Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]1([CH2:17][Cl:18])[CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C(O)C>[ClH:18].[ClH:18].[CH:14]1([CH2:17][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: ClCC1CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cl
Product: Fc1ccc(N2CCN(CC3CC3)CC2)cc1
Yield: 139.1 %

Procedure:
To 50 ml of ethanol, are added 3.6 g (0.02 mole) of 1-(4-fluorophenyl)piperazine, 2.0 g (0.022 mole) of cyclopropylmethyl chloride, and 1.9 g (0.023 mole) of sodium bicarbonate. The mixture is kept refluxing for 7 hours while being stirred. After having been cooled, the reaction mixture is freed from inorganic matters by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in diethyl ether and gaseous hydrogen chloride is introduced into the solution, while being cooled, to precipitate crystals which are collected by filtration. Upon recrystallization from ethanol there are obtained 4.7 g (77% yield) of 1-(cyclopropylmethyl)-4-(4-fluorophenyl)piperazine dihydrochloride melting at 153°-154° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[S-:16])#[N:2].[Na+].[OH2:18].[CH3:19][C:20]#[N:21]>>[O:9]=[C:6]1[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]([S:16][CH2:19][C:20](=[O:18])[N:21]2[CH2:7][CH2:8][CH2:3][CH2:1]2)=[C:3]([C:1]#[N:2])[CH:8]=[CH:7]1
Reactant: CC#N
Reactant: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Reactant: O
Agent: [Na+]
Product: N#Cc1ccc(=O)n(-c2ccccc2)c1SCC(=O)N1CCCC1

Procedure:
A mixture of Example 1 (0.5 g) and Intermediate 2 (0.35 g) in MeCN (10 mL) was heated at reflux for 1.5 h. H2O (2.5 mL) was added and the resulting mixture was concentrated in vacuo. The resulting solid precipitate was recovered by filtration and dried under vacuum to give 6-oxo-2-[2-oxo-2-(pyrrolidin-1-yl)ethylsulfanyl]-1-phenyl-1,6-dihydropyridine-3-carbonitrile (0.56 g). δH (DMSO-d6) 7.998 (1H, d, J 9.5 Hz), 7.75 (3H, m), 7.55 (2H, m), 6.85 (1H, d, J 9.5 Hz), 3.86 (2H, s), 3.62-3.37 (4H, m), 2.15-1.90 (4H, m). A mixture of this material (0.38 g) and K2CO3 (0.31 g) in EtOH (7.5 mL) was heated at reflux for 2.5 h. H2O (10 mL) was added and the mixture was concentrated under vacuum. The resulting solid product was filtered, washed with water and dried in vacuo to give the title compound as an off-white solid (0.37 g). δH (DMSO-d6) 8.12 (1H, d, J 9.4 Hz), 7.66-7.50 (3H, m), 7.44 (2H, m), 7.25 (2H, br s), 6.50 (1H, d, J 9.4 Hz), 3.36 (4H, m), 1.75 (4H, m). LCMS (ES+) RT 2.84 minutes, 340 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][NH2:45].CN1CCOCC1.[Cl:54][C:55]1[C:56]([C:72]#[N:73])=[C:57]([CH:69]=[CH:70][CH:71]=1)[O:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=1>CN(C=O)C>[C:1]([NH:11][C@H:12]([C:17]([CH:42]([NH2:41])[C:43](=[O:46])[CH2:44][NH:45][S:65]([C:62]1[CH:61]=[CH:60][C:59]([O:58][C:57]2[CH:69]=[CH:70][CH:71]=[C:55]([Cl:54])[C:56]=2[C:72]#[N:73])=[CH:64][CH:63]=1)(=[O:66])=[O:67])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)CN
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)C(N)C(=O)CNS(=O)(=O)c1ccc(Oc2cccc(Cl)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.7 %

Procedure:
Cbz-leucine (660 mg, 2.5 mmol), EDCI (480 mg, 2.5 mmol), HOBT (340 mg, 2.5 mmol) was dissolved in DMF (10 ml) with 1,3-diamino-propan-2-ol (225 mg, 2.5 mmol) and was stirred at RT overnight. N-methyl morpholine (0.41 ml, 3.75 mmol) was added followed by 4-(3-Chloro-2-cyano-phenoxy)-phenyl sulfonyl chloride (820 mg, 2.5 mmol, Maybridge) was added and the reaction was stirred 3h at RT. The reaction was partitioned between water and EtOAc and the combined organics were dried with magnesium sulfate, then concentrated in vacuo. The crude 1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido-propan-2-ol was then dissolved in acetone (5.0 ml) and Jones reagent (3.0 ml, 1.5 M) was added dropwise, and the reaction was stirred overnight at RT. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2×20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/methylene chloride), then the product was triturated from methylene chloride to give the title compound as a white solid (26 mg, 2%). MS(ES) M+H+=627.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]=[CH2:14])[O:8][C@:7]([C:19]#[C:20][CH:21]3[CH2:23][CH2:22]3)([C:15]([F:18])([F:17])[F:16])[C:6]=2[CH:24]=1.[N+](=[CH2:27])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@H:9]([CH:13]3[CH2:27][CH2:14]3)[O:8][C@:7]([C:19]#[C:20][CH:21]3[CH2:23][CH2:22]3)([C:15]([F:16])([F:17])[F:18])[C:6]=2[CH:24]=1
Reactant: C=[N+]=[N-]
Reactant: C=C[C@@H]1O[C@](C#CC2CC2)(C(F)(F)F)c2cc(Cl)ccc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a solution of 71 mg of rel-(3S,5S)-7-chloro-5-(2-cyclopropylethynyl)-1,5-dihydro-3-ethenyl-5-(trifluoromethyl)-4,1-benzoxazepin-2(3H)-one (from Example 41) in 7.5 mL of anhydrous ether was added first 4 mg of palladium (II) acetate and then a solution of approximately 1.23 mmol of diazomethane in 3.5 mL of ether. After stirring 30 min at room temperature, the reaction mixture was filtered through a pad of filter-aid and the filtrate was evaporated to dryness. The crude product was purified by column chromatography over silica gel (elution with methylene chloride) to give 65 mg of the title compound as a pure solid was recrystallized from ether-hexanes to afford 36 mg: mp 192-192.50; HRMS: Calcd. for C18H14NO2F3Cl (M-H)- : 368.0665. Found: 368.0657.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:9][CH2:8]1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:47]2[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=2)[CH2:50][Cl:51])[CH:40]=[C:41]([O:45][CH3:46])[C:42]=1[O:43][CH3:44]>>[ClH:51].[ClH:51].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[CH:15]=3)[CH2:11][CH2:12]2)[CH2:50][C:49]2[CH:52]=[CH:53][CH:54]=[C:47]([C:39]3[CH:40]=[C:41]([O:45][CH3:46])[C:42]([O:43][CH3:44])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH:48]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3cccc(SC)c3)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:19].[OH-].[Na+].Cl>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])[C:9]=2[CH:10]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 99.7 %

Procedure:
To 60.0 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole were added 240 g of a 10% sodium hydroxide aqueous solution and 200 ml of ethanol, and the mixture was heat-refluxed for 2 hours. The reaction solution was cooled, and was then adjusted to a pH of 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and were dried to give 54.7 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[CH:19]=[N:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:24])[C:13]=2[C:12]([OH:25])=[CH:11][CH:10]=1.[Cl:26][C:27]1[C:40]2[C:39](=[O:41])[C:38]3[CH:37]=[N:36][CH:35]=[CH:34][C:33]=3[C:32](=[O:42])[C:31]=2[C:30]([OH:43])=[CH:29][CH:28]=1.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(Cl)Cl.O>[F:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[CH:19]=[N:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:24])[C:13]=2[C:12]([O:25][S:50]([C:47]2[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=2)(=[O:52])=[O:51])=[CH:11][CH:10]=1.[Cl:26][C:27]1[C:40]2[C:39](=[O:41])[C:38]3[CH:37]=[N:36][CH:35]=[CH:34][C:33]=3[C:32](=[O:42])[C:31]=2[C:30]([O:43][S:50]([C:47]2[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=2)(=[O:52])=[O:51])=[CH:29][CH:28]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccncc2C(=O)c2c(Cl)ccc(O)c21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Reaction time: 1 h

Procedure:
Triethylamine (8.20 mL) is added to a stirred suspension of the 9/1 mixture of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione and 9-chloro-6-hydroxybenzo [g]isoquinoline-5,10-dione respectively of Preparative Example 14b (5.53 g) and p-toluenesulfonylchloride (8.47 mL) in methylene chloride (166 mL). The reddish-violet solution obtained is left at room temperature under a nitrogen atmosphere for 1 hour and then it is poured into water (500 mL). The organic phase is separated and the aqueous solution is further extracted with methylene chloride (100 mL). The combined organic solutions are dried (Na2SO4) and concentrated to dryness. The obtained solid is suspended in n-hexane (100 mL) for 1 hour and filtered to give a 9:1 mixture (1H-NMR evaluation) of 9-fluoro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo[g]iso quinoline-5,10-dione respectively (8.85 g).
Reaction SMILES: F.[Si]([O:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH2:35])[C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][Si](C(C)(C)C)(C)C)=[C:20]([F:32])[CH:19]=3)=[N:15][C:14]=2[CH:33]=1)(C(C)(C)C)(C)C.C1COCC1.C(#N)C>O>[F:32][C:20]1[CH:19]=[C:18]([C:16]2[O:17][C:13]3[C:12]([CH:34]=[CH2:35])=[CH:11][C:10]([OH:9])=[CH:33][C:14]=3[N:15]=2)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: C=Cc1cc(O[Si](C)(C)C(C)(C)C)cc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Agent: F
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Hydrofluoric acid (48 wt. % in water, 1 mL) was added into a solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-7-vinyl-1,3-benzoxazole (1.5 g, 3.0 mmol), THF (6 mL) and acetonitrile (3 mL). The reaction mixture was stirred at 65° C. for 8 h, and then poured into water. The precipitated solid was filtered off and dried. Crystallization of the product from acetone/ethyl ether gave a white solid (0.72 g, 81% yield, m.p. 249-251° C.); MS m/e 272 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].[H][H]>C(OCC)(=O)C.O.[Pd]>[NH2:13][C:4]1[C:5]([OH:12])=[C:6]([CH:11]=[CH:2][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(N)c1O
Yield: 58.4 %

Procedure:
A suspension of methyl 5-bromo-2-hydroxy-3-nitrobenzoate (38.4 g, 0.14 mol), sodium acetate (19.63 g, 0.24 mol) and 10% Pd/C (3.84 g) in ethyl acetate (500 mL) and water (30 mL) was stirred at 25° C. under 1 atm of hydrogen for 16 hr. The mixture was filtered and the filtrate was washed with water (500 mL×2), brine (300 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was washed with methanol at 0° C. to give methyl 3-amino-2-hydroxybenzoate (13.67 g, yield 59%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.88-3.94 (s, br, 2H), 3.91 (s, 3H), 6.70-6.74 (t, J=7.8 Hz, 1H), 6.88-6.90 (m, 1H), 7.24-7.26 (m, 1H), 10.91 (s, 1H); LC-MS (ESI) m/z 168 [M+1]−.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(NC1C(C([O-])=O)=CC=C(F)N=1)(=O)C(C)(C)C>C1COCC1.O>[F:1][C:2]1[C:3]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[N:7]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Agent: CC(C)(C)C(=O)Nc1nc(F)ccc1C(=O)[O-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-fluoro-2-pivaloylaminopyridine (2 g) in THF (30 ml) was cooled to -78° C. and BuLi (15 mL of 1.6M in hexane) was added and the reaction stirred at 0° C. for 2 h. On re-cooling to -78° C., ethyl chloroformate (2 mL) was added and the reaction allowed to warm slowly to room temperature over 1 h. Water (10 ml) was added and the products extracted into Et2O (3×50 ml) and dried (Na2 SO4). Concentration afforded an oil which was triturated with petrol to give a solid, the isomeric 2-pivaloylamino-6-fluoropyridine-3-carboxylate (1H NMR [CDCl3 ] δ1.36 (s, 9H), 1.43 (t, 3H), 4.41 (q, 2H), 6.64 (dd, 1H), 8.45 (t, 1H), 11.34 (brs, 1H). The mother liquors were concentrated and purified by flash column chromatography (SiO2, Petrol to 5% Et2O/petrol to give ethyl 2-fluoro-6-pivaloylaminopyridine-3-carboxylate (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:7]2.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN([CH:66]=[O:67])C.[CH3:68][OH:69]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:68]([O:67][CH3:66])=[O:69])=[C:6]2[C:11]=1[O:10][CH2:9][C@H:8]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: CO
Reactant: CCCN(CCC)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCN(CCC)[C@H]1COc2c(F)ccc(C(=O)OC)c2C1
Temperature: 70 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
(R)-8-Fluoro-3-(N,N-di-n-propylamino)-5-trifloromethanesulfonyloxychroman (0.95 g, 2.4 mmol), triethylamine (0.53 g, 5.2 mmol), 1,3-bis(diphenylphosphino)propane (100 mg, catalytic amount), palladium(II)acetate (50 mg, catalytic amount) and DMF/MeOH (18 mL, 6:2) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated three times). The reaction mixture was stirred at 70° C. for 7 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/2M NH3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a brown oily residue which was purified by flash chromatography (SiO2, CH2Cl2 /EtOAC, 20:1) to give 650 mg of the title compound as a clear oil (87% yield). [α]D21 -92° (c 10 mg/mL MeOH). Mass spectrum (70 eV) m/Z (relative intensity) 309 (20, M+), 281(18), 280(100), 56(10), 43(22), 42(12), 41(16).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.CO>CN(C)C=O>[CH:25]1([CH2:24][N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26]1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in dimethylformamide (40 mL) was added 60% sodium hydride (596 mg) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hr. Then, (bromomethyl)cyclopropane (1.085 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and crystallized from methanol/ethyl acetate to give the title compound (2.12 g) as white prisms.
Reaction SMILES: [C:1]([C:3]1[N:8]([NH:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[C:7](=[O:19])[NH:6][C:5](=[O:20])[CH:4]=1)#[N:2].[CH2:21]([S:23]Cl)[CH3:22]>[OH-].[Na+].C(Cl)Cl>[C:1]([C:3]1[NH:8][C:7](=[O:19])[N:6]([S:23][CH2:21][CH3:22])[C:5](=[O:20])[C:4]=1[NH:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])#[N:2].[C:1]([C:3]1[N:8]([N:9]([S:23][CH2:21][CH3:22])[C:10]2[C:11]([Cl:18])=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[C:7](=[O:19])[NH:6][C:5](=[O:20])[CH:4]=1)#[N:2]
Reactant: CCSCl
Reactant: N#Cc1cc(=O)[nH]c(=O)n1Nc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCSN(c1c(Cl)cc(Cl)cc1Cl)n1c(C#N)cc(=O)[nH]c1=O
Product: CCSn1c(=O)[nH]c(C#N)c(Nc2c(Cl)cc(Cl)cc2Cl)c1=O

Procedure:
In the same manner as above, 6-cyano-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione in aqueous sodium hydroxide is reacted with ethylsulfenyl chloride in methylene chloride, followed by chromatography yields the compounds 6-cyano-3-ethylthio-(2,4,6-trichloroanilino)-2,4-pyrimidinedione and 6-cyano-1-(N-ethylthio-2,4,6-trichloroanilino)-2,4-pyrimidinedione.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].ClCCl.[F:10][C:11]1[CH:12]=[C:13]([C@H:19]2[NH:24][C@H:23]([CH:25]([OH:27])[CH3:26])[CH2:22][O:21][CH2:20]2)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].N1C=CC=CC=1>O>[CH3:26][CH:25]1[C@H:23]2[CH2:22][O:21][CH2:20][C@@H:19]([C:13]3[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=3)[N:24]2[C:2](=[O:3])[C:1](=[O:5])[O:27]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(O)[C@@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1cc(F)c(F)c(F)c1
Reaction time: 1 h

Procedure:
Under ice-cooling, oxalyl chloride (0.27 mL) was added dropwise into a dichloromethane (5 mL) solution containing 1-[(3S,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]ethanol (269 mg) and pyridine (5 mL). Stirring was continued for 30 minutes at the same temperature and for 1 hour at room temperature. Water was added, and the organic layer was partitioned, and the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the resultant was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (136 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:31])[C:5]([N:7]([CH3:30])[C@@H:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]2[C:16](=[O:29])[C:17]([O:24]S(C)(=O)=O)=[C:18]([C:20](OC)=[O:21])[N:19]=[C:9]12)=[O:6])[CH3:3].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][C:34]=1[F:41]>CS(C)=O>[F:41][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:33]=1[CH3:32])[CH2:37][NH:38][C:20]([C:18]1[N:19]=[C:9]2[C@H:8]([N:7]([CH3:30])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:31])[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[N:10]2[C:16](=[O:29])[C:17]=1[OH:24])=[O:21]
Reactant: COC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)[C@H](C)CCC[C@H]2N(C)C(=O)C(=O)N(C)C
Reactant: Cc1ccc(CN)cc1F
Solvent: CS(C)=O
Product: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)[C@H](C)CCC[C@H]3N(C)C(=O)C(=O)N(C)C)cc1F
Temperature: 100 °C

Procedure:
The trans-rac-methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-6-methyl-3-[(methylsulfonyl)oxy]-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate from Step 10 (50 mg) was dissolved in DMSO (2 mL) and 4-methyl-3-fluorobenzylamine (0.1 mL) added. The resulting mixture was heated at 100° C. for 30 minutes. As determined by LC-MS, there was complete conversion to product which was purified by reverse phase Gilson chromatography: 1H NMR (400 MHz, CDCl3) δ 9.46 (br s, 1H), 7.05 (m, 3H), 5.96 (m, 1H), 5.56 (br s, 1H), 4.47 (qd, J=6.8, 14.5 Hz, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.94 (s, 3H), 2.21 (s, 3H), 1.61-2.24 (m, 6H), 1.47 (d, J=7.5 Hz, 3H). ES MS M+1=487.8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6](Br)[CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([C:23]3[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=3)[CH:7]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)/C=C/c1cc(Br)cc(Br)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CCOC(=O)/C=C/c1cc(-c2ccc(C(C)(C)C)cc2)cc(-c2ccc(C(C)(C)C)cc2)c1

Procedure:
The colourless glass, (E)-ethyl 3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-acrylate was prepared from (E)-ethyl 3-(3,5-dibromophenyl)-acrylate (example 109a) and 4-tert-butylphenylboronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:46])([CH2:43][CH:44]=[CH2:45])[C:40](O)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:46])([CH3:38])[CH2:43][CH:44]=[CH2:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: C=CCC(C)(C)C(=O)O
Product: C=CCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 19.4 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and mg (3.6 mmol) of 2,2-dimethyl-4-pentenoic acid, to provide 231 mg of the title compound.