Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:26][CH2:27][CH3:28])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH2:26][CH2:27][CH3:28])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:17]=2)[C:6](=[O:8])[CH:7]=1
Reactant: [H][H]
Reactant: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCc1nc(C)cc(=O)n1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 92 %

Procedure:
A solution of 5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione (5.0 g, 12.46 mmol) obtained from example 1 in 1,4-dioxane (75 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (12.0 g) at 60 psi pressure for 40 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2:1 EtOAc/petroleum ether as eluent) followed by crystallisation (CH2Cl2) to afford the title compound (4.6 g, 92%), mp 144°-146° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCCCCCc1ccccc1)CCc1ccc(C#N)cc1

Procedure:
A solution of 127 mg (0.32 mmol) of ethyl (7E)-6-[2-(4-cyanophenyl)ethyl]-8-(2-hydroxyphenyl)oct-7-enoate in 10 ml of acetonitrile is mixed with 88.42 mg (0.39 mmol) of (5-bromopentyl)benzene and 67.25 mg (0.49 mmol) of potassium carbonate and stirred under reflux for 12 hours. After cooling, the mixture is concentrated. The residue is taken up in ethyl acetate and extracted with water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The resulting residue is purified by preparative HPLC. 128 mg (0.24 mmol, 73.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CN(C)C=O.O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: OCCCCCCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
17 g of 4-phenylphenol (0.1 mol) was dissolved in 120 mL of N,N-dimethylformamide (hereafter abbreviated as DMF), 15.2 g of potassium carbonate powder (0.11 mol) was added with constant stirring, and the mixture was then stirred for one hour while heating at 90° C. Subsequently, 6-chloro-1-hexanol (14.3 g, 0.11 mol) was added dropwise to the mixture, and the reaction was allowed to proceed for 12 hours under constant stirring. Following confirmation by gas chromatography that the peaks derived from the raw materials had disappeared, the reaction mixture was diluted with water, and the precipitated solid was recovered by filtration. The resulting solid was then recrystallized from ethanol, yielding 23 g of 4-(6-hydroxyhexyloxy)phenylbenzene (yield: 85%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:20])[N:4]=1.I([O-])(=O)(=O)=[O:22].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:20][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:3]([CH:2]=[O:22])=[N:4]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)quinoxaline (Prepared in Example 95, 0.8089 g, 2.301 mmol) and sodium metaperiodate (0.9842 g, 4.601 mmol) in DMF (15.34 mL, 2.301 mmol) was heated at 150° C. with stirring. After 5 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with sat'd Na2S2O3 (50 mL×1) and brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 20 min as eluent to give 5-chloro-3-(3-fluorophenyl)quinoxaline-2-carbaldehyde as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (1H, s), 8.31 (1H, dd, J=8.2, 1.2 Hz), 8.25 (1H, dd, J=7.4, 1.2 Hz), 7.99 (1H, dd, J=8.4, 7.6 Hz), 7.56-7.70 (3H, m), 7.38-7.46 (1H, m); LC-MS (ESI) m/z 287.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[NH:17][C:18]3=[O:19])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cc(-c2ccccc2)cs1
Yield: 87.1 %

Procedure:
A solution of 4-phenyl thiophene-2-carboxaldehyde (1 g, 5.3 mmol) and rhodanine (700 mg, 5.3 mmol) in 10 mL of glacial acetic acid was heated with anhydrous sodium acetate (1.22 g, 14.8 mmol) for 2 h. The reaction mixture was then poured into cold water. The precipitate was filtered, washed with water and dried under reduced pressure to get 5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g, yield 87%). MS (ESI) m/z: Calculated for C14H9NOS3: 302.98. found: 302.0 (M−H)−. The crude product was carried through without further purification.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH3:22])=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccccc3OC)sc2Cc2ccccc2)cc1
Yield: 65.6 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and o-methoxybenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 65.6%, mp: 147-148└. 1H-NMR (CDCl3, 400 MHz) δ: 3.84 (3H, s, OCH3), 4.09 (3H, s, OCH3), 4.21 (2H, s, CH2), 6.97 (2H, d, J=8.68 Hz, ArH), 7.05 (1H, d, J=8.12 Hz, ArH), 7.14 (1H, t, J=8.12 Hz, ArH), 7.22˜7.32 (5H, m, ArH), 7.53˜7.56 (3H, m, ArH), 8.28 (1H, dd, J=7.84 Hz, 1.68 Hz, ArH), 11.05 (1H, br, CONH); EI-MS m/e (%): 430.2 (M+, 89), 135.1 (100); HREI-MS Calcd. for C25H22N2O3S: 430.1351. found: 430.1357.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=O)[N:5]=[C:4]2[C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:29])[CH:22]=3)=[N:19][O:20][C:3]=12.[NH:30]1[C:37](=[O:38])[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32]>C(O)(C)C>[Cl:1][C:2]1[C:3]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([F:29])[CH:22]=3)[C:4]=2[N:5]=[C:6]2[C:7]=1[N:8]1[CH2:9][C@@H:10]([CH3:15])[O:11][C@@H:12]([CH3:14])[C@@H:13]1[C:36]1([C:34](=[O:35])[NH:33][C:31](=[O:32])[NH:30][C:37]1=[O:38])[CH2:16]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)nc3c(-c4ccc(C#N)c(F)c4)noc3c2Cl)C[C@H](C)O1
Solvent: CC(C)O
Product: C[C@@H]1CN2c3c(nc4c(-c5ccc(C#N)c(F)c5)noc4c3Cl)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C
Yield: 26 %

Procedure:
To isopropanol (20 ml) was added to 4-(7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-5-formylisoxazolo[4,5-b]pyridin-3-yl)-2-fluorobenzonitrile (Intermediate 416, 0.126 g, 0.30 mmol) and barbituric acid (0.039 g, 0.30 mmol). The mixture was heated to 80° C. for about 2 days. The mixture was concentrated, and the residue was purified by chromatography on silica using 20% acetone in n-hexane. The solids obtained were triturated with methanol gave 41 mg of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:53].CCCCCC>C1COCC1>[Br:53][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methyl-4-hydroxypyrrolidine (910 mg, 2.0 mmol) and Ph3P (628 mg, 2.4 mmol) in THF (20 ml) was added CBr4 (993 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hr. n-Hexane (40 ml) was added thereto. The resulting solid was filtered off, and dried in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (3:2, v/v) as eluent to give cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methylpyrrolidine (1.0 g, quant.) as a pale yellow oil. 1H-NMR (CDCl3) δ1.06 (s, 9H), 1.31 and 1.45 (each s, 9H), 2.63 (m, 2H), 3.49 (m, 1H), 3.89-4.14 (m, 5H), 7.35-7.42 (m, 6H), 7.64-7.66 (,4Hm).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[C:16]([O:18][CH2:19][C:20]([O:22][C@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][N+:28]([O-:32])=[CH:27][C:26]=1[Cl:33])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:33][C:26]1[CH:27]=[N+:28]([O-:32])[CH:29]=[C:30]([Cl:31])[C:25]=1[CH2:24][C@@H:23]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:22][C:20](=[O:21])[CH2:19][O:18][C:16](=[O:17])[C:15]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:14]=1
Reactant: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.296 g, 0.367 mmol) in DCM (20 ml), HCl 4M in dioxane (0.919 ml, 3.67 mmol) was added, and the mixture was stirred at RT for 3 days. Additional HCl 4M in dioxane (1.838 ml, 7.34 mmol) was added over 2 days with stirring at the same temperature. The volatiles was removed under vacuum, and the crude was triturated with MeOH. The precipitate was collected by filtration and washed with Et2O to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonamido)benzoyloxy)-acetoxy)ethyl)pyridine 1-oxide as a white solid (0.215 g, 0.305 mmol, 83% yield, MS/ESI+ 705.25 [MH]+, [αD]=−28.15, c=0.53, DCM).
Reaction SMILES: O1CCOC1C([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(=CC(=O)[C@@H:18]4[O:27][C@@H:19]42)C=C3)CC1)C.CC1(C)CO[CH:33]([CH:36]([C@@H:38]2[C@:55]3([CH3:56])[C@H:41]([C@H:42]4[C@H:52]([CH2:53][CH2:54]3)[C@:50]3([CH3:51])[C:45](=[CH:46][C:47](=[O:58])[C@@H:48]5[O:57][C@@H:49]53)C=C4)[CH2:40][CH2:39]2)C)OC1>>[O:57]1[C:48]2=[C:49]3[C@:50]([CH3:51])([CH2:45][CH2:46][C:47]2=[O:58])[C@@H:52]2[C@H:42]([C@H:41]4[C@:55]([CH3:56])([CH2:54][CH2:53]2)[C@@H:38]([CH2:36][CH3:33])[CH2:39][CH2:40]4)[C@@H:18]2[O:27][C@:19]123
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Yield: 75 %

Procedure:
The procedure of Example 7 was repeated except that 0.295 g (0.769 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one was used in lieu of 0.328 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one to give 0.231 g of 20-(1,3-dioxolan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one (yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].C(N(CC)CC)C.[C:19]([O:23][C:24]([NH:26][NH2:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([O:23][C:24]([NH:26][NH:27][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
11.2 g 4-fluoro-3-methyl-benzoyl chloride was added to 6.1 g triethylamine and 8 g hydrazinecarboxylic acid tert-butyl ester in 150 mL dichlormethane. The reaction was stirred for 1 h at RT and extracted with water. The organic layer was evaporated and the residue was crystallized from diisopropylether to yield 13 g of the desired product. Rt: 1.22 min (method B) (M+H)+: 269
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=[O:20])[N:8]([CH3:21])[C:6]=2[N:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:19])[C:12]=1[C:10]1[C:9](=[O:20])[N:8]([CH3:21])[C:6]2[N:7]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[N:3]=[CH:4][C:5]=2[CH:11]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C

Procedure:
A mixture of 64.2 mg (0.20 mmol) of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (from Example 12) and 1 mL of acetic anhydride was heated to reflux. The resulting solution was maintained at reflux for 20 minutes and concentrated at atmospheric pressure to about 0.25 mL volume. The solution was cooled to 25° C. and diluted with diethyl ether (1 mL). The separated crystals were filtered and washed with diethyl ether to provide N-[6-(2,6-dichlorophenyl)-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]acetamide, wt 44.0 mg; mp 258°-260° C.; MS (CI) 363 (M+ +1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:22]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:30][CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1)(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:22]=[C:14]3[CH2:15][N:16]([CH:19]4[CH2:21][CH2:20]4)[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2CC2)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3CC3)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 88.6 %

Procedure:
Following the procedures as described in Example 113j, reaction of 128c (230 mg, 0.6 mmol) and 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (218 mg, 0.6 mmol) afforded 128d as a yellow solid (331 mg, 89%). LCMS: [M+H]+ 623
Reaction SMILES: C([O:4][C:5]1([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:43][C:20]4[N:21]([CH2:34][C:35]5[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=5[F:42])[CH:22]=[C:23]([C:26](=[O:33])[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:24](=[O:25])[C:19]=4[C:18]=3[CH2:44][N:45]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH3:46])=[CH:13][CH:12]=2)=[O:9])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:47]([N:45]([CH2:44][C:18]1[C:19]2[C:24](=[O:25])[C:23]([C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:22][N:21]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:20]=2[S:43][C:17]=1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]2([OH:4])[CH2:7][CH2:6]2)=[O:9])=[CH:16][CH:15]=1)[CH3:46])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OC1(C(=O)Nc2ccc(-c3sc4c(c3CN(C)Cc3ccccc3)c(=O)c(C(=O)c3ccccc3)cn4Cc3c(F)cccc3F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccccc1)Cc1c(-c2ccc(NC(=O)C3(O)CC3)cc2)sc2c1c(=O)c(C(=O)c1ccccc1)cn2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of the compound obtained in Example 19 (0.24 g, 0.33 mmol) and 5N sodium hydroxide (0.07 ml) in ethanol (8 ml) was stirred at room temperature for 1 hour. After the solvent was distilled of f under reduced pressure, the residue obtained was dissolved in chloroform (30 ml) and the solution was washed with aqueous sodium bicarbonate (saturated, 20 ml) and brine (20 ml). After the organic layer was dried (Na2SO4), the solvent was distilled off under reduced pressure and the residue obtained was recrystallized from chloroform-ether to yield pale yellow powders (0.17 g, 75%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:23](OC)=[N:22][S:21](=[O:26])[N:20]=1>CO>[NH2:18][C:19]1[C:23]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[O:12][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[N:22][S:21](=[O:26])[N:20]=1
Reactant: COC1=NS(=O)N=C1N
Reactant: NCCSCc1ccc(CN2CCCCC2)o1
Solvent: CO
Product: NC1=NS(=O)N=C1NCCSCc1ccc(CN2CCCCC2)o1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 2-[(5-piperidinomethyl-2-furyl)methylthio]ethylamine (4.0 g; 15.7 mmoles) [prepared according to the procedure described in Belgian Pat. No. 857,388 (U.S. Pat. No. 4,128,658)] in 25 ml of methanol was added all at once to a stirred suspension of 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.31 g; 15.7 mmoles) [prepared in Step A] in 25 ml of methanol at ambient temperature. After stirring for 16 hours, the solution was evaporated under reduced pressure and the residue chromatographed by flash chromatography on 100 g of silica gel (230-400 mesh) using methanol-acetonitrile. The appropriate fractions were combined and evaporated to give 3.71 g of product. Recrystallization from 95% aqueous ethanol with charcoal treatment yielded the title compound, mp 161°-163°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1C=CC=CC=1>[Cl:20][CH2:21][C:22]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1NCC=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The dimethyl acetal of 2-(2,6-dimethylanilino)-acetaldehyde (12.2 grams), triethylamine (8.1 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0° C. and chloroacetyl chloride (4.4 ml) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2,6-dimethylanilino)acetaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1N)#[N:2].N([O-])=O.[Na+].[ClH:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1[Cl:25])#[N:2]
Reactant: CCCC12CCC(c3ccc(C#N)c(N)c3)(CC1)CC2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CCCC12CCC(c3ccc(C#N)c(Cl)c3)(CC1)CC2

Procedure:
A diazonium salt solution prepared from 20.1 g of 1-(4-cyano-3-aminophenyl)-4-n-propylbicyclo[2.2.2]octane, 5.2 g of sodium nitrite and 40 ml of 20 per cent hydrochloric acid is added dropwise at 0oto a solution of 9.9 g of Cu(I) chloride in 40 ml of concentrated hydrochloric acid, the mixture is then heated on a boiling water bath until the evolution of gas is complete and is allowed to cool, giving 1-(4-cyano-3-chlorophenyl)-4-n-propylbicyclo[2.2.2]octane by extracting and working up.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[C:14](=[O:19])[S:15]3)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][C@@H:16]([SH:15])[CH2:18][C@H:13]2[C:14]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1S[C@H]2C[C@@H]1N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 7 h

Procedure:
To a solution of (1S,4S)-5-p-nitrobenzyloxycarbonyl -2-thia-5-azabicyclo[2.2.1]heptan-3-one (308 mg) in methylene chloride (2.0 g) was added N-methylpiperazine (105 mg). The mixture was stirred for 7 hours at room temperatures. After the reaction was over, the solvent was distilled to give solid 1-[(2S,4S)-1-p-nitrobenzyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperazine.