Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.1 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (170 mg, 0.38 mmol), 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (100 mg, 0.34 mmol), and 2-aminopyridine (36 mg, 0.38 mmol) in N,N-dimethylformamide (1.75 mL) was treated with N,N-diisopropylethylamine (0.12 mL, 0.73 mmol). The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a 1N aqueous hydrochloric acid solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide (127 mg, 53.3%) as a white gum: EI-HRMS m/e calcd for C20H21F3N2O (M+) 362.1605, found 362.1592.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:15])=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[NH:7][C:6]=2[CH:14]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>CN(C=O)C>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([CH2:19][N:7]2[C:6]3[CH:14]=[C:2]([Cl:1])[C:3]([I:15])=[CH:4][C:5]=3[N:9]=[C:8]2[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (1.53 g, 4.3 mmol) in DMF (21 ml) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 190 mg, 4.7 mmol). After 15 minutes, the reaction was warmed to rt and stirred for 1 hour. The mixture was then cooled to 0° C. and 4-bromomethyl-biphenyl (1.2 g, 4.7 mmol) was slowly added. The mixture was then warmed to rt and stirred overnight. The volatiles were removed on a rotary evaporator and the residue was partitioned between EtOAc and half-saturated ammonium chloride. The aqueous layer was extracted a second time and the organic extracts were combined. The combined EtOAc extracts were washed with H2O, brine, and then dried with MgSO4. The crude oil obtained upon rotary evaporation was triturated in Et2O and filtered to yield the title compound as a beige solid.
Reaction SMILES: C(N(CC)CC)C.F[C:9](F)(F)[C:10]([OH:12])=[O:11].[CH2:15]([N:22]([CH3:50])[CH2:23][CH2:24][CH:25]1[N:30]2[C:31](=[O:40])[N:32]([CH:37]([CH3:39])[CH3:38])[C:33](=[O:36])[C:34](O)=[C:29]2[C:28](=[O:41])[N:27]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:26]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)(=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([O:12][C:34]1[C:33](=[O:36])[N:32]([CH:37]([CH3:38])[CH3:39])[C:31](=[O:40])[N:30]2[CH:25]([CH2:24][CH2:23][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:50])[CH2:26][N:27]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:28](=[O:41])[C:29]=12)(=[O:11])[CH3:9]
Reactant: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)Cc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c2n(c(=O)n(C(C)C)c1=O)C(CCN(C)Cc1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (370 μL, 2.64 mmol) and DMAP (21 mg, 0.18 mmol) were added to a stirred solution of 4-{2-[benzyl(methyl)amino]ethyl}-2-(4-fluorobenzyl)-9-hydroxy-7-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione trifluoroacetate (from Example 52, 535 mg, 0.88 mmol) in anhydrous CH2Cl2 (10 mL) at 0 C. Acetyl chloride (94 μL, 1.32 mmol) was added and the mixture was then stirred at room temperature for 20 min. The solvent was removed in vacuo and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange solid which was carried directly into the hydrogenation step. ES MS (M+1)=537.6.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14](Cl)(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[C:14]([O:11][CH2:10][CH:9]([CH2:12][O:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC(CO)CO
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)O[Si](C)(C)C(C)(C)C
Reaction time: 15 h

Procedure:
In 60 ml of pyridine was dissolved 2.75 g (0.013 mol) of 2-O-(t-butyldimethylsilyl)glycerol, followed by addition of 8.82 g (0.028 mol) of oleoyl chloride under ice-cooling. The reaction was conducted at 50° C. for 15 hours. After completion of the reaction, the solvent was distilled off and the residue was diluted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, dried, and concentrated. The above procedure provided 1,3-O-dioleoyl-2-O-(t-butyldimethylsilyl)glycerol.
Reaction SMILES: C(=N[NH:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:30]([O:35][CH2:36][CH3:37])(=[O:34])[C:31]([CH3:33])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:36]([O:35][C:30]([C:31]1[NH:15][C:16]2[C:17]([CH:33]=1)=[C:18]([C:26]([CH3:27])([CH3:28])[CH3:29])[CH:19]=[C:20]([C:22]([CH3:25])([CH3:23])[CH3:24])[CH:21]=2)=[O:34])[CH3:37]
Reactant: CC(C)(C)c1cc(NN=C(c2ccccc2)c2ccccc2)cc(C(C)(C)C)c1
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2c(C(C)(C)C)cc(C(C)(C)C)cc2[nH]1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
N-Benzhydrylidene-N′-(3,5-di-tert-butyl-phenyl)-hydrazine (617 mg, 1.6 mmol) was dissolved in ethanol (12 ml). Then, ethyl pyruvate (212 μl, 1.9 mmol) and p-toluene sulfonic acid monohydrate (914 mg, 4.8 mmol) were added thereto. This was heated and stirred at 150° C. by microwave under a nitrogen atmosphere for one hour. After cooling it to room temperature, the reaction mixture was combined with water and an aqueous solution saturated with sodium bicarbonate. The product was extracted into ethyl acetate. The organic layer was isolated, and washed with an aqueous solution saturated with sodium chloride, and dried over magnesium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate=100/5). Thus, 4,6-di-tert-butyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a brown solid (268 mg, 56%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Product: CS(=O)(=O)NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Yield: 28.7 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was reacted with methanesulfonyl chloride (310 μL, 3.85 mmol) to provide 0.43 g of N-{8-[4-amino-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide as an off white powder, m.p. 153-155° C. Analysis: Calculated for C19H27N5O2S: % C, 58.59; % H, 6.99; % N, 17.98; % S, 8.23; Found: % C, 58.40; % H, 6.99; % N, 17.71; % S, 8.14.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:38])[C:21]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2NC(C3C(=O)C(CCC)(CCC)C4C(C=3O)=CC=CC=4)=NS(=O)(=O)C=2C=1)C1C=CC=CC=1>>[CH2:30]([C:21]1([CH2:34][CH2:35][CH2:36][CH3:37])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]([OH:29])=[C:19]([C:14]2[NH:13][C:12]3[CH:39]=[CH:40][C:9]([OH:8])=[CH:10][C:11]=3[S:16](=[O:18])(=[O:17])[N:15]=2)[C:20]1=[O:38])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Yield: 100 %

Procedure:
The title compound was prepared following the procedure of Example 2G, substituting the product of Example 5D for the product of Example 2F to afforded the title compound (70 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 8.16 (d, J=8.09 Hz, 1 H), 7.74 (m, 1 H), 7.54 (m, 2 H), 7.17 (m, 2 H), 7.07 (m, 1 H), 2.16 (m, 2 H), 2.00 (m, 2 H), 1.05 (m, 4H), 0.88 (m, 2 H), 0.67 (t, J=7.17 Hz, 6 H), 0.50 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])O[C:8]2=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].O.[CH2:23]1COCC1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7](=[CH2:8])[C:12]([O:11][C:10]([CH3:23])([CH3:15])[CH3:14])=[O:13])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: C1CCOC1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)c([N+](=O)[O-])c2)C(=O)O1
Solvent: CC(C)(C)O
Solvent: O
Product: C=C(Cc1ccc(Cl)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
11.1 g of 5-(4-chloro-3-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (contaminated by residual 1,3-diisopropylurea) were dissolved in 40 ml of THF and 40 ml (31 g) of tert-butanol, and 16.4 g (88.5 mmol) of N,N-dimethylmethyleneiminium iodide were added. The resulting suspension was stirred at 70° C. overnight and then, after cooling, added to water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10→50:1). This gave 8.22 g of the target product (about 78% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]3)[N:3]=1.[OH-].[Li+].O.CO>O1CCCC1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[N:22]=[CH:21]3)[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)c(N)nn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Cn1ncc2cc(Cl)cc(Cn3nc(N)c4cc(C(=O)O)ccc43)c21
Temperature: 100 °C

Procedure:
A mixture of compound 67 (0.045 g, 0.11 mmol), lithium hydroxide (0.02 g, 0.44 mmol) in a mixture of tetrahydrofuran (2 mL), water (1 mL) and methanol (1 mL) was heated at 100° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:11]=[C:12]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCN1CCC(c2cccc(O)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1CCC(c2cccc(OS(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-(1-propyl-piperidin-4-yl)-phenol (340 mg) and triethylamine (187 mg) in 20 ml of CH2Cl2 was cooled to 0° C. Then methanesulfonyl chloride (194 mg) dissolved in 10 ml of CH2Cl2 was added dropwise. The reaction mixture was allowed to reach room temperature and then stirred for 2.5 h at 25° C. The reaction was finally quenched with water. The organic layer was separated and washed with 10% HCl and then 10% Na2CO3.
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[C:13]([C:17]1[CH:24]=[C:23]([CH3:25])[C:20]([CH2:21]Cl)=[C:19]([CH3:26])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:1]([O:12][CH2:21][C:20]1[C:23]([CH3:25])=[CH:24][C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])=[C:18]([OH:27])[C:19]=1[CH3:26])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][C:20]2[C:23]([CH3:25])=[CH:24][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[C:18]([OH:27])[C:19]=2[CH3:26])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1COC(=O)c1ccc(C(=O)OCc2c(C)cc(C(C)(C)C)c(O)c2C)cc1

Procedure:
A mixture of disocium terephthalate, 16.5 g. (0.08 mole) and 4-tert.-butyl-3-hydroxy-2,6-dimethylbenzyl chloride, 35.7 g. (0.158 mole) in 200 ml. of dimethylformamide was heated at reflux for 18 hours. The salt was then filtered off, and the filtrate poured into 400 ml. of water. The resulting brown gum was dissolved in 50 ml. of methanol and reprecipitated by addition of water. This procedure was repeated to give 18.9 g. (44%) of product, m.p. 227°-230° C. Anal. calc'd. for C34H42O6 : C=74.67, H=7.75; found: C=74.03, H=7.75.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:32])[N:17]3[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=2)[C:21]2[S:29][CH:30]=[CH:31][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:32])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=2)[C:21]2[S:29][CH:30]=[CH:31][C:20]=2[CH:19]=[CH:18]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Yield: 748.6 %

Procedure:
0.23 g (0.5 mmol) of methyl 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylate in 2 ml of ethanol was stirred overnight under reflux with a solution of 0.06 g of potassium hydroxide in 1.25 ml of water. Acidification to pH 1 with 1 N hydrochloric acid and removal of the precipitate by filtration yielded 1.6 g (72%) of 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with m.p. 197-199° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>CN(C=O)C>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:16]=[CH2:17])[CH:10]=2)[C:6]([C:12]([O:14][CH3:15])=[O:13])=[N:7]1
Reactant: COC(=O)c1nn(C)c2cc(Br)ccc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(C(=O)OC)nn(C)c2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 109.3 %

Procedure:
To the solution of methyl 6-bromo-1-methyl-1H-indazole-3-carboxylate (60 mg, 0.22 mmol) in DMF (10 mL), tributyl(vinyl)tin (99 μL, 0.34 mmol), Pd(Ph3)4 (11 mg, 9 μmol) was added. After the addition was completed, the mixture was stirred at 90° C. for 4 h under Ar. Then the solvent was removed under reduced pressure. Purification by CC afforded compound 9a (52 mg, 88%).
Reaction SMILES: C([O:8][C:9]1[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][NH2:16])=O)=[CH:11][C:10]=1[CH2:20][CH3:21])C1C=CC=CC=1.[CH2:22]([C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[CH:27][CH:26]=1)[CH2:23][CH3:24]>>[CH2:20]([C:10]1[CH:11]=[C:12]([C:13]2[O:32][C:30]([C:28]3[S:29][C:25]([CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[N:16][N:15]=2)[CH:17]=[C:18]([CH3:19])[C:9]=1[OH:8])[CH3:21]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: CCCc1ccc(C(=O)O)s1
Product: CCCc1ccc(-c2nnc(-c3cc(C)c(O)c(CC)c3)o2)s1

Procedure:
2-Ethyl-6-methyl-4-[5-(5-propyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-phenol is prepared in analogy to Example 29 starting from 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide and 5-propyl-thiophene-2-carboxylic acid; LC-MS: tR=0.99 min, [M+1]+=329.13.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14].[CH3:21][CH:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH3:23]>O1CCCC1.C(Cl)(Cl)Cl>[OH2:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:1](=[O:2])[N:24]([CH:22]([CH3:21])[CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31])[CH3:14]
Reactant: CC(C)NCCCCS(=O)(=O)c1ccccc1
Reactant: CCN(CC)CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N(CCCCS(=O)(=O)c1ccccc1)C(C)C
Product: O
Yield: 69.8 %

Procedure:
A solution of 1,1'-carbonyldiimidazole (6.00 g, 0.037 mole) and N,N-diethylethylenediamine (4.00 g, 0.034 mole) was stirred at room temperature for 2 hours in 200 ml of tetrahydrofuran. A solution of N-(1-methylethyl)-4-(phenylsulfonyl]-1-butylamine (free base 7.99 g, 0.0313 mole) in 100 ml of tetrahydrofuran was added and the solution was heated overnight at reflux. The reaction was stripped to dryness and the residue dissolved in chloroform. The chloroform was extracted with water, dried (sodium sulfate), filtered, and removed in vacuo. A dark brown oil was obtained upon removal of chloroform. This oil was subjected to flash chromatography on Silica Gel using 0.1N ammonium hydroxide-methanol for elution. This chromatography furnished 5.37 g (42.2% yield) of clear oil after drying in vacuo 18 hours at 60° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-])=O.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1cccc(N)c1)OCC

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with diethyl 3-aminobenzylphosphonate to generate the title compound. The diethyl 3-aminobenzylphosphonate was prepared by sequential treatment of commercial 3-nitrobenzyl bromide with triethyl phosphite at 125° C. for 6 hours followed by reduction with Na2S2 O4 in THF/H2O at 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.32 (m, 4H), 3.73-3.77 (m, 3H), 4.11-4.14 (m, 4H), 6.78-6.90 (m, 3H), 7.19-7.44 (m, 4H), 7.64-7.80 (m, 1H).
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Zn+])#[N:3].[Cu](C#N)C#N.[Br-].[Li+].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>O1CCCC1>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:2]#[N:3])=[O:23]
Reactant: N#Cc1ccccc1[Zn+]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Agent: N#C[Cu]C#N
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1C(=O)c1ccc(F)c(Br)c1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a −20° C. solution of 2-cyanophenylzinc bromide (0.5 M in tetrahydrofuran, 20 mL, 10 mmol) was a solution of copper cyanide (0.94 g, 10.5 mmol) and lithium bromide (1.82 g, 21.0 mmol) in tetrahydrofuran (15 mL) added, the reaction was slowly allowed to reach room temperature, after 15 minutes the reaction mixture was recooled to −25° C. A solution of 3-bromo-4-fluorobenzoyl chloride (1.45 g, 10.5 mmol) in tetrahydrofuran (10 mL) was added, the reaction mixture was stirred at −25° C. 1 h and at room temperature over night. After partition between aqueous ammonium chloride and diethylether, the organic phase was dried over magnesium sulfate and concentrated to give the crude title product which was used without further purification. MS (ESI) m/z 304, 306 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]([OH:17])=O.S(Cl)(Cl)=O.[C:22]([C:27]1[CH:37]=[C:36]([C:38]([CH2:41][CH3:42])([CH3:40])[CH3:39])[CH:35]=[CH:34][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][NH2:33])([CH2:25][CH3:26])([CH3:24])[CH3:23].N12CCN(CC1)CC2>C1C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]([NH:33][CH2:32][CH2:31][CH2:30][O:29][C:28]1[CH:34]=[CH:35][C:36]([C:38]([CH2:41][CH3:42])([CH3:39])[CH3:40])=[CH:37][C:27]=1[C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[O:17]
Reactant: CCC(C)(C)c1ccc(OCCCN)c(C(C)(C)CC)c1
Reactant: CCOc1cc(C(=O)O)c(O)c2ccccc12
Agent: C1CN2CCN1CC2
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOc1cc(C(=O)NCCCOc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c2ccccc12
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
A mixture of 23.2 g of Intermediate 1 prepared above, 18 g of thionyl chloride, and 100 ml of benzene was stirred for 3 hours at 40-45° C and after adding to the mixture a solution of 60 g of -(2,4-di-tert-amylphenoxy)propylamine, 23 g of 1,4-diazabicyclo[2,2,2]octane, and 100 ml of benzene, the resultant mixture was stirred for 2 hours to provide the desired product. The solvent used for the recrystallization of the product was methanol. The melting point of the product was 130-131° C.