Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1C2C(=CC=CC=2)C(C(OCC)=O)=C1C.[C:26]1([C:39](OC)=[O:40])[C:27]2[CH:28]=[C:29]3[CH2:38][CH2:37][CH2:36][CH2:35][N:30]3[C:31]=2[CH:32]=[CH:33][CH:34]=1>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][C:39]([C:26]1[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=1[CH:28]=[C:29]1[CH2:38][CH2:37][CH2:36][CH2:35][N:30]13)=[O:40])[CH2:3]2
Reactant: COC(=O)c1cccc2c1cc1n2CCCC1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCOC(=O)c1c(C)n(C)c2ccccc12
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2c1cc1n2CCCC1
Yield: 82 %

Procedure:
Proceeding as in Example 2, Method B, but replacing (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane and ethyl 1,2-dimethylindole-3-carboxylate with methyl 6,7,8,9-tetrahydropyrido[1,2-a]indole-1-carboxylate, from Example 1, there was prepared (S)-1-[(1-azabicyclo[2.2.2]oct-3-yl)aminocarbonyl]-6,7,8,9-tetrahydropyrido[1,2-a]indole (82% yield), m.p. 163°-164° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[N-]=C=O>CC#N.C(OCC)(=O)C>[N:22]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CN1CCCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), pyrrolidine (34 μL, 0.403 mmol) and K2CO3 (112 mg, 0.806 mmol) in MeCN (5 mL) was stirred at 50° C. for 18 hrs. HPLC analysis still showed starting material and therefore, the reaction mixture was further stirred at 100° C. for 1 h to afford completion. The mixture was cooled to room temperature and ethyl acetate (20 mL) was added, the organic phase was washed with water (20 mL) and then brine (20 mL), and dried over MgSO4, and solvent evaporated. The resulting oily solid was dissolved in DCM (5 mL) and stirred overnight with polystyrene methylisocyanate (“PS-isocyanate” 276 mg, 0.4 mmol, 1.46 mmol/g) to remove any excess pyrrolidine. The polymer was filtered and the organic phase was remove in vacuo, to afford 2-pyrrolidin-1-yl-N-(3-quinoxalin-2-ylphenyl)acetamide (45 mg, 40% yield). LCMS calculated for C20H20N4O (M+H): 333.41. found 333.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.95 (s, 1H), 9.51 (s, 1H), 8.55 (s, 1H), 8.20-8.14 (m, 2H), 8.08-8.02 (m, 1H), 7.95-7.82 (m, 3H), 7.58-7.50 (m, 1H), 3.40 (s, 2H), 2.65-2.55 (m, 4H), 1.85-1.75 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.[Li]CCCC.[Cl:31][C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[CH:36]1[NH:37][C:32]([Cl:31])=[N:33][CH:34]=[CH:35]1
Reactant: Clc1ncccn1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(C(F)(F)F)cc2)nc(Br)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2ccc(C(F)(F)F)cc2)nc(Br)c1C1C=CN=C(Cl)N1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
A solution of 4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.0 g, 2.0 mmol) in dry THF (10 mL) was cooled to −78° C. under Argon. n-BuLi (1.0 mL, 2.5 M in hexane, 2.5 mmol) was added dropwise, afterwards the reaction was maintained below −70° C. for an additional 45 minutes. A solution of 2-chloropyrimidine (0.29 g, 2.5 mmol) in dry THF (2 mL) was added dropwise at −78° C. After addition, the reaction was allowed to warm to −40° C. over 25 minutes and maintained at −40° C. for 20 minutes. The reaction was then warmed to −5° C. in a brine-ice bath, quenched with water (30 mL), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic phase was separated, dried (Na2SO4), and concentrated. The resulting residue was further purified by flash chromatography (SiO2, 0-20% EtOAc in hexanes) to afford 1.1 g (2.05 mmol, 82%) of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine. A solution of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine (410 mg, 0.8 mmol) in EtOAc (20 mL) was treated with MnO2 (920 mg, 10.6 mmol) and the resulting reaction mixture was heated to and maintained at reflux for 18 hours. The reaction was allowed to cool to room temperature and was then filtered through Celite. The filter cake was washed with EtOAc (2×20 mL) and the combined filtrates were concentrated to give 400 mg (0.75 mmol, 98%) of 4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=5.4 Hz, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 5.77 (s, 2H), 3.49 (t, J=7.5 Hz, 2H), 0.83 (t, J=7.5 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C@@H:6]1[CH2:12][CH2:11][C@H:10]2[C@H](O2)C1)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)S)C=CC=CC=1.[C:35](#[N:37])C>>[CH2:12]1[CH2:6][N:5]2[C:10](=[N:37][CH2:35][CH2:2][CH2:3]2)[CH2:11]1
Reactant: O=C(N[C@@H]1CC[C@@H]2O[C@@H]2C1)C(F)(F)F
Reactant: CC#N
Agent: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C1CN=C2CCCN2C1

Procedure:
1.55 g of 2,2,2-Trifluoro-N-(1R,3R,6S)-7-oxa-bicyclo[4.1.0]hept-3-yl-acetamide (Example 3 Step B), 2.46 g of triphenylmethanethiol and 25 mL of acetonitrile were charged to a flask. To the mixture obtained 880 μL of DBN was added, and the mixture obtained was heated to 60° C. and stirred for 23 h. Upon completion of the reaction (TLC), the mixture obtained was cooled to rt, diluted with EtOAc and washed with H2O and brine. The organic layer obtained was dried over MgSO4, concentrated in vacuo and the crude product obtained was subjected to column chromatography (eluent: Cyclohexane/EtOAc 5:1). The required fractions were identified, combined and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[N:10]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:19])=[CH:16][CH:15]=2)=[CH:12][C:11]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[N:10]1
Reactant: C1COCCN1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
To a solution of 4-(1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)benzoyl chloride (28 mg, 0.062 mmol) in 0.62 mL of DCM at Rt was added morpholine (0.016 mL, 0.19 mmol) and the mixture stirred for 10 mins. The solvents were evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 30-70% CH3CN in 0.1% TFA/H2O over 10 mins to give 25 mg (69%) of the title compound as white solid containing 0.6 eq of TFA.
Reaction SMILES: NC1C(NC2C=CC=C(O)C=2)=NC(NC2C=CC=C(O)C=2)=NC=1C(OCC)=O.[CH2:29]([O:31][C:32]([C:34]1[N:39]=[C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[N:37]=[C:36]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:35]=1[N+:54]([O-])=O)=[O:33])[CH3:30].[H][H]>[Pd]>[NH2:54][C:35]1[C:36]([NH:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[N:37][C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N:39][C:34]=1[C:32]([O:31][CH2:29][CH3:30])=[O:33]
Reactant: [H][H]
Reactant: CCOC(=O)CNc1nc(NCC(=O)OCC)c([N+](=O)[O-])c(C(=O)OCC)n1
Agent: [Pd]
Agent: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N
Product: CCOC(=O)CNc1nc(NCC(=O)OCC)c(N)c(C(=O)OCC)n1

Procedure:
In a manner similar to the preparation of 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 6-ethoxycarbonyl-N2,N4-bis(ethoxycarbonylmethyl)-5-nitro-2,4-pyrimidinediamine, hydrogen, and 10% Pd/C were reacted to yield 5-amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 6.25 (bs, 2H), 4.38 (q, 2H, J=6.9 Hz), 4.23-4.14 (m, 6H), 4.05 (bs, 2H), 1.39 (t, 3H, J=6.9 Hz), 1.30-1.22 (m, 6H); LCMS: ret. time: 17.67 min.; purity: 95%; MS (m/e): 370 (MH+).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:22])=[CH:15][CH:16]=1
Reactant: CCNCC
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of diethylamine (89.1 mL), triethylamine (120.2 mL) and CH2Cl2 (500 mL) cooled in an ice-bath was added dropwine p-anisoyl chloride (133.8 g) over 40 minutes. The reaction mixture was stirred at room temperature for 40 minutes, the mixture was filtered, washed with ether and the solvent was removed in vacuo. Ether was added, then water to the residue, then the organic layer was separate and washed with 5% NaoH, then in HCl, then brine and then was dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by kugelrohr distillation at 140°-180° C. under high vacuum to afford 163.8 g of 4-methoxy-N,N-diethylbenzamide, m.p. 40°-42° C.
Reaction SMILES: CC.[CH2:3]=[CH:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][CH:19]=1.[CH:25]([O-])([O-])[O:26]CC>>[CH2:17]([C:18]1[CH:23]=[C:22]([OH:24])[C:21](=[CH:20][CH:19]=1)[CH:25]=[O:26])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Reactant: CCOC([O-])[O-]
Agent: CC
Product: CCCCCCCCCCCCCCCc1ccc(C=O)c(O)c1

Procedure:
(15:0)-Cardanol (10.2 g) is added to an equivalent proportion of ethyl magnesium bromide in dry ethereal solution to form the phenoxy magnesium bromide, completion of which is observed when evolution of ethane ceases. Ethyl orthoformate (10 cm3) is added and the ether removed by distillation so that the temperature rises to 100° C. After refluxing for three hours, the mixture is decomposed with dilute hydrochloric acid and warmed to effect the hydrolysis of the intermediate acetal formed. Etheral extraction and recovery gives a mixture of some unchanged (15:0)-cardanol and the formylated product, 4-pentadecylsalicylaldehyde which is separated by chromatography.
Reaction SMILES: O[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(OC1C(C)=C(C=CC=1)C(O)=O)(=O)C.[Cl:26][C:27]1[C:28]([CH3:34])=[C:29](O)[CH:30]=[CH:31][CH:32]=1.C(Cl)C1C=CC=CC=1>>[CH2:5]([O:7][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[C:28]=1[CH3:34])[C:4]1[CH:3]=[CH:2][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(O)cccc1Cl
Reactant: Cc1c(O)cccc1C(=O)O
Agent: CC(=O)Oc1cccc(C(=O)O)c1C
Solvent: ClCc1ccccc1
Product: Cc1c(Cl)cccc1OCc1ccccc1

Procedure:
The invention relates to a process for the preparation of 3-hydroxy-2-methylbenzoic acid and 3-acetoxy-2-methylbenzoic acid, which comprises reacting 3-chloro-2-methylphenol (3) with benzyl chloride to give 2-benzyloxy-6-chlorotoluene (4) subjecting this to a Grignard reaction with magnesium to give (3-benzyloxy-2-methylphenyl)magnesium chloride (5) reacting this with CO2 to give 3-benzyloxy-2-methylbenzoic acid (6) hydrogenating this or its alkali metal salts in the presence of a hydrogenation catalyst to give 3-hydroxy-2-methylbenzoic acid (2) and optionally acetylating this to give 3-acetoxy-2-methylbenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>C(OCC)(=O)C.CN(C)C=O>[CH:26]1([O:17][C:15]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH:16]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrC1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To N,N-dimethylformamide 3.0 mL solution of methyl 2-(4-fluoroanilino)-4-hydroxybenzoate 0.30 g were added potassium carbonate 0.16 g and cyclohexyl bromide 0.42 mL at room temperature, and it was stirred at 80° C. for 8 hours. After the reaction mixture was cooled to room temperature,11.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=8:1] to give methyl 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoate 40 mg of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].CC[O:17][C:18]([C:20]1(Br)[CH2:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:20]1([C:18]([OH:19])=[O:17])[CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Temperature: 65 °C

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (7 g, 0.03 mole), ethyl α-bromocyclobutanecarboxylate (10.23 g, 0.049 mole) and potassium carbonate (7.5 g, 0.054 mole) in N,N-dimethylformamide (60 ml) was stirred and heated at 65° C. for 18 hours. The reaction mixture was poured into ice water and the resulting mixture was extracted with ether. The ether extract was washed with a 1% sodium hydroxide solution, then with water and finally dried over MgSO4. The ether was evaporated in vacuo and the residue treated with acetic acid (60 ml) and 5% hydrochloric acid (15 ml). The mixture was stirred and refluxed overnight. The solvents were evaporated in vacuo. The residue was chromatographed over a column containing silica gel (140 g) using methylene chloride/tetrahydrofuran/acetic acid 50/1/1 as the eluent. The pertinent fractions were united, treated with toluene and evaporated in vacuo to obtain 1-(2,3-dichloro-4-butyrylphenoxy)cyclobutane-1-carboxylic acid as a liquid whose identity was confirmed by NMR and purity by thin layer chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=O)[C:17](=O)N2>>[C:15]1([CH:16]([C:17]2[CH:4]=[CH:3][CH:2]=[CH:10][CH:6]=2)[N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:12])[C:8]2=[O:11])[CH:19]=[CH:20][CH:21]=[CH:22][CH:14]=1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=C1Nc2c(F)cccc2C1=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 4A, and making non-critical variations using 7-fluoro-1H-indole-2,3-dione (Kalia, N., et al., J. Med. Chem. 2007; 50:21-39) to replace 4-chloro-1H-indole-2,3-dione, 1-(diphenylmethyl)-7-fluoro-1H-indole-2,3-dione was obtained (56%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ7.52-7.47 (m, 1H), 7.42-7.30 (m, 10H), 7.29-7.21 (m, 1H), 7.13-7.05 (m, 1H), 6.99 (br s, 1H); MS (ES+) m/z 353.9 (M+23).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:17]I>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:17])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1cccc(CC(=O)O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNc1cccc(CC(=O)OC)c1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 3-(allylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-(allylamino)phenylacetate
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1cc(C)c(Cl)cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(Cl)c(C)cc3C(C)=O)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
1-(4-Chloro-2-hydroxy-5-methyl-phenyl)-ethanone (193 mg), 4-chloro-6,7-dimethoxyquinoline (468 mg), and 4-dimethylaminopyridine (385 mg) were suspended in o-dichlorobenzene (5 ml) to prepare a suspension which was then stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (39 mg, yield 10%).
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[C:10]([Mg]Br)[CH:11]=2)[C:6]([CH3:17])([CH3:16])[CH:5]1[CH3:18])([CH3:3])[CH3:2].[Mg].BrC1C=C2C(C(C)(C)C(C)C2C(C)C)=CC=1C.S(=O)(=O)(O)O.CN(C)[CH:44]=[O:45]>>[CH:44]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH3:17])([CH3:16])[CH:5]([CH3:18])[CH:4]2[CH:1]([CH3:3])[CH3:2])=[CH:8][C:9]=1[CH3:15])=[O:45]
Reactant: Cc1cc2c(cc1[Mg]Br)C(C(C)C)C(C)C2(C)C
Reactant: CN(C)C=O
Agent: Cc1cc2c(cc1Br)C(C(C)C)C(C)C2(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Product: Cc1cc2c(cc1C=O)C(C(C)C)C(C)C2(C)C

Procedure:
40 ml Bromine is added at 10° C. to a solution of 100 g 1-isopropyl-2,3,3,5-tetramethyl indan (obtained according to Example I or II) and 1 ml pyridine in 50 ml carbon tetrachloride. Then the reaction mixture is stirred during one hour and poured out into an aqueous solution of approximately 25 g sodium thiosulphate. The organic layer is separated, washed with 25% sodium hydroxide and evaporated. The residue is distilled under diminished pressure yielding 105 g 6-bromo-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 145°-150° C./1 mm Hg. 25 g Dimethyl formamide is added to a solution of 1-isopropyl-2,3,3,5-tetramethyl-6-indanyl magnesium bromide, prepared from 9 g magnesium and 100 g of the 6-bromo indan obtained above. The reaction mixture is then heated to reflux during 30 min., poured out into a mixture of ice and diluted sulphuric acid and extracted with ether. The solution in ether is washed neutral, dried and evaporated. The residue is distilled under diminished pressure yielding 30 g 6-formyl-1-isopropyl-2,3,3,5-tetramethyl indan. B.p. 135° C./1 mm Hg.
Reaction SMILES: C(O[CH2:4][N:5]1[C:9]2=[N:10][C:11]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:15](=[O:17])[C:16]=3[N:8]2[CH2:7][CH2:6]1)C.[H][H]>[Pd].C(O)(=O)C>[CH3:26][N:12]1[C:11]2[N:10]=[C:9]3[N:5]([CH3:4])[CH2:6][CH2:7][N:8]3[C:16]=2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13]1=[O:25]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3C)n(C)c1=O

Procedure:
A mixture of (R)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (60 mg, 0.164 mmol) and 10% palladium on carbon (50% water, 100 mg) in acetic acid (25 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtration through a pad of celite, concentration of the filtrate under reduced pressure provided (R)-7,8-dihydro-1,8-dimethyl-3-(5-hydroxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-31878) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(Cl)c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 20.0 g (0.12 mole) of 2-chloro-4-nitroaniline and 17.9 g (0.14 mole) of 2,5-dimethoxytetrahydrofuran in 30 ml of glacial acetic acid was heated at reflux for three hours. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether. The extract was washed with a saturated aqueous potassium carbonate solution then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to leave a solid. The solid was purified by recrystallization from methylcyclohexane to yield 22.5 g of 1-(2-chloro-4-nitrophenyl)pyrrole (mp 54°-55° C.).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C:28]1[C:29]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:29]3[C:28]([CH3:27])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cc1cc2ccccc2nc1N1CCNCC1
Product: Cc1cc2ccccc2nc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 3-methyl-2-piperazin-1-yl-quinoline.