Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([CH3:26])=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][C:5]1[C:6]([NH:8][CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 150 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a suspension of tert-butyl 8-((2-chloro-5-methylpyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (1.04 g, 2.73 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (365.4 mg, 2.73 mmol) in n-BuOH (8 mL) was added DIPEA (1.06 g, 8.20 mmol) and the reaction mixture was stirred in a sealed tube at 150° C. overnight then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100) to give the title compound as yellow oil (1.21 g, 100%).
Reaction SMILES: [NH2:1][C:2]1([C:20]([OH:22])=[O:21])[CH2:7][CH2:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:30](=O)([O:46]N1C(=O)CCC1=O)[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2>C(#N)C.O>[C:30]([CH:7]1[CH2:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4][CH2:3][C:2]1([NH2:1])[C:20]([OH:22])=[O:21])([O:31][CH2:32][CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[C:45]1=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46]
Reactant: NC1(C(=O)O)CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: NC1(C(=O)O)CCC(c2ccccc2)(c2ccccc2)CC1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of crude 1-amino-4,4-diphenylcyclohexane-1-carboxylic acid (510 mg, 1.73 mmole), triethylamine (0.37 ml, 2.65 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 880 mg, 2.61 mmole) in acetonitrile (25 ml) and water (25 ml) was stirred at room temperature overnight. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (200 mg) and acetonitrile (5 ml) were added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 1→4→8% methanol/methylene chloride) to give Fmoc-1-amino-4,4-diphenylcyclohexane-1-carboxylic acid (350 mg, 39% yield) as a white solid, HRMS (FAB): C34H32NO4 (M+H) calc. 518.2331; observed: 518.231
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([C:11]1[N:12]([CH3:19])[CH:13]=[CH:14][C:15](=[O:18])[C:16]=1[OH:17])[CH3:10].[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]=[O:22]>C(#N)C.C(Cl)Cl>[CH2:27]([O:26][C:24]([CH2:23][NH:20][C:21]([O:17][C:16]1[C:15](=[O:18])[CH:14]=[CH:13][N:12]([CH3:19])[C:11]=1[CH2:9][CH3:10])=[O:22])=[O:25])[CH3:28]
Reactant: CCOC(=O)CN=C=O
Reactant: CCc1c(O)c(=O)ccn1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Oc1c(CC)n(C)ccc1=O
Reaction time: 0.17 h

Procedure:
2.8 ml of triethylamine are added at room temperature to a suspension of 1.89 g of 2-ethyl-3-hydroxy-1-methyl-4(1H)-pyridinone hydrochloride in 50 ml of acetonitrile and 50 ml of methylene chloride followed by the addition of 2.27 ml of ethyl isocyanatoacetate. The ensuing reaction is slightly exothermic and a solution forms within 10 minutes. The reaction is complete after 1.5 hours. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dried under a high vacuum and crystallised from ethyl acetate. A solution of 4.0 g of the resultant hydrochloride of 3-(ethoxycarbonylmethylaminocarbonyloxy)-2-ethyl-1-methyl-4(1H)-pyridinone in 40 ml of water is adjusted to pH 2.5 with phosphoric acid, saturated with sodium chloride and extracted with methylene chloride. The residue of the organic extract is crystallised from a 95:5 mixture of ethyl acetate and methylene chloride, affording 3-(ethoxycarbonylmethylaminocarbonyloxy)-2-ethyl-1-methyl-4(1H)-pyridinone with a melting point of 99°-100° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl>[Pd].CO>[NH2:15][CH2:14][C:13]1[C:12]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH3:21])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a MeOH solution (5 ml) was added (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino) -5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinonitrile (Example 1; 0.15 g, 0.4 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g). The mixture was then flushed with N2, evacuated, and then placed under 40 psi of H2 for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na2CO3 (100 ml) was added, and the mixture was shaken vigorously for 30 min. The layers were then allowed to separate, and the aqueous layer was extracted with DCM (3×100 ml). The combined organic layers were dried, filtered and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=9:1) to give the title compound (0.09 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.38 (m, 2H), 7.15 (d, J=11. Hz, 1H), 7.02-6.97 (m, 2H), 5.15-5.08 (m, 1H), 3.74 (s, 2H), 1.88-1.81 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.93-0.92 (m, 2H), 0.67-0.63 (m, 2H). MS: Calcd.: 384. Found: [M+H]+ 385.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(-c3ccccn3)cc12
Product: Clc1ncnc2ccc(-c3ccccn3)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Preparation D12, Step 3: A suspension of 6-(pyridin-2-yl)quinazolin-4-ol (106 mg, 0.47 mmol) in phosphorous oxychloride (15 mL) was heated at reflux for 1.5 h, during which time a clear, amber solution was observed. The solution was cooled to room temperature, concentrated in-vacuo, and stripped 2× from 30 mL methylene chloride to remove any remaining phosphorous oxychloride. The residue was partitioned between EtOAc and saturated sodium bicarbonate, and the mixture was stirred for 10 min. The layers were separated, and the organic phase was washed successively with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with methylene chloride followed by 1:1 methylene chloride/EtOAc, to yield 105 mg of 4-chloro-6-(pyridin-2-yl)quinazoline as a white solid. MS (ES+)=242 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:25]3[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=3)[N:19]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)C.C1CCCCC=1>[CH:30]1([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])[C:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[O:16])=[N:18]2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C(c1ccc(O)cc1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Temperature: 70 °C
Yield: 81.1 %

Procedure:
A mixture of [4-(benzyloxy)phenyl][1-cyclopentyl-7-(trifluoromethyl)-1H-indazol-3-yl]methanone (0.13 g, 0.28 mmol) and 10% palladium on carbon(0.10 g) in 10 mL ethanol/cyclohexene (3:1, v/v) was heated at 70° C. for 0.5 hours. The catalyst was filtered (celite) and the filtrate concentrated in vacuo to give crude product. The residue was crystallized from Et2O/hexane to give 0.085 g of product as a white solid (mp 225-226° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][CH2:27]O)([C:14]2[NH:18][N:17]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[N:18]([N:17]=[C:16]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=3)[CH2:27][CH2:26]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(c2cc(Cc3ccccc3)n[nH]2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCn1nc(Cc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyeth-1-yl)-4-(3-benzyl-(1H)-pyrazol-5-yl)piperidine (125 mg, 0.32 mmol) from Step I in THF (4 mL) at 0° C. was added triphenylphosphine (85 mg, 0.32 mmol) and DEAD (0.051 mL, 0.32 mmol). The reaction was stirred for 20 min and was then allowed to warm to room temperature for 2 h. The mixture was concentrated and purified by flash chromatography eluting with 80% ethyl acetate in hexanes, then 5% methanol in methylene chloride to afford the title compound (100 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:24][O:25][CH2:26][CH3:27])([OH:23])[CH:6]([N+:20]([O-])=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1)[CH3:2].[H][H]>[Ni].C(O)(C)C>[CH2:26]([O:25][CH2:24][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:23])[CH:6]([NH2:20])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:13]=1)[CH3:27]
Reactant: [H][H]
Reactant: CCCCCCc1ccc(CC([N+](=O)[O-])C(O)(COCC)COCC)cc1
Agent: [Ni]
Solvent: CC(C)O
Product: CCCCCCc1ccc(CC(N)C(O)(COCC)COCC)cc1
Yield: 85.5 %

Procedure:
A mixture of α, α-diethoxymethyl-β-nitro-4-hexylbenzenepropanol (2.31 g) and Raney nickel (0.6 g) in isopropanol (70 ml) was stirred under hydrogen at atmospheric pressure until the hydrogen absorption was complete. The mixture was degased in vacuo for 15 minutes and filtered through celite. Evaporation of solvent gave α, α-diethoxymethyl-β-amino-4-hexylbenzenepropanol (1.82 g) as an oil. This oil was reacted with di-tert-butyl-dicarbonate (1.19 g) in methanol (40 ml). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by chromatography [silica gel 290 g, elution with ethyl acetate: cyclohexane, 2:8 (2 1)]. Two isomers of the title compound were isolated. Isomer A (0.90 g) and isomer B (0.90 g) were obtained as oils, Rf isomer A=0.30, Rf isomer B=0.19 (silica gel, ethyl acetate: cyclohexane, 1:4)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:37])/[CH:24]=[CH:25]/[CH2:26][N:27]([CH3:36])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:23](=[O:37])/[CH:24]=[CH:25]/[CH2:26][N:27]([CH3:36])[CH2:28][C:29]([OH:31])=[O:30])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1)CC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
The compound of Example 97 (60 mg, 0.11 mmol) was dissolved in DCM (1.0 mL) and cooled to 0° C. TFA (0.30 mL) was added, and the mixture was warmed to rt and stirred overnight. Subsequently, the solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 43 mg (78%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[CH3:30][N:31]([CH3:43])[CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][N:31]([CH3:30])[CH3:43])=[CH:42][CH:41]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CN(C)CCOc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.050 g, 0.13 mmol, 1 eq), EtOH (2.2 mL) and DMF (0.29 mL), 4-(2-dimethylaminoethoxy)benzaldehyde (0.027 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.010 g, 15%); 1H-NMR (500 Mz, DMSO-d6): 2.24 (s, 6H, NMe2), 2.66 (t, J=5.5 Hz, 2H, CH2NMe2), 2.75-2.80 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.70-3.76 (m, 4H), 4.13 (t, J=5.8 Hz, 2H, CH2O), 7.10 (d, J=8.5 Hz, 2H, ArH C6H4), 7.23 (d, J=4.0 Hz, 1H) and 7.49 (d, J=3.50 Hz, 1H) (thiazole H-4, H-5), 8.04-8.11 (m, 3H, imidazo[4,5-b]pyridine 5-H and ArH C6H4), 11.88 (br s, 1H, NHCO), 13.24 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.63 min—587/589 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (1.5 g, 07.5 mmol) in dry DCM (40 mL) was added triethylamine (2.59 mL, 18.8 mmol) and 4-chlorobenzenesulfonyl chloride (3.15 g, 10.5 mmol) and the reaction stirred at room temperature for 48 h. To the reaction was added resin supported-triamine (5 g) and the mixture stirred for 4 h. The reaction mixture was filtered and the filtrate washed with 0.5 M HCl (aq., 100 mL) followed by water (100 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was dissolved in DCM (40 mL) and TFA (10 mL) was added. The solution was stirred for 20 min. The solvent was evaporated and the residue tajen up in DCM (40 mL) and washed with 50% aqueous sodium bicarbonate (100 mL) followed by water (100 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound (1.62 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH2:9][C:10]#[N:11])[C:4]=2[CH:3]=1.[ClH:20].C1(C2SC3C=CC=CC=3C=2CCN)C=CC=CC=1>>[ClH:20].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH2:9][CH2:10][NH2:11])[C:4]=2[CH:3]=1
Reactant: N#CCc1c(-c2ccccc2)sc2ccc(F)cc12
Agent: Cl
Agent: NCCc1c(-c2ccccc2)sc2ccccc12
Product: NCCc1c(-c2ccccc2)sc2ccc(F)cc12

Procedure:
Substitution of an equivalent quantity of 5-fluoro-2-phenylbenzo[b]thiophene-3-acetonitrile for the 2-phenylbenzo[b]thiophene-3-acetonitrile of Example 9 and repetition of the procedure which is described in Example 9 affords 5-fluoro-2-phenylbenzo[b]thiophene-3-ethanamine hydrochloride, melting at 260° C. (decomposition). This compound is represented by the following structural formula. ##STR29##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:9][CH:10]=1)=[O:4]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)nc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CCC(C(=O)OC(C)(C)C)NC1
Yield: 87.4 %

Procedure:
Pyridine-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester (5.8 g, 24.45 mmol) was dissolved in glacial acetic acid (30 mL) and hydrogenated at 50-60 psi for 3 days with 10% palladium on carbon catalyst (0.6 g). The reaction mixture was filtered through a pad of Celite which was then washed with methanol. The filtrates were combined and concentrated under reduced pressure. The residue was dissolved in water (100 mL) and solid sodium carbonate (15 g) was added to bring the pH to 8. The solution was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.2 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:22]=[C:21]4[C:15]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[N:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:18]2[CH2:19][CH2:20][C:21]3=[CH:22][N:13]([C:10]4[CH:11]=[CH:12][C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[N:6]=5)=[CH:8][CH:9]=4)[N:14]=[C:15]3[CH2:16][CH2:17]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: Cc1noc(-c2ccc(-n3cc4c(n3)CCNCC4)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C3CCCC3)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 35) (31 mg, 0.10 mmol) in dichloromethane (4 ml) was added cyclopentanone (35 mg, 0.42 mmol) and acetic acid (3 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring continued overnight. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E27). MS (ES+) m/e 364 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=[C:18]([F:21])[C:19]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:1][C:2]1[S:6][N:5]=[C:4]([C:7]([F:9])([F:10])[F:8])[C:3]=1[CH2:11][O:12][C:19]1[C:18]([F:21])=[CH:17][C:16]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15][C:14]=1[F:13]
Reactant: OCc1c(C(F)(F)F)nsc1Br
Reactant: COC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)nsc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (200 mg, 0.76 mmol, 1.00 equiv), methyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (199 mg, 0.92 mmol, 1.20 equiv), PPh3 (401 mg, 1.53 mmol, 2.00 equiv), tetrahydrofuran (3 mL), DIAD (3.9 mg, 0.02 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 190 mg (51%) of methyl 3-(4-[[5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:3].[C:10]([O:15][CH2:16]CCCCCCCCCCCCCCCCC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C(OCC(CC)CCCC)(=O)C(C)=C.C(OCCCCCCCCCCCC)(=O)C(C)=C>>[CH3:3][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:1].[C:10]([O:15][CH3:16])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Agent: C=C(C)C(=O)OCC(CC)CCCC
Agent: C=C(C)C(=O)OCCCCCCCCCCCC
Agent: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)OC

Procedure:
The HEMA-stearyl methacrylate copolymer (90:10) was generally best in weatherability and dirt resistance, on the concrete substrate. It was somewhat inferior only to 100% polyHEMA in graffiti resistance. Subsequent experiments of the same type showed that neither 60:40 copolymers with (a) 2-ethylhexyl methacrylate, nor (b) lauryl methacrylate had the solvent resistance needed for repeated graffiti removal cycling.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1>[C:15]1([CH2:14][NH:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][NH:7][C:8]3=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccc2c1CCNC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCc2c(NCc3ccccc3)cccc21
Temperature: 0 °C
Yield: 19.3 %

Procedure:
To a solution of 2.0 g (12.3 mmol) of 5-amino-3,4-dihydro-1(2H)-isoquinolinone, monohydrochloride in 10 ml of THF was added 2.6 g (14.76 mmol) of benzylbromide and 2 ml of triethylamine. The mixture was heated under reflux for six hours and then poured into ice water and extracted with ether. The ether extracts were washed with water, dried (MgSO4), and concentrated. The residue was chromatographed (SiO2, ether to 10:1 ether/methanol) to provide 0.6 g of the dibenzylated product and 0.95 g (31%) of the desired monobenzylated product after crystallization from ethanol; mp. 142°-144°.