Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[OH:24].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:24][C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH3:23])=[CH:21][C:16]=2[O:15][CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(S(C)(=O)=O)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a suspension of Cu(OAc)2 (3.0 mmol; 543 mg), 4-(methanesulphonyl)benzeneboronic acid (4.0 mmol; 800 mg) and activated molecular sieves (800 mg) under air, in anhydrous dichloromethane (5 mL), were added 2-methoxy-4-ethylphenol (2.0 mmol; 0.28 mL), anhydrous triethylamine (10 mmol; 1.4 mL), and anhydrous pyridine (10 mmol; 0.8 mL). The reaction was stirred for 2 days at room temperature. The crude was filtered on silica gel, washed with ethyl acetate, concentrated. The residue was then purified by column chromatography (gradient cyclohexane/dichloromethane) to yield the title compound as clear oil (617 mg; 2.0 mmol; quantitative).
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@H:15]1[C@:19]2([CH3:33])[CH2:20][C@H:21]3[C@H:30]([CH2:31][C@H:18]2[CH2:17][CH2:16]1)[C@@H:29]1[C@@H:24]([CH2:25][C:26](=[O:32])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3.CC(O)C>CC(C)=O>[CH3:33][C@:19]12[C:15](=[O:14])[CH2:16][CH2:17][C@@H:18]1[CH2:31][C@H:30]1[C@@H:21]([CH2:22][CH2:23][C@H:24]3[C@@H:29]1[CH2:28][CH2:27][C:26](=[O:32])[CH2:25]3)[CH2:20]2
Reactant: C[C@@]12C[C@@H]3CC[C@@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CC[C@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C[C@@]12C[C@@H]3CC[C@@H]4CC(=O)CC[C@@H]4[C@H]3C[C@H]1CCC2=O
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
Jones reagent was added to a solution of compound 53 (115 mg, 0.42 mmol) in acetone (20 mL) at 0° C. until a brown-yellowish color persisted. After 10 min, 2-propanol (1.0 mL) was added to consume excess oxidant and then brine (50 mL) was added. The product was extracted into EtOAc (50 mL×3), and the combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to give compound 54 (110 mg 4aR:4aS ratio 2.5:1) as a white solid: 1H NMR (CDCl3) δ 0.84 (s, 3H); 13C NMR (CDCl3) 4aR diastereomer δ 220.3, 212.2, 47.8, 45.6, 42.6, 39.8, 39.0, 38.5, 38.2, 38.1, 36.3, 35.4, 30.7, 28.5, 28.4, 27.1, 23.9, 13.5.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28]([NH:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:28]([NH:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CCCNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CCCNC(=O)CN)NC(=O)OC(C)(C)C

Procedure:
1030 mg (1.82 mmol) of the compound from Example 263A are dissolved in 60 ml of ethanol, and 100 mg (0.09 mmol) of Pd/C (10%) are added. The mixture is hydrogenated under atmospheric pressure overnight and, after filtration through celite, the filtrate is concentrated in vacuo. The solid obtained in this way is reacted further without purification.
Reaction SMILES: C(OCC[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)C.C(O)C.[OH-].[Na+].[C:21]([O:24][CH2:25][CH3:26])(=O)[CH3:22]>O.[Zn]>[CH2:21]([O:24][CH2:25][CH2:26][C:7]1([NH2:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[NH2:13])[CH3:22]
Reactant: CCOC(C)=O
Reactant: CCOCCNc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCOCCC1(N)C=CC=CC1N
Reaction time: 0.5 h

Procedure:
Combine N-(2-ethoxyethyl)-2-nitroaniline (85.4 g, 406 mmol) and ethanol (300 mL). Add a solution of sodium hydroxide (6 g) in water (60 mL). Heat to reflux. Remove the heating and add portionwise zinc metal (106 g, 1.62 mol) at a rate such that the reaction is maintained at reflux. After the addition of zinc metal is complete stir for 30 minutes. Filter the reaction mixture and rinse with water. Extract the filtrate three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(2-ethoxyethyl)-1,2-phenylenediamine.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)=[O:5]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)O)CC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4c(c3)CC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from oxo-(4-p-tolyloxy-piperidin-1-yl)-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 176-178° C. (diethyl ether)
Reaction SMILES: [CH2:1]([O:4][C:5]([CH3:16])([C:11]([F:15])([F:14])[CH:12]=[CH2:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[F:15][C:11]1([F:14])[CH:12]=[CH:13][CH2:1][O:4][C:5]1([CH3:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CCOC(C)(C(=O)OCC)C(F)(F)C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CCOC(=O)C1(C)OCC=CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A stirred de-gas solution of ethyl 2-(allyloxy)-3,3-difluoro-2-methylpent-4-enoate (165 mg, 0.704 mmol) and Grubbs II (29.9 mg, 0.035 mmol) in DCM (20 mL) was stirred at rt overnight. The reaction mixture was evaporated to dryness and purified by silica gel FCC (2% EtOAc in hexanes) to afford ethyl 3,3-difluoro-2-methyl-3,6-dihydro-2H-pyran-2-carboxylate as a clear oil (˜138 mg, 95%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 6.26-6.20 (m, J=10.5, 2.4, 2.4 Hz, 1H), 5.96-5.87 (m, 1H), 4.57-4.48 (m, 1H), 4.36-4.26 (m, 3H), 1.60 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=2)=[N:4][N:3]=[N:2]1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:34])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:26]=2)=[O:43])=[N:1][N:2]=[N:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2S(=O)c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a solution of 2.5 g of N-[2-[2-(1H-tetrazol-5yl)phenylthio]phenyl]-4-hexyloxybenzamide in 30 ml of chloroform was added 1.5 g of 80% m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 2 hours, at the end of which time the solvent was distilled off. Then, ethyl acetate-chloroform was added to the residue and the resulting crystals were collected by filtration and recrystallized from ethanol-chloroform to give 0.67 g of the title compound as white crystals, m.p. 206°-210° C. (decomp.)
Reaction SMILES: C[O-].[Na+].[CH3:4][C@:5]12[C:13](=[O:14])[CH2:12][C@H:8]([C:9]1([CH3:11])[CH3:10])[CH2:7][CH2:6]2.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O.O>C1CCCCC1>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[C:12]1[CH:8]2[C:9]([CH3:10])([CH3:11])[C:5]([CH3:4])([CH2:6][CH2:7]2)[C:13]1=[O:14]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Reactant: COc1ccc(OC)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: COc1ccc(OC)c(C=C2C(=O)C3(C)CCC2C3(C)C)c1
Temperature: 50 °C

Procedure:
A suspension of 9.2 g (0.17 mol) of sodium methoxide in 200 ml of cyclohexane is initially introduced into an apparatus rendered inert with nitrogen and the mixture is treated with a solution of 18.2 g (0.12 mol) of DL-camphor in 100 ml of cyclohexane. The mixture is heated to 50° C. with stirring and 25 g (0.15 mol) of molten 2,5-dimethoxybenzaldehyde are then added. The reaction mixture is heated under reflux for 3 hours. After cooling, it is treated with 300 ml of water. The organic phase is separated off, washed with 1N hydrochloric acid and then with saturated sodium chloride solution, and dried over sodium sulfate. After removing cyclohexane in vacuo, 17.1 g of crude product are obtained. Excess DL-camphor is removed by steam distillation. After chromatography on silica gel 60 using toluene/ethyl acetate in the ratio 3:1 as the eluent, an oil is obtained which after some time solidifies to give 9.2 g of crystalline 3-(2',5' -dimethoxybenzylidene)camphor of melting point 70°-72° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4].C(N(CC)CC)C.O.O1CCCC1>CO.C(Cl)(Cl)Cl>[CH3:26][N:2]([CH3:1])[C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:4]
Reactant: COC(=O)CCCc1ccc(OCC(=O)N(C)C)c(-c2ccccc2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C(=O)COc1ccc(CCCC(=O)O)cc1-c1ccccc1
Reaction time: 240 h

Procedure:
The compound in the title (366 mg) was obtained by reacting the intermediate 62 (455 mg) with triethylamine (2.0 ml) in the mixture of purified water (2 ml) and tetrahydrofuran (10 ml) according to the process described in the process a in example 1. Proviso that the reaction was carried out for 10 days. Rf 0.60 (chloroform:methanol=10:1)
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:22])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:23][C:10]1[C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[C:5]([C:4]([CH3:22])=[C:3]([CH2:1][CH3:2])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [Br-]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccn2)c(C(=O)O)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(Br)c(NS(=O)(=O)c2ccccn2)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 130B (50 mg, 0.16 mmole) in DMF (5 mL) was added tetra-n-butylammonium tribromide (85 mg, 0.176 mmole), then water (5 mL). After stirring overnight at ambient temperature, the solvents were evaporated and the residue was partitioned between water and ethyl acetate (20 mL each). The two phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column eluting with 5% methanol in dichloromethane with 1% acetic acid to provide the desired product, 70 mg (95%). 1H NMR (DMSO-d6) δ 1.2 (t, 3H), 2.04 (s, 3H), 2.55 (q, 2H), 7.15 (s, 1H), 7.25 (t, 1H), 7.68 (d, 1H0, 7.86 (t, 1H), 8.58 (d, 1H), 10.05-13.00 (br s, 2H). MS (ESI(−)) m/e 397, 399 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.N>O>[Cl:27][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(-c2c(-c3ccccc3)oc3nc[nH]c(=O)c23)cc1
Agent: N
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Put 72 g (227.6 mmol) 5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4(3H)-one in 360 ml (4.6 mol) phosphoryl chloride and heat to reflux. Stir the mixture for approx. 1 h at 120° C., before adding the reaction mixture dropwise, after cooling to RT, at controlled dose and with vigorous stirring, to a mixture of 2.2 liters of 25% ammonia solution and 1.2 liters water (pH>9, temperature 55-75° C.). Extract the aqueous mixture three times with dichloromethane, combine the organic phases, dry over sodium sulphate and concentrate by vacuum evaporation. Wash the residue with a little diisopropyl ether, and after filtration and drying at high vacuum, 66.1 g (85.2% of theor.) of the target product is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7]/[C:8](=[C:13](\[CH:18]([CH3:20])[CH3:19])/[C:14]([O:16][CH3:17])=[O:15])/[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:12][O:11][C:9](=[O:10])/[C:8](/[CH2:7][C:6]1[CH:21]=[CH:22][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1)=[C:13](/[CH:18]([CH3:19])[CH3:20])\[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C(Cc1ccc(CO)cc1)=C(\C(=O)OC)C(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: COC(=O)/C(Cc1ccc(C=O)cc1)=C(\C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a solution of dimethyl 2-[4-(hydroxymethyl)benzyl]-3-isopropylmaleate (96 mg, 0.31 mmol) in benzene (2.0 mL) was added active manganese dioxide (602 mg), and the mixture was vigorously stirred at room temperature for 3 h. After the reaction mixture was filtered, the filtrate was concentrated to dryness to give 79 mg of 2-(4-formylbenzyl)-3-isopropylmaleic acid dimethyl ester as colorless oil (yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[CH:14]([C:18](=O)[CH3:19])[C:15](=[O:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([C:14]1[N:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]2=[N:1][C:18]=1[CH3:19])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])(=[O:17])[CH3:16]
Reactant: Nc1nccc2c(Cl)cccc12
Reactant: CC(=O)C(Cl)C(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)nc2c3cccc(Cl)c3ccn12
Yield: 9 %

Procedure:
To a suspension of 1-amino-5-chloroisoquinoline (10 g) in chloroform (150 ml) was added dropwise 3-chloro-2,4-pentanedione (11.3 g). The mixture was refluxed for 6 hours and then allowed to stand at room temperature over night. The mixture was washed successively with aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g) with chloroform as an eluent to afford a solid. This solid was recrystallized from ethyl acetate to give 3-acetyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)cc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2-(bromoacetamido)benzoic acid from Example 41 (10 g, 0.03 mol), aniline (8 g, 7.8 mL, 250 mol %) and DMF (60 mL) was heated at 100°-110° C. for 4 h. The reaction mixture was poured into ice-water (200 mL) and the resulting solid product was solubilized by adding 5% KOH (40 mL). The mixture was extracted with CH2Cl2 (3×100 mL) and the aqueous layer was acidified with 5% HBr to pH=3 and extracted with EtOAc (3×200 mL). The EtOAc washings were dried (Na2SO4), filtered and concentrated to afford, after drying under vacuum, 7.8 g (75%) of the title compound as a white solid, mp 210°-212° C.; 1H NMR (DMSO-d6) δ 13.99 (s, 1H, NH), 11.96 (s, 1H, COOH), 8.75 (d, 1H, J=8), 7.87 (d, 1H, J=2.8), 7.68 (d, 1H, J=2.4), 7.65 (d, 1H, J=2.8), 7.10 (t, 2H, J=7.6), 6.61 (m, 4H), 3.84 (s, 2H); 13C NMR (DMSO-d6) δ 171.08, 167.81, 148.05, 139.36, 133.81, 130.25, 128.97, 126.20, 121.25, 117.77, 117.14, 112.45, 48.90; MS (EI, m/z) 304 (M+).
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH3:11])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]1(C(C)O)[CH2:14][CH2:13]1>>[CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH3:11])/[C:3]([O:5][CH:6]([CH:12]1[CH2:14][CH2:13]1)[CH3:7])=[O:4]
Reactant: CC(O)C1CC1
Reactant: CCC/C=C(\C)C(=O)OCC
Product: CCC/C=C(\C)C(=O)OC(C)C1CC1

Procedure:
Prepared from ethyl (E)-2-methyl-2-hexenoate and cyclopropyl methyl carbinol according to the ester preparation method C described above.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23]C)=O)[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:26]>CO>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21](=[O:23])[NH2:26])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1

Procedure:
A solution of methyl 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]imidazole-4-carboxylate (10 g.) in methanol (100 ml.) is reacted in a bomb with ammonia (44 g.) at 100° C. for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel. The product is eluted with chloroform that is washed with concentrated aqueous ammonia (90%) and methanol (10%) and is recrystallized from acetonitrile to yield the 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-carbamoylimidazole as a white solid, m.p. 149°-154° C.
Reaction SMILES: [CH2:1]([N:8](CCC)[C:9]1[C:14]2[N:15]([CH3:28])[C:16]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1C=CC=C[CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[C:20]1([CH3:27])[CH:21]=[C:22]([CH3:26])[CH:23]=[C:24]([CH3:25])[C:19]=1[NH:18][C:16]1[N:15]([CH3:28])[C:14]2[C:9]([NH:8][CH2:1][CH2:2][CH3:3])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CCCN(Cc1ccccc1)c1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCNc1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
To a solution of 0.50 g (1.2 mmol) of N7-benzyl-N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine in 30 mL of methanol was added 0.43 g (10 mol % Pd) of 20% Pearlman's catalyst (50% wet). The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 48 h. The catalyst was removed via filtration and the filtrate was concentrated in vacuo. Purification by flash chromatography eluting with a 7% methanol/dichloromethane mixture gave 0.23 g (58%) of the title compound as a cream colored solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:27])[C:16]4([CH3:29])[CH3:28])=[CH:10][CH2:9]1)[CH3:7].[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.N1C=CN=C1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([O:27][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:16]4([CH3:29])[CH3:28])=[CH:10][CH2:9]1)[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: 70 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
3β-Hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester (18.0 g) is suspended in 300 ml of DMF and 14.8 g of imidazol, and 13 g of tert-butyldimethylsilylchloride is added. The reaction mixture is stirred at 70° C. for 20 hours. After aqueous work-up, and crystallisation from diethyl ether/methanol, 21.0 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid methyl ester is isolated. Melting point, 124-125° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1c[nH]nn1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COc2cccc(CCCn3ccnn3)c2)cc1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
In an argon atmosphere, 1H-1,2,3-triazole (0.9 g) was dissolved in DMF (20 ml); 65% oily sodium hydride (0.48 g) was added. After stirring for 30 minutes, a solution of benzyl 3-(3-iodopropyl)phenyl ether (3.53 g) in DMF (5 ml) was added, followed by stirring at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was subjected to column chromatography to yield the titled compound (1.1 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[Br:35])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:35][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:29]=1[O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1ccc(Oc2ccncc2Br)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccncc2Br)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-bromo-pyridin-4-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:11])[C:3]=1C(=O)C(C)C>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[O:5][C:4](=[O:11])[CH:3]=1
Reactant: CC(C)C(=O)c1c(O)cc(C(C)C)oc1=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(O)cc(=O)o1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
4-Hydroxy-3-isobutyryl-6-isopropyl-pyran-2-one (11.7 g, 52 mmol) was taken up in conc. Sulfuric acid (40 mL) and stirred at 130° C. for 15 mins. The dark oil obtained was left to cool to room temperature and was then cooled further to 0° C. in an ice bath before the addition of 200 mL crushed ice with stirring. The resulting solution was extracted with ethyl acetate (3×200 mL) and the combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to a light brown oil that was purified by column chromatography using a gradient of pentane in ethyl acetate 3:1→30:70 as eluant to provide the title compound as a light brown oil which solidified on standing (6.1 g, 77%).