Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[N:19]=2)=[C:9]1[CH3:41])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:39][C:37]([F:38])([F:40])[C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:42])=[O:5])[C:9]=2[CH3:41])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:28])=[O:29]
Reactant: Cc1c(C2=NN(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=NN(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)O

Procedure:
{3-[2-(3-Trifluoromethyl-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid tert-butyl ester (61 Amok) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.18 (d, 1H), 7.95 (t, 1H), 7.86 (t, 1H), 7.70 (m, 4H), 7.48 (d, 1H), 7.37 (dd, 1H), 6.89 (dt, 1H), 6.52 (dd, 1H), 5.18 (bs, 2H), 4.48 (s, 2H), 2.07 (s, 3H) ppm. MS calculated for C26H19F4N3O4S—H: 544, observed: 544.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[C:10](=[O:17])[CH2:9][N+:8]([O-])=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:6]=2[CH:26]=1>CO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[C:10](=[O:17])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:6]=2[CH:26]=1
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO
Agent: [Ni]
Solvent: CO
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO

Procedure:
400 mg of 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide are dissolved in 20 ml of methanol, treated with 200 mg of Raney nickel paste and shaken under hydrogen. After uptake of the calculated amount of hydrogen, the mixture is filtered off from catalyst and the clear filtrate concentrated. By chromatography on silica gel with ethyl acetate/methanol (9:1) there is isolated from the residue 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 117°-118°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])[CH:10]=1)[N:7]([CH3:24])[CH:6]=[C:5]2[CH:25]([CH3:27])[CH3:26].Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(Cl)Cl.O>[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]4[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=4[CH3:21])=[O:12])[CH:10]=2)[N:7]([CH3:24])[CH:6]=[C:5]3[CH:25]([CH3:26])[CH3:27])=[CH:35][CH:34]=1)[CH3:31]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
In a glass pressure tube was added 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxamide (225 mg, 0.523 mmol), 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (200 mg, 0.672 mmol), potassium phosphate (340 mg, 1.602 mmol), dioxane (12 mL) and water (3 mL). The reaction was stirred and purged with N2 then PdCl2 (dppf)-CH2Cl2 adduct (40 mg, 0.049 mmol) was added. The reaction was capped and stirred at 110° C. for 4 h LCMS indicated that the reaction was complete. The dark black reaction was transferred to a round bottom flask and evaporated to dryness. The crude material was purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 70% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). A short DASi column was used and the compound loaded as a suspension in CH2Cl2. The pure fractions were combined and evaporated to dryness to give the product as a very dark brown-black solid. The solid was taken up in CH2Cl2 and treated with Silicycle Si-Thiol derivatized silica gel (2 g, 1.46 mMol/g, cat. no. R51030B). After swirling for ˜30 minutes the mixture was filtered through a pad of Celite, washed with CH2Cl2, and evaporated to dryness. The now light yellow colored solid was dissolved in a small amount of CH2Cl2, triturated with hexanes, filtered and dried under vacuum to give 5-{4-[(dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxamide (95 mg, 0.196 mmol, 37.5% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.50 (t, J=4.93 Hz, 1H), 7.83 (d, J=1.52 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.33 (d, J=1.52 Hz, 1H), 7.10 (s, 1H), 5.87 (s, 1H), 4.36 (d, J=5.05 Hz, 2H), 3.69 (s, 3H), 3.34 (br. s., 3H), 3.22 (dt, J=6.73, 13.58 Hz, 1H), 2.26 (br. s., 6H), 2.24 (s, 2H), 2.11 (s, 3H), 1.31 (d, J=6.82 Hz, 6H). MS (ES)+m/e 485.3 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([CH3:21])[C:7]=1[C:8]([NH2:10])=[O:9])(=[O:5])=[O:4])[CH3:2].[OH-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:10][C:8](=[O:9])[C:7]2[C:11]([CH3:21])=[CH:12][C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:14][C:6]=2[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:27][CH:26]=1
Reactant: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C(N)=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 115 %

Procedure:
To a solution 2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzamide (0.27 g, 0.88 mmol) in benzene-tetrahydrofuran (1:1) (10 ml) are added tetrabutylammonium hydrogensulfate (0.03 g, 0.09 mmol) and 15% sodium hydroxide solution (8 ml) at RT. 4-Chlorobenzyl bromide (0.083 g, 0.40 mmol) in tetrahydrofuran (1.5 ml) is added and the reaction mixture is slowly heated to 70° C. The reaction mixture is stirred at 70° C. for additional 25 min. After completion of the reaction (monitored by TLC), the organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 15% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzamide (example 8) (0.20 g, 0.46 mmol, 74%). [M+H]+ 437.1.
Reaction SMILES: [ClH:1].C(OC([NH:9][C:10](=[O:17])[C@@H:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][NH:12]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:16][C@H:15]1[CH2:14][CH2:13][NH:12][C@@H:11]1[C:10]([NH2:9])=[O:17]
Reactant: C[C@H]1CCN[C@@H]1C(=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CCN[C@@H]1C(N)=O

Procedure:
A solution of hydrogen chloride in dioxan (7.5 N, 5 ml) was added to a solution of N-t-butoxycarbonyl-trans-3-methyl-L-prolineamide (0.65 g) in 10 ml dioxan. After 2 hours the crystalline solid was filtered and recrystallised from ethanol/ether to give the product (0.47 g), m.p. 235°-237° [α]D20 -14.8° (c, 1.0, water).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:14]2[S:15][CH:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[N:18]=2)[N:3]=1.ClC1N=C(O[CH:36]2[CH2:53][CH:52]3[N:38]([C:39](=[O:59])[N:40]([CH3:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:46][CH:47]4[C:49]([C:55]([OH:57])=[O:56])([NH:50][C:51]3=[O:54])[CH2:48]4)[CH2:37]2)C2C(C=1)=CC(OC)=CC=2>>[CH:19]([C:17]1[N:18]=[C:14]([C:4]2[N:3]=[C:2]([O:1][CH:36]3[CH2:53][CH:52]4[N:38]([C:39](=[O:59])[N:40]([CH3:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:46][CH:47]5[C:49]([C:55]([OH:57])=[O:56])([NH:50][C:51]4=[O:54])[CH2:48]5)[CH2:37]3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[S:15][CH:16]=1)([CH3:21])[CH3:20]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(O)nc(-c3nc(C(C)C)cs3)cc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3nc(C(C)C)cs3)cc2c1

Procedure:
The title product 69 was prepared from 1-hydroxy-3-(4-isopropylthiazol-2-yl)-6-methoxyisoquinoline (6) following the same procedures described for the preparation of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42, Example 10): m/z=634 (M+H)+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][C:10]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[C:11]=4[CH2:12]3)[C:7]=2[CH:23]=1>N1C=CC=CC=1>[C:3]([O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][C:10]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][C:17](=[O:20])[CH3:16])[C:11]=4[CH2:12]3)[C:7]=2[CH:23]=1)(=[O:2])[CH3:23]
Reactant: COc1cc2c(cc1O)C1Cc3ccc(OC)c(O)c3CN1CC2
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC(C)=O)C1Cc3ccc(OC)c(OC(C)=O)c3CN1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.1 %

Procedure:
A product obtained in Example 2 (0.1 g, 0.27 ml) was dissolved in pyridine (10 ml), adding acetyl anhydride (0.5 ml). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and added water. Then the aqueous phase was adjust to pH 8 with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give pale desired product (0.073 g, 64.6%). mp 212˜214° C. 1HNMR (CDCl3) δ: 2.33 (3H, s, COCH3), 2.34 (3H, s, COCH3), 2.63˜2.75 (3H, m, CH2), 3.13˜3.20 (3H, m, CH2), 3.41˜3.56 (2H, m, CH2 and N—CH), 3.81 (3H, s, Ar—OCH3), 3.82 (3H, s, Ar—OCH3), 4.02 (1H, d, CH2), 6.70 (1H, s, ArH), 6.83 (1H, d, ArH), 6.92 (1H, s, ArH), 7.00 (1H, s, ArH).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[OH-:19].[K+].CO>>[OH:15][C:16]1[C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:18])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:19])=[O:17]
Reactant: Cc1ccccc1Sc1cccc2c1OC(=O)C2
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1Sc1cccc(CC(=O)O)c1O

Procedure:
Thus obtained 7-(o-tolylthio)-2,3-dihydrobenzofuran-2-one was hydrolyzed by treating with potassium hydroxide-methanol to give 2-[2-hydroxy-3-(o-tolylthio)phenyl]acetic acid, mp. 96°-97° C.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=1)=O.C(OP([CH2:56][C:57]#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-:42])=[O:41])[CH:35]=2)=[CH:56][C:57]#[N:58])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2cccc([N+](=O)[O-])c2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3′-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-3′nitrobenzophenone (1.44 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3 M) with a reaction time of 24 hours at room temperature. The crude product was purified by flash chromatography (silica gel, 3% hexane/methylene chloride) to afford 1.12 g (72%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120° C.; 1H NMR (CDCl3) δ 8.40-8.17 (m, 4 H), 7.90-7.55 (m, 4 H), 7.08-6.89 (m, 6 H), 5.84 (s, 1 H), 5.71 (s, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H); 13CNMR (CDCl3) δ 160.2, 160.1, 151.7, 151.1, 149.2, 148.3, 148.2, 141.0, 138.8, 135.4, 134.4, 129.9, 129.7, 129.7, 128.1, 124.8, 124.6, 124.4, 123.3, 123.1, 122.3, 117.4, 117.3, 112.3, 111.0, 110.4, 95.7, 94.8, 56.0, 55.9; Anal. Calcd for C17H14N2O4. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.57; H, 4.64; N, 8.92.
Reaction SMILES: [F-:1].[Cs+].Cl[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8].O>S1(CCCC1)(=O)=O>[F:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: [F-]
Agent: [Cs+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: N#Cc1ccnc(F)c1
Temperature: 100 °C
Yield: 89345.7 %

Procedure:
Cesium fluoride (30 g, 0.22 mmol) was slurried in dry sulfolane (150 mL) and concentrated via vacuum distillation at 0.5 mm Hg. After removal of 20% of the solvent, the suspension was cooled and 2-chloroisonicotinonitrile (15 g, 0.11 mmol) was added, then stirred and heated at 100° C. for 20 h. It was cooled to 25° C., poured into H2O (200 mL) and extracted with Et2O. The Et2O phase was washed with H2O, then brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over SiO2 with CH2Cl2 to give 2-fluoroisonicotinonitrile (12.0 g) as a low-melting colorless solid: EIMS m/z: 122 ([M]+); 1H NMR (CDCl3): δ 8.45 (dd, 1H), 7.47 (dd, 1H), 7.24 (m, 1H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14].[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14]
Reactant: CC(c1nc2ccccn2c(=O)c1Br)N1C(=O)c2ccccc2C1=O
Reactant: CSc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CSc1ccccc1-c1c(C(C)N2C(=O)c3ccccc3C2=O)nc2ccccn2c1=O
Temperature: 85 °C
Reaction time: 25.5 h

Procedure:
A mixture of 2-(1-(3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.9836 g, 2.470 mmol), 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) in DME (12.35 mL) was stirred at 85° C. After 25.5 h, to the mixture were added 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) and the mixture was stirred at 85° C. After 4 days 21 h, the mixture was cooled to rt. The insoluble solid was filtered off and the solid was washed with DCM (50 mL). The filtrate was cond under reduced pressure. The residue was dissolved in DCM (50 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and cond under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 20 min as eluent to give 2-(1-(3-(2-(methylthio)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (1 H, ddd, J=7.2, 1.6, 0.8 Hz), 7.98-8.05 (1 H, m), 7.77-7.84 (2 H, m), 7.68-7.75 (3 H, m), 7.43 (1 H, td, J=6.9, 1.5 Hz), 7.31 (1 H, dd, J=8.1, 0.9 Hz), 7.18-7.24 (1 H, m), 6.79-6.85 (1 H, m), 6.70-6.76 (1 H, m), 5.36-5.44 (1 H, m), 2.41 (3 H, s), 1.64 (3 H, d, J=7.2 Hz); Mass Spectrum (ESI) m/e=442.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: N
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 380 mg, 47%). mp 208-210° C. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 2H), 7.27 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H) 7.51 (d, J=9 Hz, 4H), 7.6 (t, 1H), 7.7 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.94 (dd, 1H), 8.25 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F2Cl2N3O3S.0.5 H2O: C, 55.76; H, 2.98; N, 8.87. Found: C, 56.05; H, 3.42; N, 8.65.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][CH:13]1[CH2:17][CH:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][CH:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[CH:24]1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][CH:13]1[CH2:17][CH:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][CH:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[C:24]1[Br:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC1CC(OC(C)=O)C(n2cnc3cc(Cl)c(Cl)cc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(OC(C)=O)C(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Temperature: 70 °C

Procedure:
N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of (±)-(1R*, 2R*, 4S*)-4-(acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclopentyl acetate (8.95 g, 23.2 mmol) in dry N,N-dimethylformamide (46 mL). The solution was maintained at ca. 70° C. (oil bath) for 5 hours. Volatiles were removed in vacuo and the residual orange syrup chromatographed on silica gel. Title compound was eluted with chloroform as a pale yellow solid (5.14 g, 48%), m.p. 122°-125° C.; 1H-NMR (DMSO-d6)δ: 8.16 (s, 1, benzimidazole H7), 7.95 (s, 1, benzimidazole H4), 5.60-5.55 (m, 1, OCH), 5.12-5.03 (m, 1, NCH), 4.15 (d, J=6.3 Hz, 2, OCH2), 2.66-2.60 (m, 1, CHCH2), 2.29-2.14 (m, 3, CH), 2.06 (s, 3, CH3CO), 1.93 (s overlapped by m, 4, CH3CO+CH); mass spectrum (CI): 469 (5.8), 467 (37.5), 465 (95), 463 (54, M+1), 199 (100, M-B).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[CH2:29]([O:32][C:33](=[O:38])[CH2:34][C:35]([CH3:37])=O)[CH2:30][CH3:31]>C(O)(=O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9]2[C:8]3[C:7](=[CH:24][C:23]([O:25][CH3:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[N:6]=[C:35]([CH3:37])[C:34]=2[C:33]([O:32][CH2:29][CH2:30][CH3:31])=[O:38])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 79 %

Procedure:
Conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, propylacetoacetate and acetic acid. The mixture was treated according to the same manner as in Reference Example 1 to give propyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline-3-carboxylate (79%). This compound was recrystallized from ethyl acetateisopropyl ether. Colorless prisms, mp. 153°-155° C.
Reaction SMILES: [F:1][C:2]1[C:3]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.FC(F)(F)C(O)=[O:22].OO>C(O)(=O)C>[F:1][C:2]1[C:3]([S:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:22])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1cc(C(F)(F)F)cnc1Sc1ccccc1
Agent: OO
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ncc(C(F)(F)F)cc1F
Temperature: 22 °C

Procedure:
20 g (0.0693 mol) of 95% pure 3-fluoro-2-phenylthio-5-trifluoromethylpyridine were introduced into 100 ml of glacial acetic acid and 20 ml of trifluoroacetic acid and over a period of 5 min, with stirring at 22° C., 5.64 g (0.083 mol) of 50% strength hydrogen peroxide were added. The reaction mixture was stirred at 22° C. for 10 h and then poured into 1 l of ice-water and extracted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate solution and water. After drying, filtration through silica gel and concentration under reduced pressure, 19.1 g (95.4% of theory) of the title compound of 24 n D
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[OH-].[Na+].[CH:11]1([CH2:14]Cl)[CH2:13][CH2:12]1.[I-].[K+]>C(O)(C)C.O>[CH:11]1([CH2:14][O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:13][CH2:12]1
Reactant: ClCC1CC1
Reactant: Oc1ccccc1O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Oc1ccccc1OCC1CC1
Temperature: 25 °C

Procedure:
Catechol (110 g) is dissolved in 800 ml isopropanol. A solution of sodium hydroxide (41 g) in 45 ml water is added followed by cyclopropylmethyl chloride (155 g, 70% pure) and potassium iodide (5 g). The reaction mixture is stirred under nitrogen at reflux for 16 hours. The mixture is cooled to room temperature and the solid filtered off and washed with isopropanol. The filtrate is concentrated under reduced pressure, the brown residue dissolved in toluene (600 ml), 3 N hydrochloric acid added to acidify to pH 1 and the organic phase washed consecutively with water (4×100 ml), aqueous sodium bisulfite and water (3×100 ml). The organic layer is dried over anhydrous sodium sulfate, filtered through basic alumina (300 g) to remove any remaining catechol and concentrated under reduced pressure. The residue is distilled in vacuo through a Vigreaux column with reflux distilling head to give 2-(cyclopropylmethoxy)phenol, bp. 66°-68°/0.1 mm.