Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1(C)C=CC=CC=1>[CH:10]1([N:9]([C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:8]([O:16][N:17]2[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]2([CH3:24])[CH3:23])=[N:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N(C(=NC1CCCCC1)ON1C(C)(C)CC(OC(C)=O)CC1(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.46 ml, 10.5 mmol) and stearoyl chloride (3.2 g, 10.5 mmol). The mixture is stirred at room temperature for 30 minutes and then additional triethylamine (1.46 ml, 10.5 mmol) and stearoyl chloride (3.2 g, 10.5 mmol) is added. The suspension is stirred at room temperature for 18 hours, then evaporated and chromatographed over silica gel with hexane-ethyl acetate (9:1) to afford 4.03 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[CH:12](=O)[CH:13]([CH3:15])[CH3:14]>CCOCC>[CH3:12][CH:13]([CH3:15])[CH:14]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)C=NC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.9 %

Procedure:
To a stirred solution of t-butylamine (20.0 mL, 190 mmol) in anhydrous ether (200 mL) was added magnesium sulfate (20 g). A solution of isobutyraldehyde (17.3 mL, 190 mmol) in ether (50 mL) was then added dropwise over 30 minutes. After stirring at ambient temperature for 3 days, the reaction was filtered and the ether removed in vacuo (300 mm). The residual liquid was distilled to afford the title compound (14.0 g, 58%) as a colorless liquid; bp 52° C. (75 mm);
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[Si:12]([O:19][CH2:20][C:21]1[C:30]2[C:25](=[C:26]([CH3:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([O:32][CH2:33][O:34][CH3:35])=[C:23](C=O)[CH:22]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[Si:12]([O:19][CH2:20][C:21]1[C:30]2[C:25](=[C:26]([CH3:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([O:32][CH2:33][O:34][CH3:35])=[C:23]([O:9][CH3:8])[CH:22]=1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1c(C=O)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Solvent: ClCCl
Product: COCOc1c(OC)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Yield: 72.6 %

Procedure:
10.8 g of 80 to 85% m-chloroperbenzoic acid was added to a dichloromethane (130 ml) solution of 10 g of 1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methyl-3-naphthalenecarbaldehyde and heated for 1 hour under reflux. The reaction solution was washed with a sodium thiosulfate aqueous solution, after which it was further washed with water, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation. 9.3 g of the resultant brown oily substance and 2.1 g of sodium hydride were suspended in 21 ml of methanol and 21 ml of water and refluxed for 15 minutes. After cooling, the suspension was rendered acidic by means of dilute hydrochloric acid, followed by extraction with ethyl acetate. After washing with a saturated saline solution, the extract was dried with anhydrous magnesium sulfate, from which the solvent was distilled off. 5 ml of methyl iodide was added to an N,N-dimethylformamide (100 ml) solution of 8.5 g of the resultant brown oily substance and 22.1 g of potassium carbonate, followed by reaction at 60° to 70° C. for 1 hour. The insoluble matters were removed by filtration and the resultant filtrate was diluted with ether. After washing with water, the diluted filtrate was washed with a saturated saline solution and dried with magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 7.3 g of the captioned compound as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([O:25]C)=[O:24])=[CH:22][C:12]=2[N:11]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([OH:25])=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Yield: 93.5 %

Procedure:
The title compound was prepared following the procedure described for Step-2 of Intermediate-3 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (1.0 g, 2.47 mmol), Aq. NaOH (2.0 g, 50.0 mmol) and methanol (2.0 mL) to afford 0.9 g of desired product. 1HNMR (DMSO-d6): δ 1.46 (s, 6H), 3.34 (s, 2H), 3.53 (s, 3H), 6.99 (m, 1H), 7.06 (s, 1H), 7.18 (m, 1H), 7.27 (m, 1H), 10.36 (bs, 1H), 12.08 (bs, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][C:24](=O)[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO.C(O)(=O)C>[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][CH:24]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[O:8])[CH2:3][CH2:2]3)[CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(C1CCNCC1)N1CCOCC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCOCC1
Temperature: 120 °C
Yield: 83.2 %

Procedure:
4-(Piperidin-4-ylcarbonyl)morpholine (0.30 g, 1.26 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.30 g, 1.5 mmol) were dissolved in a mixture of methanol (5 mL) and acetic acid (0.1 mL). (Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.38 g) was added and the reaction mixture was heated for 10 min at 120° C. using microwave single node heating. The mixture was filtered through a phase separator and the resin washed with methanol. The solvent was removed by evaporation and the residue was dissolved in methylene chloride. The solution washed twice with a saturated solution of NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol/methylene chloride, 5% methanol). There was obtained 0.44 g (83%) of 4-({1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl}carbonyl)morpholine as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.9 (m, 4H), 2.2 (m, 1H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 4H), 3.3-3.5 (m, 3H), 3.5-3.7 (m, 6H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 420 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:29][CH2:28][C:27]([O:26][CH3:25])=[O:30])=[O:19])=[C:5]2[OH:23]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.810 g, 2.41 mmol), glycine methyl ester hydrochloride (0.39 g, 3.11 mmol, 1.3 eq.), 1,4-dioxane (7.0 mL) and DIPEA (1.3 mL, 7.46 mmol) was heated at 80° C. for 6 hours. The mixture was then cooled to room temperature and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with 2N HCl and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give a pale yellow solid. The product was recrystallized from EtOAc to give a colorless solid (0.68 g). MS m/e=380.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C@@H:3]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:4][C:5]([OH:7])=O.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:5](=[O:7])[CH2:4][C@@H:3]([CH3:2])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)=CCC[C@H](C)CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)=CCC[C@H](C)CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46.9 %

Procedure:
Proceeding as in Example 1, but substituting (S)-3,7-dimethyloct-6-enoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 248, (S)—N—((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-3,7-dimethyloct-6-enamide (3 mg, 46.9%). MS (EI) for C32H37FN2O4. found 533.7 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2=[C:6]([CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=3)[C:7]3[C:12]([N:4]2[CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:26][OH:27]>CO>[OH:27][NH:26][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]3[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]=23)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(Cc2c3n(c4ccccc24)CN(C)CC3)cc1
Reactant: NO
Solvent: CO
Product: CN1CCc2c(Cc3ccc(C(=O)NO)cc3)c3ccccc3n2C1

Procedure:
A solution of methyl 4-((2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)methyl)benzoate (0.07 g) and 1 mL of 50% aqueous solution of NH2OH in 3 mL of MeOH was stirred at r.t. for 12 h, and the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography eluted with up to 10% MeOH/CH2Cl2 to give 0.02 g of the title product as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[CH3:10][N:11]1[C:15]([C:16](O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[CH:12]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][N:11]1[C:15]([C:16]2[S:9][C:3]3[N:4]=[CH:5][N:6]=[C:7]([SH:8])[C:2]=3[N:1]=2)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[CH:12]1
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)O
Reactant: Nc1c(S)ncnc1S
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cnc(-c2ccccc2)c1-c1nc2c(S)ncnc2s1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
5-Aminopyrimidin-4,6-dithiol (Intermediate 41) (1.26 g) and 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (Intermediate 3) (1.6 g) were dissolved/ suspended in pyridine (30 mL) and heated at 55° C. under an inert atmosphere. POCl3 (1.55 mL) was added dropwise over 5 minutes, after 2 hours the reaction mixture was concentrated in vacuo and 2M NaOH (15 mL) added cautiously. After stirring for 15 minutes, concentrated HCl was added to acidify to pH 5, the precipitated solid was filtered, washed with water (40 mL), diethyl ether (50 mL) then dried under high vacuum to give the title compound as a yellow solid (1.83 g, 71%);
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=O)[CH2:14][CH2:13]1)=[O:11]>C(Cl)Cl>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][CH2:14]1)#[N:5]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Chlorosulfonyl isocyanate (1.0 mL, 0.012 mol) was added to a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 0.0107 mol) in DCM cooled to 0° C. The resulting solution was heated at reflux for 15 minutes and then cooled 0° C. and treated dropwise with DM. The mixture was stirred at room temperature overnight then poured onto ice water and the organic phase separated and washed with a saturated solution of sodium bicarbonate. The solvent was removed in vacuo and the crude material was taken up in ethyl acetate, washed with 1N aq. NaOH (10 mL) and the ethyl acetate removed in vacuo. The resulting crude product was used in subsequent steps without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.70 (4H, m), 2.01-2.18 (4H, m), 2.24-2.54 (2H, m) and 3.68 (3H, s).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:5]1.CN1CCOCC1.[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](Cl)=[O:47]>C(Cl)Cl>[ClH:43].[CH3:2][N:3]([CH:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:23][CH2:24][CH3:25])[CH2:18][CH2:17]2)[CH2:5]1)[C:46]([C:45]1[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=1[Cl:43])=[O:47]
Reactant: CCCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(NC)CC2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C)C(=O)c3ccccc3Cl)CC2c2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-(RS)-(methylamino)-3-(SR)-((4-(N-(benzyloxycarbonyl)-N-(propyl)amino)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane hydrochloride from Step A (5.5 mg, 0.012 mmol) in methylene chloride (1 mL) was added N-methyl morpholine (0.005 mL, 0.035 mmol) and 2-chlorobenzoyl chloride (4 mg, 0.024 mmol). After 16 h, the reaction was concentrated and the residue purified on Prep TLC to afford the free amine of the title compound. This was taken up in ether and excess 1N hydrogen chloride in ether was added. The volatiles were removed under a stream of nitrogen and evaporated to dryness under vacuum.
Reaction SMILES: C([NH:4][C:5]([NH2:7])=[NH:6])(=O)C.Br[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:11]([C:10]1[NH:6][C:5]([NH2:7])=[N:4][CH:9]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: CC(=O)NC(=N)N
Solvent: CN(C)C=O
Product: Nc1ncc(CCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of 1-acetylguanidine (1.34 g, 13.2 mmol) in dimethylformamide (7 ml) a solution of 1-bromo-4-phenyl-butan-2-one (1.5 g, 6.6 mmol) in dimethylformamide (7 ml) was added at 0° C. The mixture was stirred overnight at room temperature and then the solvent was evaporated. Upon addition of ethyl acetate/heptane (1:1) a white solid was formed that was filtered off and washed with ethyl acetate/heptane (1:1). After drying in vacuo the solid was dissolved in a mixture of concentrated hydrochloric acid (2 ml) and methanol (4 ml) and stirred for 2.5 hours at 85° C. The solvent was evaporated and the residue was purified by chromatography (column: Isolute Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=1:1) to yield a light yellow solid (0.063 mg, 5%); MS (EI): 187.2 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[CH2:4][CH2:3]1.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[C:4](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:3]1
Reactant: COc1ccc2c(c1)C(=O)CCC2(C)C
Reactant: CCOC(OCC)N(C)C
Product: COc1ccc2c(c1)C(=O)C(=CN(C)C)CC2(C)C

Procedure:
The 3,4-dihydro-4,4-dimethyl-2-dimethylaminomethylene-7-methoxy-1 (2H) naphthalenone was prepared from 4,4-dimethyl-7-methoxy-1-tetralone [2.3 g; H. Hart et al J. Chem. Soc. 85, 3260, (1963)] and N,N-dimethylformamide diethylacetal (6 ml) in a method analogous to that used in Example 1, to give the desired product as a yellow solid (2.26 g) m.p. 108-110°. MS (ES+) 260 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][OH:12])=[O:10])#[N:2].C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>O1CCCC1>[C:32]([O:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: N#CC(CCCCCC(=O)NO)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)ONC(=O)CCCCCC(C#N)(c1ccccc1)c1ccccc1
Yield: 89.5 %

Procedure:
To a solution of 7-cyano-7,7-diphenylheptanohydroxamic acid (4.0 g, 12.4 mmol) and triethylamine (2.5 g, 25 mmol) in tetrahydrofuran (80 ml) was added, while stirring under ice-cooling, propionyl chloride (1.15 g, 12.4 mmol). The mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, which was washed with 0.5N HCl and a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate--hexane to give 4.2 g of the titled compound.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([C:1]1[CH:7]=[C:8]([NH2:9])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:18]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccc(F)cc2)n1

Procedure:
The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2002, 45, 2994-3008.): 4.17 g (32.3 mMol) of pivaloylacetonitrile are added to a solution of 4.20 g (32.3 mMol) 4-fluoro-phenylhydrazine in 150 ml of toluene at rt, and the resulting yellow solution is heated to and kept under reflux for 12 h. After completion, the reaction mixture is concentrated, and the resulting crude product is purified by flash chromatography (SiO2, 100% CH2Cl2) to give the title compound as a yellow solid: 1HNMR (CDCl3) δ ppm 7.59 (d, 2H), 7.10 (d, 2H), 5.58 (s, 1H), 3.62 (brs, H2N), 1.32 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:14])[CH2:10][CH2:11][CH:12]=[O:13].[CH3:15][Mg]I.Cl>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:10][CH2:11][CH:12]([OH:13])[CH3:15])[CH3:14]
Reactant: C=C(CCC=O)c1ccc(Cl)cc1Cl
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Product: CC(O)CCC(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 315.8 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)pent-4-enal (26.0 g) in dry diethyl ether was added dropwise to a stirred solution of methylmagnesium iodide [from magnesium (4.09 g) and methyl iodide (24.14 g)] in diethyl ether (total volume of diethyl ether ca. 200 ml). Following the addition, the reaction mixture was stirred at room temperature for 1 hour then poured into a mixture of ice and dilute hydrochloric acid, and extracted with ether. The extracts were washed with water, dried over magnesium sulphate, concentrated under reduced pressure, and chromatographed on a column of silica gel (eluting with dichloromethane: 60°-80° petrol, 1:1) to give 2-(2,4-dichlorophenyl)hexan-5-ol (19.2 g, 69%) as an almost colourless oil.
Reaction SMILES: CC([O-])(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:25][O:26][N:27]=[C:28]([C:33]1[NH:34][CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH3:32])=[O:30].[CH3:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>CCOCC>[CH3:25][O:26][N:27]=[C:28]([C:33]1[N:34]([CH2:38][C:39]2[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=2[CH3:41])[CH:35]=[CH:36][CH:37]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: CON=C(C(=O)OC)c1ccc[nH]1
Reactant: Cc1ccccc1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CON=C(C(=O)OC)c1cccn1Cc1ccccc1C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
4 g (35.7 mmol) of potassium tert-butylate are added to a solution of 730 mg (2.7 mmol) of 18-crown-6 in 50 ml of ether, after which a solution of 5 g (27.5 mmol) of the pyrrole from Example 18 in 50 ml of ether are added dropwise and stirring is carried out for 30 minutes at room temperature. Thereafter, a solution of 6.6 g (37.5 mmol) of o-methylbenzyl bromide in 25 ml of ether is added and stirring is carried out overnight at room temperature. The mixture is poured onto water and extracted with ether, and the organic phase is dried and evaporated down. Chromatography over silica gel using hexane/ethyl acetate gives 4.1 g (52%) of the product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15](O)C>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH3:15])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Reactant: CCO
Agent: [Pd]
Product: CCOC(=O)CC(C)c1ccc(F)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of ethyl 4-fluorocinnamate (47.5 g, 0.228 mol) and 10% palladium on carbon (0.85 g, Aldrich) in 95% ethanol was shaken in a Parr hydrogenator under 2-3 atm of H2 pressure for 1 h. The mixture was filtered and concentrated by spin evaporation in vacuo. Fractional distillation gave 46.5 g (97%) of ethyl 3-(4-fluorophenyl)butyrate as a clear oil, b.p., 122-128° C.: c) Preparation of 3-(4-Fluorophenyl)butanoic Acid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].ClCCl.Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2c(-c3cc(OCCN(CC)CC)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: -140 °C

Procedure:
Cesium carbonate was added to a solution of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in DMF, 2-Bromo-N,N-diethylethylamine hydrobromide was added and the suspension heated, at −140° C., for ˜2 hrs. The resulting suspension was allowed to cool and dichloromethane added. The mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a dark brown gum. The crude product was purified by chromatography on silica eluting with mixtures of dichloromethane and methanol.