Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:46]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([Cl:46])[CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Cl)CN2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-hydroxy-(2S)-pyrrolidinyl)methoxybenzoate (351 mg, 1.0 mmol) and Ph3P (393 mg, 1.5 mmol) in CHCl3 (5.0 ml) was added CCl4 (5.0 ml) at room temperature. The reaction mixture was stirred at 50° C. for 24 hr. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (4:1, v/v) as eluent to give methyl 4-(cis-1-tert-butoxycarbonyl-4-chloro-(2S)-pyrrolidinyl)methoxybenzoate (340 mg, 92%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.48 (s, 9H), 2.38-2.65 (m, 2H), 3.50-3.60 (m, 1H), 3.88 (s, 3H), 3.89-4.05 (m, 1H), 4.26-4.41 (m, 4H), 6.95-6.97 (m, 2H), 7.98 (d, J=8.5 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CO>[NH2:18][CH:15]1[CH2:16][CH2:17][N:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]3[NH:2][C:28](=[O:29])[NH:26][N:27]=3)[N:4]=2)[CH2:14]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(C#N)cc3ccccc23)C1
Solvent: CN1CCCC1=O
Solvent: CO
Product: NC1CCN(c2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C
Yield: 17 %

Procedure:
To a crude reaction mixture containing tert-butyl (1-(3-cyanoisoquinolin-1-yl)pyrrolidin-3-yl)carbamate (786 mg) was added ethyl hydrazinecarboxylate (242 mg, 2.323 mmol) in NMP (5 mL). The resulting suspension was heated at 175° C. overnight and was subsequently cooled, diluted with MeOH, and filtered. The crude product was purified using mass-triggered HPLC eluting with a gradient of 20-45% ACN in water (acid mode). The product-containing fractions were concentrated to give the title compound (117 mg, 17.0% over 2 steps). ESI-MS m/z [M+H]+ 297.5.
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12]>CO>[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([O:13][CH3:3])=[O:12]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccc[nH]1
Solvent: CO
Product: COC(=O)c1ccc[nH]1
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65%), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=309.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-4-methyl-pyrimidine (prepared according to Harden, D. B.; Makrosz, M. J.; Strekowski, L.; J. Org. Chem. 1988, 53, 4137).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Br)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-Bromo-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A stirred mixture of 4-bromo-2-methylbenzoic acid (6 g, 27.9 mmol), iodomethane (5.21 mL, 84 mmol) and potassium carbonate (11.57 g, 84 mmol) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between water (250 mL) and 4:1 hexanes:ethyl acetate (650 mL). The organic layer was washed with water and dried over Na2SO4. The solvent was removed under vacuum to give 6.39 g of desired product as an oil in 100% yield. 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.65 (m, 7H) 7.50 (br. s., 2H) 3.88 (s, 3H) 2.56 (s, 3H).
Reaction SMILES: C(O[C@H:5]1[CH:14]=[C:13]([CH3:15])[C@H:12]([C:16](=[O:18])[CH3:17])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.Cl.[CH2:20]1CCN2C(=NCCC2)CC1>>[CH3:20][CH2:17][C:16]([C:12]1[C:7]2([CH2:6][CH:5]=[CH:14][C:13]=1[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:18]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)O[C@H]1C=C(C)[C@H](C(C)=O)C2(CCCC2)C1
Agent: Cl
Product: CCC(=O)C1=C(C)C=CCC12CCCC2
Yield: 72 %

Procedure:
A solution of 8:92 cis/trans-10-acetyl-9-methylspiro[4.5]dec-8-en-7-yl acetate (4.1 g, 16.4 mmol) in DBU (30 ml) was stirred for 19 h at 40° C. The reaction mixture was poured into cold 2N aqueous HCl (100 ml), and extracted twice with cyclohexane (50 ml). The combined organic phases were washed with water (50 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4), concentrated. FC (500 g SiO2, hexane/MTBE 50:1) of the crude product (2.92 g) gave methyl 1-(7-methylspiro[4.5]deca-6,8-dien-6-yl)ethanone (2.25 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.O1[CH2:42][CH2:41]OCC1>C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:13]3[CH:14]=[N:15][CH:11]=[CH:41][CH:42]=3)=[CH:30][CH:29]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
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: [Na+]
Solvent: O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3cccnc3)cc2)nc1

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (300 mg) synthesized in Example 402-1 and (3-diethylboryl)pyridine (76 mg) were dissolved in dioxane (2.6 mL) and sodium carbonate (2 mol/L, 1.3 mL), tetrakis(triphenylphosphine)palladium (30 mg) was added, and the mixture was refluxed for 2 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (223 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1.C1COCC1>CCO.[C].[Pd]>[NH2:10][C@@H:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: CN(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.8 %

Procedure:
A suspension of 1.67 g of the compound obtained in Step 87-1 and 0.17 g of 10% palladium-carbon in EtOH (20 ml) was stirred at room temperature for 14 hours under hydrogen atmosphere. The stirred solution was added with THF (1 ml) and stirred at room temperature for 1 hour under hydrogen atmosphere. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure to obtain 0.97 g of the title compound (pale yellow solid, crude form).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:11])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH3:1][CH:2]([NH:11][C:25]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:10]
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)N1CCOCC1)C(O)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 15.2 grams of norephedrine in 200 ml. of CH2Cl2 was cooled to 0-5° C. To this 11.0 grams of triethylamine was added with stirring. To the stirred mixture a solution of 14.9 grams of morpholine carbonyl chloride in 10 ml. of CH2Cl2 was added dropwise. The mixture was then stirred for 2 hours and left to stand at room temperature for 16 hours. The mixture was washed with water and the organic layer was dried over anhydrous sodium sulfate. The organic layer was then filtered and evaporated to a small volume. The hydroxyethylurea, N-(1-methyl-2-phenyl-2-hydroxyethyl)-4-morpholinecarboxamide was filtered off as a white solid and recrystallized from CH2Cl2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[N:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:38][CH2:37][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:13])(=[O:6])=[O:7]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCN1CCOCC1
Yield: 44.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.76 g (5.8 mmol) of 2-morpholin-4-yl ethanol and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.42 g (44% yield) of the title compound (26a) as a colorless oil. Rf=0.31 (EtOAc/Hxn=1.2). 1H NMR (400 MHz, CDCl3): δ=1.09 (s, 3H), 1.11 (s, 3H), 2.25-2.32 (m, 2H), 2.49-2.53 (m, 4H), 2.62-2.65 (m, 2H), 3.22-3.26 (m, 2H), 3.63-3.68 (m, 6H), 3.87 (s, 1H), 4.03 (d, J=9.2 Hz, 1H), 4.22 (d, J=9.6 Hz, 1H), 4.24-4.30 (m, 1H), 4.37 (d, J=11.2 Hz, 1H), 4.37-4.43 (m, 1H), 4.67 (d, J=11.2 Hz, 1H), 7.26-7.36 (m, 5H) ppm. MS (ESI) m/z 492.04 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12].[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][Br:25])[C:5]=1[N:11]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH3:12]
Reactant: COC(=O)c1cccc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a solution of 0.723 g (2.072 mmol) of the product of Example 187 in 70 mL of carbon tetrachloride was added 0.406 g (2.279 mmol) of N-bromosuccinimide and 0.14 g of dibenzoyl peroxide. The resulting mixture was heated to reflux for 18 h and then cooled to room temperature, washed with sodium bisulfite solution and water, dried over MgSO4, filtered and concentrated in vacuo. The residue was titurad with ether/hexanes (1:1) and then filtered to provide 0.504 g (57%) of the desired product as a white solid. Electrspray Mass Spec: 428 (M+H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:11][CH:10]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][C:15]([NH2:22])=[N:16][C:17]=3[Cl:21])[C:9](=[CH2:23])[CH:8]1[CH2:24][O:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[NH2:22][C:15]1[N:16]=[C:17]([Cl:21])[CH:18]2[CH:13]([N:14]=1)[N:12]([CH:10]1[CH2:11][CH:7]([OH:6])[CH:8]([CH2:24][O:25][C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:9]1=[CH2:23])[CH:20]=[N:19]2
Reactant: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)CC1N1C=NC2C(Cl)=NC(N)=NC21
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.9 %

Procedure:
The compound of formula (V) obtained in Example 1-7 (3.2 g, 4.12 mmol) was dissolved in anhydrous tetrahydrofuran (32 ml). To the resulting solution, 1 M tetrabutyl ammonium fluoride solution in tetrahydrofuran (8.24 mL, 8.24 mmol) was added and stirred at room temperature for 13 hrs. After completion of the reaction, the resulting mixture was quenched by adding distilled water (30 ml). The solution thus obtained was extracted with ethyl acetate (30 ml), dried over anhydrous sodium sulfate, filtered, and condensed. The resulting material was stirred in methanol (32 ml) to obtain the title compound (1.6 g, yield: 71.6%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[N:20]=[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]2=[O:21])[N:13]=1.[H][H]>CO.[Ni]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[N:20]=[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]3=[O:21])[N:13]=2)=[C:3]([N:2]([CH3:22])[CH3:1])[CH:8]=1
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C1=NC2=NC=NC(=O)C2=N1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CN(C)c1cc(N)ccc1C1=NC2=NC=NC(=O)C2=N1

Procedure:
An amount of 0.9 gm of 8-(2-dimethylamino-4-nitro-phenyl)purin-6-one is hydrogenated in 50 ml of methanol in the presence of 0.5 gm of Raney nickel at ambient temperature and under 5 bars of pressure with hydrogen for three hours until the calculated quantity has been taken up. After the catalyst has been subjected to suction filtration, the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[O:5][C:6]=1[CH3:7].[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23]CCCCC)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]>>[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23][CH2:8][C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH:3]=2)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Cc1cc(C=O)oc1C
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Product: COC(=O)c1cccc(NCc2cc(C)c(C)o2)c1C(=O)OC
Yield: 75 %

Procedure:
4,5-Dimethyl-furan-2-carbaldehyde (0.98 ml, 8 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 10% ethyl acetate/hexanes) to give 0.95 g (75%) of product as a yellow oil: 1H NMR (CDCl3) δ 7.32 (t, J=8.2 Hz, 1H), 6.97 (bs, 1H), 6.88-6.83 (m, 2H), 5.99 (s, 1H), 4.28 (d, J=5.5 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.17 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:14])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:7][CH:8]=1
Reactant: NNc1ccccn1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2=NN(c3ccccn3)C(=O)CC2)cc1
Temperature: 25 °C

Procedure:
In a 1 neck round bottom flask equipped with a Dean-Stark trap and condenser, 4-(4-methoxyphenyl)-4-oxo-butyric acid (5.0 g, 20 mmol), 2-hydrazinopyridine (3.9 g, 36 mmol) and p-toluene sulfonic acid (0.3 g) in 100 mL benzene were heated to reflux for 2 h while water was removed. The reaction was cooled to rt, an equal volume of Et2O was added and the product collected; Mp>300° C. This solid was dissolved in HOAc (50 mL) and heated at 100° C. for 6 h. The reaction was concentrated, dissolved in EtOAc and washed with saturated NaHCO3 solution, water, NaCl solution and dried (MgSO4). The solvent was concentrated to a thick oil; MS m/z 282 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([Cl:16])[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-:18].[K+].[K+].ClC1C=CC=C(C(OO)=O)C=1.[Na]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([OH:18])([CH3:15])[C:11]([Cl:16])=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)[nH]n(-c2cc(Cl)cc(Cl)c2)c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: CC1(O)C(=O)N(c2cc(Cl)cc(Cl)c2)N=C1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
1 g of 1-(3,5-dichlorophenyl)-3-chloro-4-methyl-5-pyrazolone, 30 ml of ethyl acetate and 1 g of potassium carbonate were cooled to 0° C. and 0.9 g of 75% m-chloroperbenzoic acid were added. The mixture was stirred for 1 hour at 0° C. and the reaction mixture was poured into ice to which sodium hydrogenosulfite had been added. The mixture was extracted with ethyl acetate and the organic phases were washed with a saturated aqueous solution of sodium bicarbonate, then with a solution of ammonium sulfate, and finally with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure. The residue was dissolved in hot isopropyl ether and pentane was added. Cooling was carried out to obtain 0.97 g of 1-(3,5-dichlorophenyl)-3-chloro-4-hydroxy-4-methyl-5-pyrazolone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O.Cl.[OH-].[Na+]>O.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC(=Cc1ccc(OC)c(OC)c1)C2=O
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
6-Methoxy-1-tetralone (7.04 g, 40 mmol) and 3,4-dimethoxybenzaldehyde (6.44 g, 40 mmol) are mixed with 100 ml of absolute ethanol. The mixture is stirred for 0.5 h to dissolve as much as possible of the reagents. The introduction of gaseous hydrogen chloride is commenced. An exothermic reaction is noted which enables the complete dissolution of all of the reagents. The round-bottomed flask is cooled from time to time with an ice bath so that the temperature does not exceed 80° C. The mixture is thus saturated with hydrogen chloride after 1 h to give an intense red color. This mixture is allowed to stand at room temperature for 2 h. The reaction mixture is poured into a mixture of 400 ml of water and 40 ml of aqueous NaOH (3N). It is stirred vigorously for 3 h at room temperature. The precipitated solid is filtered over a glass frit, washed with water and finally dried under vacuum, over P2O5, to give a solid (12.35 g, 95%). A small quantity of product is recrystallized from the mixture AcOEt/hexane=1:2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]4[CH2:22][CH:23]5[NH:27][CH:26]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]([CH3:21])[CH3:20])[C:14]2[CH2:22][CH:23]4[NH:27][CH:26]([C:13]3=2)[CH2:25][CH2:24]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)n1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)n1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the product of step B (100 mg, 0.06 mmol) in dichloromethane was added 2M HCl in diethylether (2 mL). After stirring at ambient temperature for 5 h the reaction mixture was concentrated in vacuo, triturated with ethyl acetate and lyophilized from water to give 2-phenylsulfonyl-5-isopropyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (50 mg, 57%, AUC HPLC >99%) as a white solid: mp 260-265° C., 1H NMR (CD3OD, 300 MHz) δ 8.26 (d, J=1.5 Hz, 1H), 7.93-7.97 (m, 2H), 7.67-7.76 (m, 2H), 7.51-7.59 (m, 3H), 5.28-5.30 (m, 1H), 4.69-4.75 (m, 1H), 4.52 (br s, 1H), 3.55 (dd, J=17.2, 5.1 Hz, 1H), 3.11 (d, J=17.4 Hz, 1H), 2.28-2.43 (m, 3H), 1.93-2.02 (m, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.56 (d, J=6.9 Hz, 3H); ESI, m/z 381 [M+H]+.