Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:54][C@@H:55]2[O:57][CH2:56]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:54][C@@H:55]3[O:57][CH2:56]3)=[CH:35][CH:36]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OC[C@H]3CO3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-hydroxyphenyl)methyl]-5-isopropyl-1H-pyrazole (0.55 g), (R)-1-(3-nitrobenzenesulfonyloxy)-2,3-epoxypropane (0.38 g) and cesium carbonate (0.57 g) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(R)-2,3-epoxypropoxy]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.4 g). This material (43 mg) was dissolved in ethanol (1.5 mL). To the solution was added 2-amino-2-methyl-1,3-propanediol (51 mg), and the mixture was stirred at 75° C. for 14 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol 90/10-10/90) to give the title compound (12 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11](Cl)(Cl)=[O:12].C1(C)C=CC=CC=1>C1COCC1>[CH:7]1[C:3]2[CH2:4][CH2:5][O:6][C:11](=[O:12])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1CCO
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2CCO1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of 2-aminophenethyl alcohol (4.0 g, 29.16 mmol) in THF (200 mL) was added a solution of 2M phosgene in toluene (17 mL, 34 mmol) at room temperature. The reaction was stirred for 15 minutes, concentrated, and purified with flash chromatography using ethyl acetate (5% 20%) in hexanes to yield 8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (4 g, 84%): 1H NMR (300 MHz, CDCl3) δ 8.02 (bs, 1H), 7.17 (dt, 1H), 7.09 (d, 1H), 6.99 (dt, 1H), 6.90 (d, 1H), 4.51 (t, 2H), 3.21 (t, 2H).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:23]1([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1

Procedure:
A solution of 11 (0.315 g, 0.62 mmol), acetic acid (30 μL, 0.63 mmol) and tetrabutylammonium fluoride (1M in THF, 0.65 mL, 0.65 mmol) in 3 mL THF was stirred for 10 minutes under nitrogen. The solvent was removed in vacuo and the residue flash chromatographed with dichloromethane followed by 19:1 chloroform/methanol to give 0.164 g (98%) of the anomers. The anomers were separated by centrifugal chromatography with 19:1 chloroform/methanol: yield of β-anomer 10 mg; mp. 125°-128 C; [α]D25 +2.5° (c=0.1CH3OH); FAB MS 271 (M+H)+ ; 1H NMR (CDCl3) δ 9.0 (s, 1, H-2), 8.8 (s, 1, H-8), 6.3 (m, 1, 5'-OH), 3.8 (m, 1, 5'-H), 3.65 (m, 2, 4'-H, 5'-H), 2.6 (m, 1, 2'-H), 2.45 (m, 1, 2'-H), 2.2 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].[F-].[K+]>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>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(=Cc2ccc(Br)cc2)CC(C)C)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(=Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)CC(C)C)cc1
Yield: 32.6 %

Procedure:
3-{4-[1-(4-bromo-benzylidene)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (2.6 g, 5.86 mmol), 4-t-butyl phenyl boronic acid (2.08 g, 12 mmol), potassium fluoride (1.02 g, 17.6 mmol) and tetrakis(triphenylphosphine)palladium (0.677 g, 0.59 mmol) are placed in a flask. The system is purged with nitrogen. Toluene (40 mL) and water (10 ml) are added and the resulting mixture is refluxed overnight. The reaction is loaded directly onto silica gel and chromatographed using EtOAc/hexanes to yield the titled compound as a yellow oil (0.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2cc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nn2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.495 mmol) and 4-methoxyphenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (180.1 mg, 94.7%). Melting point: 146.7-148.2° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24]#[CH:25]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[N:26]1([CH2:23][C:24]#[C:25][C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Reactant: C#CCN1CCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A 100 mL Schlenk flask was charge with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (4.0 g, 12.6 mmol), tetrakis(triphenylphosphine) palladium(0) (1.5 g, 1.3 mmol, 10 mol %), cuprous iodide (0.48 g, 2.5 mmol, 20 mol %), triethylamine 50 mL and 1-(prop-2-ynyl)pyrrolidine (2.8 g, 25.2 mmol). The flask was flushed with nitrogen three times and the mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as a yellow solid (2.2 g, 44.9%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[SH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([S:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCSc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (2.60 g, 0.014 mole) and methyl 3-mercaptopropionate (1.92 g, 0.016 mole) in DMF (10 mL) was added anhydrous K2CO3 (2.07 g, 0.016 mole). After stirring at ambient temperature for 16 hr, the reaction was quenched with ice water. The precipitated product was collected by suction filtration, washed well with water, and dried in vacuo to give a bright yellow solid (3.65 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[O:24][C:23]([C:25]([OH:29])([C:27]#[CH:28])[CH3:26])=[N:22][N:21]=1>>[OH:29][C:25]([C:23]1[O:24][C:20]([CH3:19])=[N:21][N:22]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC(C)(O)c1nnc(C)o1
Product: Cc1nnc(C(C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)o1
Yield: 10 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-methyl-1,3,4-oxadiazol-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (14 mg, 10%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[OH-:9].[Ba+2].[OH-]>O>[CH3:1][NH:2][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:9]
Reactant: CN1CCCCC1=O
Reactant: [OH-]
Agent: [Ba+2]
Solvent: O
Product: CNCCCCC(=O)O
Temperature: 110 °C
Yield: 83.4 %

Procedure:
1-methyl-2-piperidone (5 ml, 44.1 mmol) was combined with barium hydroxide (3.8 g, 26.95 mmol) and water (55 ml). The suspension was warmed to 110° C. for 6 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 5-(methylamino)pentanoic acid as a white solid (2.95 g). 5-(Methylamino)pentanoic acid (2 g, 15.3 mmol), and potassium carbonate (13 g, 94 mmol) were suspended in water (30 ml) and dioxane (10 ml) then cooled to 0° C. Methyl chloroformate (5 ml, 65 mmol) was added over 30 seconds, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)(methyl)amino]pentanoic acid as a thick clear oil (2.56 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: [Li]CCCC
Reactant: Cc1cc2cccnc2[nH]1
Solvent: CI
Solvent: CCOCC
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by f-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54]=[O:55].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 70 °C
Reaction time: 21 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 3j (2.4 g, 3.23 mmol) was dissolved in 20 mL 1,4-dioxane, followed by addition of 5 mL 37% formaldehyde solution and 13 mL 1 M sodium hydroxide. The reaction mixture was stirred for 21 hours at 70° C. Thereafter, the reaction mixture was extracted with ethyl acetate (50 mL×3) after 20 mL of saturated sodium chloride solution were added. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 3k (1.6 g, yellow grease), yield: 64.0%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][O-:11].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][C:10](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Yield: 193.4 %

Procedure:
acetophenone (30.0 grams; 0.25 mol); sodium methoxide (17.3 grames; 0.3 mol) and xylene 28.,0 grams) were added to the resulting mixture (347.0 grams) from the azetropic distillation. The reaction procedure set forth hereinabove was repeated with this reaction mixture giving dibenzoylmethane (54.2 grams; 92% yield) 92% pure by GLC analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Cn1cc(N)cn1
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Temperature: 125 °C
Yield: 17.9 %

Procedure:
A mixture of 0.405 g (4.27 mmol) of 4-amino-1-methylpyrazole and 0.695 g (1.90 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (5 mL) was heated at 125° C. for 15 min. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration, washed with water, and dried. Chromatography on alumina, eluting with hexanes/EtOAc (1:1) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.145 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 225-226° C.; 1H NMR (DMSO-d6) (rotamers) δ 10.00 (s, 1H), 9.73 (s, 0.2H), 8.60 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 0.2H), 7.92 (t, JHF=52.8 Hz, 1H), 7.86-7.80 (m, 2.6H), 7.68 (t, JHF=52.6 Hz, 0.2H), 7.59 (s, 1H), 7.52-7.42 (m, 2.9H), 3.85-3.82 (m, 8.4H), 3.75-3.73 (m, 4.8H); Anal. Calcd. for C19H19F2N9O 0.06EtOAc 0.24H2O: C, 52.9; H, 4.6; N, 28.8. Found: C, 52.9; H, 4.5; N, 28.6%.
Reaction SMILES: [CH2:1]1[O:17][C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.S(Cl)(Cl)=O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:6][CH2:5]2)[O:17][CH2:1]1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2ccncc2)CCC2(C1)OCCO2
Temperature: 0 °C
Yield: 86.6 %

Procedure:
In 40 ml of pyridine was dissolved 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone ethyleneacetal and, 8 ml of thionyl chloride was added to the solution at -10° C. Then, after stirring at 0° C., the reaction solution was poured onto ice. After an excess of a sodium hydroxide aqueous solution was added to the mixture, it was extracted with methylene chloride and the extract was purified to give 4 g of 4-(4-pyridyl)cyclohex-3-enone ethyleneacetal.
Reaction SMILES: [C:1]1(=[O:13])[NH:9][C:8](=[O:10])[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[Br-].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:30][CH2:29][N+:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:9]2[C:8](=[O:10])[CH:7]3[C:4]([CH3:6])([CH3:5])[C:2]([CH3:3])([CH2:12][CH2:11]3)[C:1]2=[O:13])[CH2:29][CH2:30]1
Reactant: c1ccc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: CC12CCC(C(=O)NC1=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC12CCC(C(=O)N(CCCCN3CCN(c4ccccn4)CC3)C1=O)C2(C)C

Procedure:
A mixture of 4.07 g (0.0225 mol) of DL-camphorimide (II), 6.71 g (0.0225 mol) of 8-(2-pyridyl)-8-aza-5-azoniaspiro[4,5]-decane bromide (III) and 3.73 g (0.027 mol) of potassium carbonate was refluxed in 80 ml of absolute dimethylformamide for 24 hours, then the resulting mixture was cooled, filtered, and dimethylformamide was distilled off under reduced pressure. The residue was dissolved in 100 ml of 5% HCl, the resulting solution was extracted twice with 50 ml of ether to remove impurities of non-basic nature, and saturated with soda. The precipitated base was extracted with ethyl acetate, the extract was dried with potassium carbonate and purified by passing through a column packed with a neutral aluminum oxide 5 cm thick (with ethyl acetate as eluent). After the solvent was distilled off, there was obtained a free base in the form of an oil which was then crystallized. Mp. 96°-97° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:47][C:48]1[C:49]([CH3:55])=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:51][C:50]4[CH:52]=[CH:53][CH:54]=[C:48]([Cl:47])[C:49]=4[CH3:55])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(N)cccc1Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccc(Cl)c2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-chloro-2-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 788 [(M+H)+].
Reaction SMILES: [CH2:1]1[O:4][C@@H:2]1[CH3:3].[Cl:5][C:6]1[CH:15]=[C:14]([SH:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>>[Cl:5][C:6]1[CH:15]=[C:14]([S:16][CH2:1][C@H:2]([OH:4])[CH3:3])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[C@@H]1CO1
Reactant: COC(=O)c1ccc(S)cc1Cl
Product: COC(=O)c1ccc(SC[C@@H](C)O)cc1Cl

Procedure:
140 mg of (R)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of (R)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 403 mg of (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 298 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.1 (M)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[CH2:10](I)[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:10]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:9])[CH:11]([CH3:13])[CH3:12]
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-Methyluracil (3.0 mg, 23.8 mmol), isobutyl iodide (7 mL, 60 mmol) and cesium carbonate (11.6 g, 35.7 mmol) in DMF (30 mL) is stirred at room temperature over a weekend. Solvent is removed under vacuum. The residue is treated with water, and then extracted with dichloromethane four times. The combined organic phase is washed with brine, dried over anhydrous sodium sulfate, and then filtered through a short silica gel column. The filtrate is concentrated to dryness to give product as off white solids, which is used for the next reaction without further purification. MS (ESI) m/z 183.1 [M+H]+.