol) and potassium bromide (120 mg, 1.00 mmol) in acetone (50 mL) and saturated sodium bicarbonate (40 mL) below 7° C. was added dropwise a 10-14% sodium hypochlorite (50 mL) solution during 30 minutes. After being stirred for 2 hours, the reaction mixture was diluted with water and adjusted to pH about 1.5 with 6N HCl. The solid was filtered and washed with water to give 5-(benzyloxy)-3-chloro-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (2.89 g) as a white solid. Yield=56%; 1H NMR (DMSO-D6, 90 MHz) δ (ppm): 7.79 (s, 1H), 7.16-7.62 (m, 5H), 5.03 (s, 2H) and 3.67 (s, 3H); MS m/z 294 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[OH:10][C:11]1[C:16]([CH2:17][CH2:18][CH3:19])=[C:15]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=2)[CH:14]=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1c(OCc2ccc(I)cc2)ccc(C(C)=O)c1O
Reaction time: 48 h
Yield: 52.1 %

Procedure:
Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (6.54 g, 33.7 mmol) and cesium carbonate (13.2 g, 40.4 mmol) in acetone (500 mL) and stir. After 48 hours, pour the reaction into water and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a yellow solid (7.20 g, 52%): 1H NMR (CDCl3) δ 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.09 (s, 2H), 6.43 (d, 1H), 7.15 (d, 2H), 7.57 (d, 1H), 7.73 (d, 2H), 12.74 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:14])[CH2:12][Cl:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:15]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].Cl>C(OCC)C>[C:15]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:1]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:14])[CH2:12][Cl:13])=[CH:6][CH:5]=2)([OH:3])[CH3:2])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)c1ccc(CC(C)CCl)cc1
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(CCl)Cc1ccc(C(C)(O)Cc2ccc(C(C)(C)C)cc2)cc1
Yield: 57 %

Procedure:
168.4 g of 3-(4-acetylphenyl)-2-methylpropyl chloride in 100 ml of diethyl ether were added dropwise to a Grignard suspension prepared from 182.5 g of 4-tert.-butylbenzyl chloride and 26 g of Mg in 400 ml of diethyl ether. After completion of the dropwise addition, the mixture was refluxed for a further 2 hours and then hydrolyzed by adding ice-cooled dilute aqueous HCl until the pH was 2. The organic products were extracted with ether, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Distillation of the residue gave 163.4 g of (VI) of boiling point 190° C./0.1 mbar.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH:32]=O>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:32][C:24]5[N:23]([CH3:22])[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[N:25]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: C[C@@H]1CN(Cc2nc3ccccc3n2C)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 1-methyl-1H-benzo[d]imidazole-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 7.98 (s, 1H), 7.73 (m, 1H), 7.35 (dd, J=7.1, 1.2 Hz, 1H), 7.29-7.21 (m, 2H), 5.13-5.09 (m, 1H), 4.11-4.06 (m, 2H), 3.97 (s, 3H), 3.37 (t, J=8.3 Hz, 1H), 3.06 (d, J=10.4 Hz, 1H), 2.88-2.85 (m, 1H), 2.77-2.73 (m, 1H), 2.16-1.92 (m, 8H), 1.70-1.66 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). MS: (M+H m/z=432.1).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].C([O-])(=O)C.[Na+:32]>O1CCCC1.CO>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+:32]
Reactant: C#CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C#CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 100.1 %

Procedure:
To a solution of 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in tetrahydrofuran (22 ml) was added a solution of sodium acetate (0.234 g) in methanol (2.3 ml) at ambient temperature. After the mixture was stirred under ice-cooling for 30 minutes, the precipitates were collected by filtration to give sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (1.16 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH3:14])[CH:8]=2)[NH:3]1.ClC(C)(C#C)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([O:12][CH2:13][CH3:14])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1([CH3:15])[CH3:1])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc2c(c1)C=CC(C)(C)N2
Agent: C#CC(C)(C)Cl
Product: CCOc1ccc2c(c1)C=CC(C)(C)N2C(C)=O
Temperature: 100 °C

Procedure:
A solution of 30.2 mmol (6.15 g) of 2,2-dimethyl-6-ethoxy-1,2-dihydroquinoline (prepared according to the procedure described in Steps 1 and 2 of Example 1 starting from 2-chloro-2-methyl-3-butyne) in 45 ml of acetic anhydride is heated at 100° C. under an inert atmosphere for 3 hours. After cooling, the medium is concentrated and the residue is purified by chromatography on silica gel, using a dichloromethane:ethyl acetate mixture 95:5 as eluant, to yield the expected compound.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:16]1[S:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:19])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(Br)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Yield: 92.7 %

Procedure:
A mixture of (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride (4 g), 5-bromothiophene-2-carboxylic acid (4.25 g), 1-hydroxybenzotriazole hydrate (2.77 g), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (6.6 g), and N,N-diisopropylethylamine (14 mL), in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The chloroform layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel and eluted with 5%–20% 3.5N methanolic ammonia/chloroform mixtures. Evaporation of solvent gave yellow solid (5.87 g); MS (ES+) 315, 317 (MH+).
Reaction SMILES: N1(CC[SH:12])C2C(=CC=CC=2)C=C1.N1(CCO)C2C(=CC=CC=2)C=C1.CC1C2C(=CC=CC=2)N(CCO)C=1.[CH:38]([CH:41]([N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2[CH3:54])[C:47]([CH3:55])=[CH:46]1)[CH:42]([CH3:44])O)([CH3:40])[CH3:39]>>[CH:38]([CH:41]([N:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2[CH3:54])[C:47]([CH3:55])=[CH:46]1)[CH:42]([CH3:44])[SH:12])([CH3:40])[CH3:39]
Reactant: SCCn1ccc2ccccc21
Reactant: Cc1cn(C(C(C)C)C(C)O)c2c(C)cccc12
Agent: Cc1cn(CCO)c2ccccc12
Agent: OCCn1ccc2ccccc21
Product: Cc1cn(C(C(C)C)C(C)S)c2c(C)cccc12

Procedure:
By following procedure A or B of Example 2 other indole-1-ethanethiol intermediates of formula III, for example those described in Examples 57 to 106 may be prepared by the appropriate choice of indole-1-ethanol intermediates of formula III. For example, by replacing 3-methylindole-1-ethanol with an equivalent amount of β-isopropyl-α,3,7-trimethylindole-1-ethanol, β-isopropyl-α,3,7-trimethyl-indole-1-ethanethiol is obtained. Likewise, by replacing 3-methylindole-1-ethanol with an equivalent amount of 3-isopropylindole-1-ethanol, 3-isopropylindole-1-ethanethiol is obtained.
Reaction SMILES: Cl.C[C:3]1[S:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[NH2:12][C:13](N)=[O:14].[OH-].[Na+].Cl>>[N:11]1[C:6]2=[CH:5][S:4][CH:3]=[C:7]2[C:8]([OH:9])=[N:12][C:13]=1[OH:14]
Reactant: Cc1scc(N)c1C(=O)O
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(O)c2cscc2n1
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 115.1 %

Procedure:
A mixture of methyl 4-aminothiophene-3-carboxylic acid mono hydrochloride (1.00 g) and urea (1.8 g) was stirred at 180° C. for 1.5 h. The mixture was left stand for cooling to room temperature, followed by addition of 1 M aqueous sodium hydroxide to dissolve the solids, and the mixture was neutralized with 1 M hydrochloric acid. The precipitated crystals were collected by filtration to obtain thieno[3,4-d]pyrimidine-2,4-diol (1.0 g). (2) To a mixture of thieno[3,4-d]pyrimidine-2,4-diol (1.00 g) and phosphorus oxychloride (10 mL) was added N,N-dimethylaniline (2.0 mL) at room temperature, and the mixture was stirred at 100° C. for 2.5 h. The reaction solution was added dropwise to water (30 g) with ice cooling, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform) to obtain 2,4-dichlorothieno[3,4-d]pyrimidine (0.52 g).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:8][C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])(=O)[CH:4]([CH3:6])[CH3:5].Cl.P([O-])(O)(O)=O.[Na+]>CO.O>[CH3:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:10]2[C:9]=1[N:8]=[C:3]([CH:4]([CH3:6])[CH3:5])[NH:13][C:11]2=[O:12]
Reactant: Cc1cccc(C(N)=O)c1NC(=O)C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc2c(=O)[nH]c(C(C)C)nc12
Temperature: 25 °C
Yield: 75.9 %

Procedure:
5N Sodium hydroxide solution (0.56 mL, 0.0028 mol) was added to a mixture of 2-(iso-butyryl)amino-3-methylbenzamide (0.62 g, 0.0028 mol) in methanol (6 mL) and water (14 mL) at room temperature. The mixture was heated at reflux for 1 hr. then cooled to room temperature and acidified with 2N hydrochloric acid solution. Saturated sodium dihydrogen orthophosphate solution was added and the mixture extracted with methylene chloride (4 times). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo to leave 8-methyl-2-iso-propylquinazolin-4-one (0.43 g, 76%) identical with the material isolated in step A.
Reaction SMILES: O1CCOCC1.[CH3:7][N:8]1[CH2:16][C:15]2[C:10](=[C:11]([N+:26]([O-:28])=[O:27])[CH:12]=[CH:13][C:14]=2B2OC(C)(C)C(C)(C)O2)[C:9]1=[O:29].[CH3:30][C:31]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:36][CH2:35][C:34](OS(C(F)(F)F)(=O)=O)=[CH:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:30][C:31]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:36][CH2:35][C:34]([C:14]2[CH:13]=[CH:12][C:11]([N+:26]([O-:28])=[O:27])=[C:10]3[C:15]=2[CH2:16][N:8]([CH3:7])[C:9]3=[O:29])=[CH:33][CH2:32]1
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOC(=O)C1(C)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 70 °C
Yield: 84.3 %

Procedure:
A mixture of dioxane and water (15 mL, 4:1) was degassed for 30 min. 2-Methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (373 mg, 1.19 mmol), ethyl 1-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (Compound 282E, 300 mg, 0.92 mmol), Pd (PPh3)4 (106 mg, 0.092 mmol), and cesium carbonate (747 mg, 2.3 mmol) were then added. The reaction mixture was heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and concentrated to dryness, the residue was purified by column chromatography (SiO2, 5% ethyl acetate/dichloromethane) to give 278 mg (yield: 77%) of the desired compound. 1H NMR (CDCl3, 300 MHz): δ=1.26 (t, J=6.9 Hz, 3 H), 1.76-1.78 (m, 1 H), 2.07-2.22 (m, 3 H), 2.40 (m, 1 H), 2.80-2.42 (m, 1 H), 3.21 (s, 3 H), 4.15 (q, J=6.9 Hz, 2 H), 5.92 (s, 1 H), 7.44 (d, J=8.5 Hz, 1 H), 7.70 (d, J=8.5 Hz, 1 H).
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:27]1[CH2:31][CH:30]([OH:32])[CH2:29][CH:28]1[CH:33]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:34][CH:35]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH:35]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[O:34][CH:33]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:28]2[CH2:29][CH:30]([OH:32])[CH2:31][N:27]2[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Palmitic acid (2.57 g, 10 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.54 g, 1.2 eq.) and DIEA (5 mL, 3.00 eq). After work-up and column purification the pure amide 102d was isolated as a white solid (Yield, 6.15 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ=7.74-7.66 (m, 1H), 7.37-7.22 (m, 4H), 7.21-7.12 (m, 5H), 6.87-6.79 (m, 4H), 4.98 (d, J=3.90 Hz, 1H), 4.90 (d, J=3.90 Hz, 1H), 4.40-4.07 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.13 (m, 2H), 3.02-2.87 (m, 3H), 2.20-1.80 (m, 6H), 1.46-1.08 (m, 32H), 0.82 (t, J=6.35 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.84, 170.92, 170.81, 158.11, 157.98, 145.09, 144.74, 135.87, 135.72, 135.46, 135.41, 129.59, 129.55, 127.84, 127.74, 127.57, 126.55, 113.16, 113.07, 85.78, 85.12, 68.59, 67.45, 65.19, 63.33, 59.74, 55.61, 55.06, 54.95, 53.44, 44.58, 39.08, 38.87, 38.22, 38.02, 36.30, 35.44, 34.18, 32.54, 31.32, 29.09, 29.05, 29.00, 28.81, 28.74, 28.69, 26.20, 25.34, 24.55, 24.15, 22.12, 21.20, 14.06, 13.92.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9](=[O:15])[NH:8][C:7]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[O:15]=[C:9]1[NH:8][C:7]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:3]([CH2:2][NH:1][C:20](=[O:22])[CH3:21])[C:4]=3[CH2:5][C:6]=2[N:11]2[CH:12]=[CH:13][N:14]=[C:10]12
Reactant: NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g of 9-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one and 20 ml of acetic anhydride is stirred under an argon atmosphere for 2 hours at a temperature in the region of 20° C. The reaction mixture is filtered and the insoluble material is washed successively with 10 ml of acetic anhydride and two times 40 ml of methyl-tert-butyl ether and then dried under reduced pressure (15 mm Hg; 2 kPa) at 20° C. The white solid is suspended in a mixture of acetone (30 ml) and methanol (5 ml), then filtered and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. 1.03 g of N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl) methyl]acetamide are obtained in the form of a white solid, the melting point of which is greater than 260° C. (Analysis C16H14N402; % Calculated C: 65.30, H: 4.79, N: 19.04; % Found C: 65.20, H: 5.10, N: 19.30).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][NH:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNc1cc(Nc2ccc(C(=O)OC)cc2[N+](=O)[O-])ncn1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
6-chloro-N-methylpyrimidin-4-amine, 3 (3 g, 20.97 mmol) and methyl 4-amino-3-nitrobenzoate (3.9 g, 20.97 mmol) were taken in toluene (5 mL) in a seal tube under Argon atmosphere at room temperature. The Argon gas was purged for 5-10 min. Then Cs2CO3 (17.0 g, 52.4 mmol) and Xantphos (3.6 g, 6.29 mmol) were added and the resulting reaction mixture was purged with argon gas for 5 min, followed by Pd2(dba)3 (3.8 g, 4.19 mmol) was added. The argon gas purging was continued for additional 5 min before sealing the reaction vial. Then the reaction mixture was heated at 110° C. for 16 h. After completion of the reaction by TLC, the reaction mixture was cooled to rt, filtered through celite bed and the filtrate was evaporated under vacuum to get a crude residue. The crude residue was purified by column chromatography on silica gel to afford the title compound (3.2 g, yield: 51%) as a solid; MS (ESI): 304.2 [M+H]+.