Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1.Cl>>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=4)[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C#N)cc1)C3=O

Procedure:
Using procedure 48, 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.12 g, 0.4 mmol) was treated with alpha-bromo-p-tolunitrile (0.08 mL, 0.4 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 97 as a white solid (m.p. 263-264° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC2C=CC=CC=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Yield: 101.6 %

Procedure:
1 g of Pd/C 10% was added to a solution of 13 g (0.039 mol) of [2-(3-benzyloxy-phenyl)ethyl]-carbamic acid tert-butyl ester in 100 ml of ethanol. The mixture was hydrogenated at 40 psi overnight. The catalyst was filtered off and washed with ethanol. The solvent was removed under vacuum and 9.4 g of the title compound were obtained as a colourless oil in quantitative yield.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([NH:26][C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)NC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of benzyl (2R)-2-carboxymethyl-4-methylvalerate (527 mg) and cyclohexylamine (238 mg) in methylene chloride (10 ml) was added WSCD·HCl (460 mg) at room temperature. After being stirred overnight, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 5% HCl, water, saturated sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with n-hexane to give benzyl (2R)-2-(cyclohexylcarbamoylmethyl)-4-methylvalerate (410 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH3:5].Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[CH3:5][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]1=[O:28])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN(C)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A mixture of 80% sodium hydride (2.2 g) and 3-(N,N-dimethylaminomethyl)phenol (6.95 g) in dry dimethylformamide was stirred at 5° for 2 hr. N-(3-Bromopropyl)phthalimide (12.2 g) was then added and after 16 hours the reaction was treated with water and extracted with ethyl acetate. Evaporation of the dried organic extracts gave the title compound as a yellow oil (13 g). TLC silica; ethyl acetate; Rf 0.35. m.p. (oxalate salt) 204°-207°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[N:26]=[C:27]=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:27]([NH:26][C:19]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=3[O:17][CH3:16])=[O:28])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OC)c(N=C=O)c1
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Product: COc1ccc(OC)c(NC(=O)Nc2cc(Nc3cccc(Cl)c3)ncn2)c1

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,5-dimethoxyphenyl isocyanate.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccc(C#N)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution (10 mL) of 2-[cyclohexyl(hydroxy)methyl]-3-methyl-1-benzofuran-5-carbonitrile (922 mg) synthesized above in toluene was added thionyl chloride (374 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (868 mg, 88%) as a pale-yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([OH:18])(=O)=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:19]S(O)(=O)=O>>[C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15]([Cl:19])(=[O:18])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)O)c2ccccc12
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
At 0° C., 4-acetamidonaphthalene-1-sulfonic acid (5 g, 19 mmol) was slowly added to chlorosulfonic acid (25 ml). The mixture was allowed to warm to RT over 30 minutes and then stirred for 2 h. After slowly adding the reaction mixture to ice water, a fine yellow precipitate formed which was filtered, washed with water and dried under vacuum to give 4-acetamidonaphthalene-1-sulfonyl chloride (4.73 g, 87%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=284.0; tR=3.06 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCBr
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
6-Bromo-1-hexanol (20 g, 110.42 mmol) was dissolved in dry tetrahydrofuran (700 ml) and cooled to 0° C. under argon atmosphere, to which were added imidazole (15 g, 220.84 mmol) and t-butyldimethylsilyl chloride (33 g, 220.84 mmol) and the resulting solution was stirred overnight. After the reaction was completed, the mixture was poured in ice-water and extracted with ethyl acetate. The organic solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This crude product was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane=1:40. After removal of the solvent, 30 g of the title compound was obtained as colorless oil. (yield: 92.4%)
Reaction SMILES: [Cl:1]Cl.[CH2:3]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:4][CH2:5][NH2:6].[ClH:13]>Cl>[ClH:1].[ClH:1].[Cl:13][CH:3]([CH2:4][CH2:5][NH2:6])[CH2:7][C@@H:8]([C:9]([OH:11])=[O:10])[NH2:12]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: ClCl
Agent: Cl
Product: NCCC(Cl)C[C@H](N)C(=O)O
Temperature: 7 °C

Procedure:
Chlorine was bubbled trough a solution of L(+)-lysine monohydrochloride (150 g, 821 mmol) in HCl (36%) at 70° C. The mixture was irradiated with a medium pressure mercury lamp while stirring. After 2 h the reaction mixture was cooled to 7° C. and a seed crystal was added to induce crystallization. After one hour the resulting crystals were filtered off and the crude product was triturated twice with MeOH. The crystals were collected to afford 4.1 as a white solid. Yield: 12.6 g, 49.7 mmol, 6%. 1H-NMR (300 MHz, DMSO-d6) δ 8.81 (br s, αNH3, 3H), 8.43 (br s, εNH3, 3H), 4.48 (m, γCH, 1H), 3.96 (br s, αCH, 1H), 2.94 (m, εCH2, 2H), 2.31 (m, βCH2+δCH, total 3H), 2.04 (m, δCH, 1H). 13C-NMR (75 MHz, DMSO-d6) δ 169.9 (C═O), 56.6 (γCH), 49.6 (αCH), 38.4 (εCH2), 36.1 (βCH2), 35.1 (δCH2). LC-MS program 3: Rt=1.05 min, MS ES+ (amu): 180.94 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[ClH:1].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCC(=O)O
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 22.8 mg (259 μmol) butyric acid are dissolved in 5 ml DMF, 119 mg (1.18 mmol) triethylamine and 90.2 mg (470 μmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is then purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:42][CH2:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[N:47][N:48]3[CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
2-Chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 84.3 mg, 0.393 mmol) was suspended in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. BOP reagent (191 mg, 0.432 mmol) was added in one portion, followed by 4-aminomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Example 12; 91 mg, 0.393 mmol) with a 2×0.25 mL wash of dichloromethane. Duisopropylethylamine (0.21 g, 1.62 mmol) was added over 1 min at ˜0° C. The mixture was stirred at ˜0° C. for 30 min and then at room temperature for 3.5 h. The mixture was concentrated to remove dichloromethane, and ethyl acetate (60 mL) was added. The solution was washed with 1 M HCl , sodium hydrogen carbonate solution, and brine (10 mL each), then dried (MgSO4), filtered, and concentrated. Ethyl acetate/petroleum ether was added and the insoluble material was filtered off to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (93 mg, 55%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][C:24]=1[OH:33])=[O:22])[CH3:19]>>[OH:33][C:24]1[CH:25]=[C:26]([CH2:29][C:30]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:31])[CH:27]=[CH:28][C:23]=1[C:21]([O:20][CH2:18][CH3:19])=[O:22]
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1O
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-ethoxycarbonyl-3-hydroxy-phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)N1Cc2nc(N)nc(O)c2C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)N1Cc2nc(N)nc(Cl)c2C1
Yield: 57.1 %

Procedure:
Intermediate (h) (11 g, 49 mmol) was azeotroped×2 with toluene. Anhydrous acetonitrile (250 mL) and POCl3 (25 mL, 270 mmol) were added and the mixture was refluxed for about 2.5 h. Additional POCl3 (50 mL) was added and the mixture was refluxed for an additional 2 h. The volatile components were concentrated under vacuum at 40° C. to give a red solution. A minimum amount of dry acetonitrile was added until the solution was readily transferable whereupon it was poured onto ice in a large beaker. The flask was further rinsed with a small amount of acetonitrile which was added to the ice. Water (about 50 mL) was added to the ice mixture to help it with stirring. Concentrated NH4OH (25 mL) was added slowly with stirring until the ice slurry mixture was strongly basic, then 50% aqueous NaOH (25 mL) was also added to the still stirring slurry of ice. Additional ice was added. After about 5 minutes stirring as ice slurry, EtOAc was added. After stirring in the beaker for several more minutes, water was added to help melt the ice. The mixture was poured into a separatory funnel and the layers were allowed to partition. The aqueous layer was extracted with EtOAc×3. The combined EtOAc extracts were washed ×2 with saturated aqueous KHSO4, ×2 with saturated aqueous NaHCO3, ×1 with brine, dried over Na2SO4, filtered and evaporated to afford a pale pink powder which was triturated with ethyl acetate to give compound I(C) as pale pink solids (6.8 g, 28 mmol) in 57% yield. HPLC/LCMS purity was greater than 90%. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.20 (s, 2H), 4.48 (s, 2H), 4.45 (s, 2H), 4.17-4.08 (m, 2H), 1.24 (t, 3H). LCMS (M+H)+: 243.2, 245.2.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:16][C:17]([OH:21])([CH3:20])[C:18]#[CH:19].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Pd].[Cu]I.C(N(CC)CC)C>[OH:21][C:17]([CH3:20])([CH3:16])[C:18]#[C:19][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCN(CC)CCOc1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
To 142 g (0.45 mole) of 1-(4'-iodophenoxy)-2-diethylaminoethane, 1.2 liters of triethylamine and 37.8 g (0.45 mole) of 3-methyl-1-butin-3-ol are added, under nitrogen, 3.4 g of the palladium complex PdCl2 [P(C6H5)3 ]2 and 1.9 g of copper(I) iodide. After the exothermic reaction has subsided, the reaction mixture is stirred for 15 hours at room temperature, then filtered, and the solution is evaporated in vacuo to dryness. The oily residue crystallises immediately. The product is dried in vacuo at 40° C., affording 123 g (99%) of 1-(3-hydroxy-3-methyl-1-butyn-1-yl)-4-(2-diethylaminoethoxy)benzene with a melting point of 64° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]#[C:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]>C1COCC1.N1C=CC=CC=1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([O:3][C:4](=[O:11])/[CH:5]=[CH:6]\[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C#CCC(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C\CC(C)C
Yield: 56.5 %

Procedure:
5-Methyl-hex-2-ynoic acid ethyl ester 7 (20.97 g) in THF (540 mL), pyridine (60 mL), and 5% Pd/BaSO4 (1.10 g) was hydrogenated in 3.25 hours. The solvent was evaporated, and the light oil was chromatographed on a silica gel coulmn. After recovering some unreacted acetylene, the olefin was eluted with 5% ether in pet ether to give pure fractions of (Z)-5-methyl-hex-2-enoic acid ethyl ester 8 (12.0 g).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28](=[O:40])[CH2:29][N:30]1[C:35](=[O:36])[C:34](Cl)=[N:33][C:32]([Cl:38])=[C:31]1[CH3:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][CH2:17][NH:18][C:34]1[C:35](=[O:36])[N:30]([CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:40])[C:31]([CH3:39])=[C:32]([Cl:38])[N:33]=1)[CH3:8])=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CN(Cc1cccc(CCN)c1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 74.8 %

Procedure:
tert-Butyl-N-[3-(2-aminoethyl)benzyl]-N-methylcarbamate (preparation 15) (0.5 g, 1.89 mmol), benzyl-2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (0.6 g, 1.83 mmol) and triethylamine (0.5 ml, 3.66 mmol) in ethyl acetate (30 ml) were stirred at reflux for 24 hr. The resultant mixture was diluted with ethyl acetate (20 ml) and washed with water, sat aq brine, dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a red oil which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 99:1 CH2Cl2:MeOH; 98:2 CH2Cl2:MeOH) to give the desired product (0.76 g, 75%). 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.20 (s, 3H), 2.80 (s, br, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 4.20 (s, br, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=555.3 (M+1)+. Found C, 62.50, H, 6.34, N, 9.98%; C29H35N4O5Cl requires C, 62.75, H, 6.36, N, 10.09%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.O1CCCC1.CO.[Li+].[OH-]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[N:17][N:16]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1nnnc1C(C(=O)O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a chilled (0° C.) solution of ethyl 3,3-bis(4- fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenoate (0.95 g, 2.39 mmoles) in 20 mL of 1:1 (v/v) mixture of tetrahydrofuran and methanol was added an aqueous solution of LiOH (4.0 mL, 3 Molar) in one single portion. The reaction mixture was stirred at 0° C. for 15 minutes followed by warming up to ambient temperature. Saponification was allowed to proceed at room temperature for four hours forming a very pale clear solution. The crude reaction mixture was diluted with 12 mL of 2M H2SO4 and the product was extracted into diethyl ether (40 mL×2). The organic layers were combined, dried over MgSO4, concentrated under reduced pressure and then vigorously dried under high vacuum (0.01 mmHg) at room temperature for 24 hours to yield the title compound. The propenoic acid was then utilized in the next step without further purification.
Reaction SMILES: C(O[K])(C)(C)C.[S:7]1[C:14]2[C:13]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8]1.[CH:21]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22]1.[OH-].[Na+]>C1COCC1>[CH:21]1([S:24]([N:11]2[CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[C:14]3[S:7][CH:8]=[CH:9][C:10]2=3)(=[O:26])=[O:25])[CH2:23][CH2:22]1
Reactant: CCOC(=O)Cc1c[nH]c2ccsc12
Reactant: O=S(=O)(Cl)C1CC1
Agent: CC(C)(C)O[K]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(S(=O)(=O)C2CC2)c2ccsc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 3.11 %

Procedure:
A solution of tBuOK (0.1 mL, 1.2 equiv, 1.0 M in THF) was added to a solution of ethyl 2-(4H-thieno[3,2-b]pyrrol-6-yl)acetate (0.024 g, 0.11 mmol, 1.0 equiv.) in THF (0.5 mL) in a 20 mL vial. This vial was capped and shaken at room temperature for 10 min. To the mixture a solution of cyclopropanesulfonyl chloride (0.7 mL, 1.2 equiv, 0.2 M in THF) was added and the reaction was shaken at room temperature for 4 h. After which time NaOH (aqueous) (1.0 mL, 1.0 M, 9.5 equiv) was added and the reaction was shaken at room temperature overnight. The crude reaction mixture was then concentrated to dryness under reduced pressure and taken up in 1.5 mL 1:1 DMSO/MeOH and purified by reverse phase HPLC (Table 1, Method h) to give the title compound (0.001 g, 3.11%): LC/MS (Table 1, Method e) Rt=1.29 min; MS m/z 285.9 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28].ClCCl>CN(C=O)C>[O:5]=[C:4]1[CH2:3][CH2:2][C:1](=[O:6])[N:24]1[C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:10][C:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])([CH3:29])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOCc1nc2c(N3C(=O)CCC3=O)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)O
Reaction time: 48 h
Yield: 99.8 %

Procedure:
Succinic anhydride (3.20 g, 32.0 mmol) was added to a 100° C. solution of 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in U.S. Patent Publication No. 2004/0091491, 2.00 g, 6.39 mmol) in DMF (20 mL). After 2 days, the reaction mixture was concentrated under reduced pressure to give an off-white solid. The solid was stirred with 100 mL of dichloromethane and was isolated by filtration. The filtrate was concentrated, stirred with dichloromethane (25 mL), and filtered to yield additional solid. The combined solids were dried under vacuum to give 3.16 g of 4-({2-[4-(2,5-dioxopyrrolidin-1-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoic acid as a white solid that was used without further purification.