Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:23].[H-].[Na+].Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)[N:11]([CH:32]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[C:10]1=[O:23]
Reactant: BrC1C=CCCC1
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ncc2c(n1)N(C1C=CCCC1)C(=O)N(c1c(Cl)cccc1Cl)C2
Yield: 28.6 %

Procedure:
A solution, cooled in ice, of 200 mg (0.54 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 12 ml of dimethylformamide was treated with 22 mg (0.54 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.07 ml (0.6 mmol) of 3-bromocyclohexene and then heated at reflux for 4 hours. The mixture was evaporated and 30 ml of dichloromethane and 30 ml of water were added to the residue. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 70 mg (29%) 3-(2,6-dichlorophenyl)-1-[2-cyclohexen-1(RS)-yl]-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a brown oil. [Mass spectrum (ESI) MH+ =453].
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[S:14](Cl)(=[O:16])=[O:15])=[O:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>N1C=CC=CC=1>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][S:14]([C:9]1[C:10]2[C:5](=[C:4]([NH:3][CH:1]=[O:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:16])=[O:15]
Reactant: Nc1nccs1
Reactant: O=CNc1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: c1ccncc1
Product: O=CNc1cccc2c(S(=O)(=O)Nc3nccs3)cccc12
Yield: 48.4 %

Procedure:
5-Formylamino-naphthalene-1-sulfonyl chloride (0.25 g, 0.93 mmol), 2-aminothiazole (0.09 g, 0.93 mmol) and pyridine (1.00 ml) were stirred under N2 at 25° C. for 19 h. The solution was purified via silica gel chromatography using 3% MeOH/97% CH2Cl2 to obtain 5-formylamino-naphthalene-1-sulfonic acid thiazol-2-ylamide as a white solid (150 mg, 49%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=334.20; tR=1.93 min.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2cccs2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 81.8 %

Procedure:
A mixture of 1.64 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.9 g of 2-tri-n-butylstannyl thiophene and 200 mg of tetrakis(triphenylphosphine)palladium(O) in 200 ml of toluene is refluxed under nitrogen for 16 hours. The reaction mixture is evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 5:1 hexane:ethyl acetate to give 1.2 g of the desired product as a solid. Mass spectrum: M+H:371.
Reaction SMILES: C[C@@H]1O[C@@H](OC(C[C@H](CC(O[C@H](CC([O:36][C@@H:37]2[C@@H:44]([C:45]([OH:47])=[O:46])[N:43]([CH3:48])[C:41](=[O:42])[C@H:40]([C@H:49]([O:65][C@@H:66]3[O:70][C@H:69]([CH2:71][NH2:72])[C@@H:68]([OH:73])[C@H:67]3[OH:74])[C@H:50]3[O:54][C@@H:53]([N:55]4[C:61](=[O:62])[NH:60][C:58](=[O:59])[CH:57]=[CH:56]4)[C@H:52]([OH:63])[C@@H:51]3[OH:64])[N:39]([CH3:75])[CH2:38]2)=O)CCCCCCCCCCCC(C)C)=O)C)=O)[C@H](OC)[C@H](OC)[C@H]1OC.N>CN(C)C=O>[CH3:75][N:39]1[C@@H:40]([C@H:49]([O:65][C@@H:66]2[O:70][C@H:69]([CH2:71][NH2:72])[C@@H:68]([OH:73])[C@H:67]2[OH:74])[C@H:50]2[O:54][C@@H:53]([N:55]3[C:61](=[O:62])[NH:60][C:58](=[O:59])[CH:57]=[CH:56]3)[C@H:52]([OH:63])[C@@H:51]2[OH:64])[C:41](=[O:42])[N:43]([CH3:48])[C@H:44]([C:45]([OH:47])=[O:46])[C@@H:37]([OH:36])[CH2:38]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)C[C@@H](C)CC(=O)O[C@@H](CCCCCCCCCCCC(C)C)CC(=O)O[C@H]2CN(C)[C@@H]([C@H](O[C@@H]3O[C@H](CN)[C@@H](O)[C@H]3O)[C@H]3O[C@@H](n4ccc(=O)[nH]c4=O)[C@H](O)[C@@H]3O)C(=O)N(C)[C@@H]2C(=O)O)[C@@H]1OC
Agent: N
Solvent: CN(C)C=O
Product: CN1C[C@H](O)[C@@H](C(=O)O)N(C)C(=O)[C@@H]1[C@H](O[C@@H]1O[C@H](CN)[C@@H](O)[C@H]1O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 100.4 %

Procedure:
Caprazamycin B (150 mg) was dissolved in N,N-dimethylformamide (1.5 ml), and to the resultant solution was then added 28% aqueous ammonia solution (1.5 ml). The resulting mixture was stirred at room temperature for 4 days to effect the intended hydrolysis. Insolubles formed in the reaction solution were filtered off, and thereafter the reaction solution was concentrated and the resulting residue was washed with acetone and dried. Thus, there was afforded caprazol (74.7 mg) as a colorless solid.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: [Br-]
Reactant: CC(=O)c1csc2ccc(Cl)cc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 261.2 %

Procedure:
Phenyltrimethylammonium tribromide (3.6 g) was added in portions under nitrogen over 30 minutes to a stirred suspension of 3-acetyl-5-chlorobenzo[b]thiophen (2 g) in tetrahydrofuran (25 ml), then the mixture was stirred at ambient temperature for 3 hours and filtered. The filter cake was washed with tetrahydrofuran (10 ml), then the filtrate and washings were combined, and the solvent removed in vacuo to leave 3-(2-bromoacetyl)-5-chlorobenzo[b]thiophen as a grey solid (4.2 g) which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([OH:26])[CH2:25][NH:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:24]3[CH2:25][C:22]([CH3:21])([OH:26])[CH2:23]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC1(O)CNC1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2CC(C)(O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (150 mg, 0.51 mmol) in DCE (10 mL) was added 3-methyl-azetidin-3-ol (65 mg, 0.75 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (215 mg, 1.01 mmol) was added and the resulting mixture stirred for a further 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (83 mg, 45%). LCMS (Method H): RT=2.29 min, [M+H]+ 367.5
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12](O)=[O:13])[CH3:6]>>[CH2:5]([O:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([Cl:3])=[O:13])[CH3:6]
Reactant: CCOc1ccccc1OCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCOc1ccccc1OCC(=O)Cl

Procedure:
1.30 g (11 mmol) of thionyl chloride was added to 1.96 g (10 mmol, 1.0 eq.) of (2-ethoxy-phenoxy)acetic acid. The mixture was heated under reflux for 30 minutes and distilled under reduced pressure to obtain (2-ethoxy-phenoxy)acetyl chloride. 20 ml of THF and 2.78 ml (20 mmol, 2.0 eq.) of triethylamine were added to 2.44 g (10 mmol, 1.0 eq.) of (R)-(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzene sulfonamide and the reaction solution was cooled down to 0° C. The obtained (2-ethoxy-phenoxy)acetyl chloride was added dropwise thereto and the whole mixture was stirred for 1 hour. The formed solids were filtered, and the filtrate was distilled under reduced pressure and extracted with 40 ml of ethyl acetate. Subsequently, the extract was washed with 1 N HCl, a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate and then, filtered. The filtrate was distilled under reduced pressure to obtain 3.80 g (yield: 90%) of 2-(2-ethoxy-phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)-1-methyl-ethyl]-acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][N:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:21][CH:22]=1
Reactant: Cc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)C2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
To a solution of 9a (0.7 g, 2.3 mmol) in CH2Cl2 (15 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was neutralized with aqueous NaOH solution and extracted with CH2Cl2 (2×15 mL). The organic layer was washed with brine, dried and concentrated to give the crude product. The crude product was purified with column chromatography to afforded 10a (0.33 g, 70%). 1H NMR (CDCl3): δ 1.62-1.87 (m, 6H), 2.63 (s, 3H), 2.77 (m, 2H), 3.16-3.22 (m, 2H), 3.33 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 8.12 (dd, J=8.1, 2.4 Hz, 1H), 9.04 (d, J=2.4 Hz, 1H).
Reaction SMILES: Cl.Cl.Cl.[C:4]1([CH:10]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])[N:28]=4)[N:25]=3)[CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:37]1([CH:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])[N:28]=4)[N:25]=3)[CH2:15][CH2:16]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 51.4 %

Procedure:
1.08 g of ethyl 2-[6-[3-[4-(diphenylmethyl)piperazino]propyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate trihydrochloride was dissolved in 8 ml of ethanol; 8.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and ajusted to pH 4.5 by the addition of 1 N hydrochloric acid. The mixture was crystallized by the addition of acetone, washed with water-acetone (2:1) and dried to yield 435 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:24](=[O:25])[N:12]2[C@@H:13]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C:14](=O)[C@H:15]([CH3:16])[C@@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[CH2:26]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([SH:37])[CH2:34][C@H:33]1[CH2:38][OH:39])=[O:31])[CH:27]=[CH2:28]>>[CH2:26]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([S:37][C:14]2[C@H:15]([CH3:16])[C@@H:11]3[C@@H:10]([C@H:8]([O:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH3:9])[C:24](=[O:25])[N:12]3[C:13]=2[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:34][C@H:33]1[CH2:38][OH:39])=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CO
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2[C@@H](C(=O)OCC=C)C(=O)[C@H](C)[C@@H]12
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(S[C@H]3C[C@@H](CO)N(C(=O)OCC=C)C3)[C@H](C)[C@H]12
Yield: 37 %

Procedure:
The same operation as in Reference Example 9 was carried out by using allyl (1R,3R,5S,6S)-6-[(R)-1-allyloxycarbonyloxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate (700 mg, 2 mmol) and (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-mercaptopyrrolidine (the compound obtained in Reference Example 1; 470 mg, 1.8 mmol) to obtain the title compound (410 mg, 37% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>>[Si:21]([O:20][C:19]1[CH:18]=[C:17]([CH:30]=[CH:29][CH:28]=1)[CH2:16][O:14][C:13]1[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccc(O[Si](C)(C)C(C)(C)C)c2)n1
Yield: 52.6 %

Procedure:
Following the method according to Example 3, Steps B and C, 5, 2-(4-methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 5.0 g, 24 mmol), (3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane (7.3 g, 24 mmol) [J. Med. Chem. (1992), 35, 3498] and potassium carbonate (8.3 g, 60 mmol) were combined to provide 3-(3-(tert-butyldimethylsilyloxy)benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (5.4 g, 48% yield) as a clear and colorless oil. 1H NMR (CDCl3) δ 8.61 (bs, 1H), 7.94 (dd, 1H), 7.26 (m, 1H), 7.06 (dd, 1H), 7.00 (m, 1H), 6.84 (m, 2H), 6.79 (dd, 1H), 6.38 (s, 1H), 5.06 (s, 2H), 2.33 (s, 3H), 0.97 (s, 9H), 0.20 (s, 6H). Mass spectrum (apci) m/z=428.2 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([S:33]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(S(=O)(=O)C2CC2)C3)cc1

Procedure:
Compound ec was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with cyclopropylsulfonyl chloride. LC-MS: m/z=+501 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: COc1ccccc1C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3OC)sc2c1
Yield: 96.6 %

Procedure:
By the procedure of Example 5, 5.0 g. (0.0208 mole) of 3-phenyl-6-methoxybenzothiophene were treated with 3.60 g. (0.021 mole) of o-methoxybenzoyl chloride and 2.80 g. (0.021 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane as solvent. The crystalline product, 2-(2-methoxybenzoyl)-3-phenyl-6-methoxybenzothiophene (7.52 g.; 97 percent) was obtained from methanol, m.p. 111°-112° C. The product was sufficiently pure to be employed in the next succeeding step; however, a portion of the product was further purified by recrystallization from methanol with the following analytical result.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14]C)[CH:10]=2)[CH:5]=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[CH:3]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1
Reactant: COC(=O)C1CCN(C(c2ccc3cc(OC)ccc3c2)C(F)(F)F)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CCN(C(c2ccc3cc(O)ccc3c2)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
To a solution of methyl 1-(2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate (500 mg, 1.3 mmol) in DCM (10 mL) was added BBr3 (3 N in DCM, 0.9 mL, 2.6 mmol, 2 eq) at 0° C. Then the reaction mixture was stirred at 0° C. for 5 h. Methanol (5 mL) was added into the mixture. The reaction was stirred at room temperature for another 2 h, and then was poured into the NaHCO3 aqueous solution, extracted with DCM (10 mL*3). The combined organic layers were washed with water (5 mL*3) and concentrated to give the crude product, which was purified by chromatography (Petroleum ether:ethyl acetate=1:1) to give methyl 1-(2,2,2-trifluoro-1-(6-hydroxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate as a yellow solid (230 mg, yield: 47%). ESI-MS (M+1)+: 368.1. 1HNMR (400 MHz, CDCl3) δ: 7.69-7.67 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.09-7.05 (m, 2H), 4.13 (q, J=8.8 Hz, 1H), 3.59 (s, 3H), 2.97-2.90 (m, 2H), 2.39-2.37 (m, 1H), 2.19-2.17 (m, 2H), 1.72-1.59 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[C:11]([C:13](=[C:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:9])[C:14]([NH2:16])=[O:15])#[N:12]
Reactant: CC(=O)Cc1ccccc1
Reactant: N#CCC(N)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(Cc1ccccc1)=C(C#N)C(N)=O

Procedure:
A mixture of (phenyl)acetone (5 g), cyanoacetamide (3.15 g), ammonium acetate (0.29 g) and acetic acid (0.45 mL) was refluxed in toluene (50 mL) using a Dean and Stark head to remove water for 6 h. The mixture was cooled and the crystalline product was filtered off (3 g) and used without further purification.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][C:30]=1F>CN(C=O)C>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:30]2[CH:29]=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][C:25]=2[F:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)n1C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Temperature: 0 °C
Yield: 83.7 %

Procedure:
Ethyl 5-benzoyl-1,4-dimethylpyrrole-2-acetate (5.0 g, 17.5 mmol) [prepared as in Example 1, Step (a)], was dissolved in DMF (50 ml) and the solution was cooled in an ice bath to 0° C. under an argon atmosphere. Sodium hydride, 50%/mineral oil, (1.3 g, 27.1 mmol) was added, and after 5 min 3,4-difluoronitrobenzene (3.36 g, 21.1 mmol) was added to the reaction mixture. After 1 h the reaction mixture was poured into 10% HCl/ice and the product was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and evaporated to dryness. Purification on a Florisil® column (hexane-ethyl acetate, 9:1) gave ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(2-fluoro-4-nitrophenyl)acetate (6.22 g, 84%) as a solid. ##STR19##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][NH2:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:21][CH2:20][CH2:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(C2=NCCN=C2c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
The compound, 1-(4-Fluorophenyl)-2-(pyridin-4-yl)ethanedione, the procedure of which may be found in U.S. Pat. No. 5,656,644, Example 13(b) whose disclosure is incorporated herein by reference in its entirety, (0.2 g, 0.87 mmol), and 1,2-diaminoethane (0.1 g, 1.67 mmol) were dissolved in methylene chloride (1 mL) and stirred under argon at 23° C. for about 12 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluted with 1-3% methanol in methylene chloride. Recrystallization from methylene chloride hexane gave the title compound as an yellow crystalline solid. ES (+) MS m/e=254 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:4]2[N:3]=1.[CH3:24][NH2:25]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([NH:25][CH3:24])[N:5]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:4]2[N:3]=1
Reactant: CN
Reactant: Clc1nc2nc(-c3ccccn3)nn2c(Cl)c1-c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1c(-c2ccccc2)c(Cl)nc2nc(-c3ccccn3)nn12
Temperature: 100 °C
Yield: 26.9 %

Procedure:
1 g (2.9 mmol) 5,7-dichloro-6-phenyl-2-pyridine-2-yl-[1,2,4]triazolo[1,5-a]pyrimidine are given in 8.2 mL DMF (no complete dissolution). After addition of 3.65 mL of a 2M (7.3 mmol) solution of methylamine in THF the reaction mixture is heated in a microwave oven at 100° C. for 20 minutes. From the clear brown solution the DMF is evaporated, the residue is diluted with brine and extracted three times with dichloromethane. The combined organic extracts are dried over Na2SO4 and the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane, methanol). 265 mg (26.9%) of the desired product are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22].[CH2:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1Cl
Reactant: OCc1ccccc1
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1OCc1ccccc1

Procedure:
This compound was prepared analogous to Example 3 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzyl alcohol.