Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][O:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([O:40][CH3:41])[C:32]=1[CH:33]=O>O1CCCC1>[CH3:41][O:40][C:35]1[CH:36]=[C:37]([OH:39])[CH:38]=[C:31]([O:30][CH3:29])[C:32]=1[CH2:33][CH2:1][CH3:2]
Reactant: CCBr
Reactant: COc1cc(O)cc(OC)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OC)cc(O)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
Anhydrous tetrahydrofuran (36 ml) was added to triphenylphosphine ethyl bromide (12.3 g) prior to stirring at room temperature for 20 minutes. To the resulting mixture was added potassium tert-butoxide (4.5 g), for stirring at room temperature for 30 minutes. Then, 2,6-dimethoxy-4-hydroxybenzaldehyde (3.0 g) was added to the result mixture for stirring at room temperature for 2 hours. The resulting solution was partitioned between ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=2:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-4-propylphenol (1.8 g; yield of 55%). By 2H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].C1(O)C=CC=CC=1>>[CH:1]([C:4]1[C:5]([OH:10])=[CH:6][C:7]2[C:12]([CH3:20])([CH3:13])[CH2:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:8]=2[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: CC(C)c1ccccc1O
Solvent: Oc1ccccc1
Product: CC(C)c1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a) above, by the reaction of 30 g (0.22 mol) of 2-isopropylphenol with 40.3 g (0.22 mol) of 2,5-dichloro-2,5-dimethylhexane, 48.9 g (90%) of the expected phenol of melting point 79°-80° C. were obtained after chromatography on a silica column eluted with a mixture of dichloromethane and hexane (40/60).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([C:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH2:8].[Cl-].[NH4+]>[Cu](I)I.C1COCC1>[CH2:6]([C:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:1][CH2:2][CH2:3][CH3:4])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH2:8]
Reactant: [Li]CCCC
Reactant: C=CCC(CCCCCI)(C(=O)OCC)C(=O)OCC
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CCCCCCCCC)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.7 %

Procedure:
To a THF suspension (2.1 ml) containing copper iodide (0.228 g, 1.2 mmol) was added dropwise at −10° C. butyl lithium (2.4 mmol in 0.88 ml of 2.68M hexane solution). The reaction liquid was heated to 0° C. over 30 minutes and then given diethyl allyl(5-iodopentyl)malonate (0.40 g, 1 mmol), followed by stirring at 0° C. for 5 hours. After addition of a saturated aqueous solution of ammonium chloride, the reaction product was purified as in Referential Example 1. Thus there was obtained 0.234 g of diethyl allyl(nonyl)malonate (yields: 75%). Characteristic Values of diethyl allyl(nonyl)malonate
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1)[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1
Reactant: O=C1OCc2cccc(Cl)c21
Reactant: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(OC)nc(C2(c3nc(OC)nc(OC)n3)OC(=O)c3c(Cl)cccc32)n1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1.48 g of 7-chlorophthalide are dissolved in 80 ml of THF. The solution is cooled to -70° C. and 1.5M IDA in THF (6 ml) is syringed in at -70° C. over 3 min. Stirring is continued for 15 min at -70°, 1.54 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine in 50 ml of THF added dropwise and the mixture is then allowed to warm to -20°. The mixture is again cooled to -70°, and 1 ml of conc. HCl in 10 ml of water is added. The mixture is stirred for 25 min and allowed to warm to RT and the THF is removed by evaporation. The residue is partitioned between CH2Cl2 and water (50 ml each) and the aqueous phase extracted with an additional 30 ml of CH2Cl2. The combined organic phases are washed with 30 ml of water and concentrated to give a yellow gum. This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml). Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane yielded title product m.p. 126°-127° as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][S:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:13][C:3]1[S:4][CH:5]=[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cscc1C1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2CCCCC2)csc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To an icebath-chilled solution of 3-methyl-4-cyclohexylthiophene (10 g, 55.55 mmol) in DMF (60 mL) was added solid N-bromosuccinimide (9.89 g, 55.55 mmol). After addition, the mixture was allowed to warm to room temperature and was stirred for about 1 hr at which point HPLC analysis indicated the reaction was complete. The product mixture was poured into 200 mL of cold water and the aqueous phase was extracted with ether (3×125 mL). The combined ether extracts were washed with water (3×250 mL) and brine (1×200 mL), then passed through a cone of DRIERITE. Solvent was removed by rotary evaporation to afford the crude product 2-bromo-3-methyl-4-cyclohexylthiophene (13.6 g, 94%) as a light amber oil which was judged to be of greater than 95% purity product. 1H NMR (CDCl3) δ 6.88 (s, 1, ArH), 2.53 (m, 1, cyclohexylmethine) 2.19 (s, 3,ArCH3), 1.9 and 1.35 ppm (m, 10, cyclohexyls).13C NMR 147.81, 135.93, 118.32, 109.44 (thiophene carbons), 39.27, 33.55, 26.86, 26.24 and 13.73 (aliphatic carbons). 2D NMR confirmed that the bromine was bonded to the carbon adjacent to the 3-methyl substituent.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2=[CH:8][NH:9][CH:10]=[C:4]2[C:3]1=[O:11].CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2=[C:8]([CH:15]=[O:16])[NH:9][CH:10]=[C:4]2[C:3]1=[O:11]
Reactant: CN(C)C=O
Reactant: CN1CCc2c[nH]cc2C1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCc2c(c[nH]c2C=O)C1=O
Yield: 33 %

Procedure:
5-Methyl-2,5,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-4-one was formylated under standard Vilsmeier conditions using DMF (3 equiv.) and POCl3 (1.1 equiv.) to give 250 mg (33%) of 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Clc1cccc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Cl)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][CH2:9][C:8]([F:13])([F:12])[S:7]1(=[O:15])=[O:14].FC(F)(F)C(O)=O>C(Cl)Cl>[F:12][C:8]1([F:13])[S:7](=[O:15])(=[O:14])[NH:6][CH2:11][CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCCC(F)(F)S2(=O)=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)NCCCC1(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-6,6-difluoro-1,2-thiazinane-1,1-dioxide (0.090 g, 0.3 mmol) in methylene chloride (7 mL) was added trifluoroacetic acid (4 mL), and the resultant red solution stirred for 3 hrs at room temperature. The mixture was concentrated in vacuo to afford the crude residue. The crude product was purified by silica gel chromatography (10-60% ethyl acetate/hexanes) to give a clear oil (0.034 g). 1H NMR (CDCl3, 300 MHz) δ 4.85 (br s, 1H), 3.46-3.40 (m, 2H), 2.60-2.47 (m, 2H), 2.01-1.93 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]3[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1ccc2nc(N)sc2c1
Product: CCOC(=O)c1cn2c(n1)sc1cc(OC)ccc12
Yield: 57.9 %

Procedure:
Ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was prepared according to the procedure as outlined in Example 1, (Step 1). Starting from 6-methoxy-2-amino benzothiazole (27 g, 0.15 mol) and ethyl bromopyruvate (39.9 g, 0.2 mol), 24 g (43% Yield) of ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate was isolated as a brown solid. (M+H) 277.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(Cl)Cl.[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH2:23])[CH3:19]>C(N(CC)CC)C>[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][NH:23][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:13])[C:10]([NH2:12])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:19]
Reactant: CCN(CC)CCN
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Reaction time: 18 h
Yield: 60.5 %

Procedure:
2-Methoxy-4-amino-5-chlorobenzoic acid (1.0 g) and 1-methanesulfoyloxy-1,2,3-benzotriazole (1.07 g) are suspended into chloroform (15 ml) and therto is added dropwise triethylamine (0.7 ml) with stirring under ice-cooling to give a clear solution. To the solution is added 2-(diethylamino)ethylamine (0.6 g) at room temperature and the mixture is allowed to stand for 18 hours. The solvent is then distilled off and thereto are added water and 1 N aqueous sodium hydroxide. The resulting crystals are separated by filtration, washed with water and then dried to give N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide (0.9 g), melting point: 145°-146° C. The product is identified with an authentic sample by infrared spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4]>C1COCC1>[OH:12][CH2:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CO)CC1
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (5.44 g, 29.2 mmol) in dry THF at −78° C., was added borane-methyl sulfide complex (19.0 mL, 38.0 mmol) dropwise over 20 min. The mixture was stirred for 3 h and was then allowed to slowly attain r.t. The reaction was quenched with water (20 mL) and the mixture was extracted with EtOAc. The organic phase was washed once with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (4.80 g, 95% yield) as a mixture of two diastereomers: MS (EI) m/z 172 M+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[O:12]1CCOCC1>>[CH3:1][C:2]1[N:3]=[C:4]([CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C1COCCO1
Reactant: Cc1ccc([N+](=O)[O-])c(C)n1
Product: Cc1nc(C=O)ccc1[N+](=O)[O-]
Yield: 75 %

Procedure:
A solution of 2,6-dimethyl-3-nitropyridine (50 g, 329 mmol) and SeO2 (5.02 g, 27.9 mmol) in dioxane (500 mL) was heated at reflux for 16 hours. The solution was filtered, the solvent removed and the residue purified by column chromatography directly (20% EtOAc/hexanes). The material was recrystalized from ethyl acetate to give 41 g of 6-methyl-5-nitropicolinaldehyde (41 g, 75%), a pale yellow solid; 1HNMR (CDCl3, 400 MHz) δ 2.94 (s, 3H), 7.98 (d, J=8.34, 1H), 8.41 (d, J=8.34, 1H), 10.09 (s, 1H). Exact mass calculated for C7H6N2O3: 166.04. found: 167.12 MS m/z (MH+).
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:19]([C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[O:16][CH3:15])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (400 mg, 2.0 mol), 2,4-dimethoxyaniline (305 mg, 2.0 mmol) reacted to give 1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 316 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[N:13]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=[C:14]([C:23]([F:24])([F:26])[F:25])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Oc1ccc(F)cc1
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
4-Fluoro-phenol (116 mg, 1.03 mmol) and sodium hydride (53 mg, 1.3 mmol) were added in DMF (7 mL). The reaction mixture was stirred for 10 mins and then 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (132 mg, 0.52 mmol) was added into the reaction mixture. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/1) to give the title product (57 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C.[CH3:28][C:29]([CH3:31])=[O:30].C1COCC1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16](/[CH:17]=[CH:28]/[C:29](=[O:30])[CH3:31])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)/C=C/c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reaction time: 3 h
Yield: 76.47 %

Procedure:
To a solution of aldehyde 29 (15 g, 0.0519 mol) in a mixture of 200 ml of Acetone:THF (1:1) was added 10% aq. NaOH solution and stirred for 3 hours. Dilute acetic acid was added till pH of mixture was acidic. The reaction mixture was evaporated to half volume and poured into water (200 ml). The solid separated out was filtered to yield (E)-4-{3-[(E)-2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-but-3-en-2-one (13 g, 76.47%) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][S:12][C:11](=[NH:10])[NH2:13])[CH:5]=1
Reactant: ClCc1cccnc1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1cccnc1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A solution of 3-chloromethylpyridine hydrochloride (100 g) in ethanol (310 cc), at 60° C. is added dropwise and in the course of 15 minutes to a suspension of thiourea (55 g) in boiling ethanol (310 cc). The reaction mixture is stirred for 1 hour 45 minutes at the boil and then cooled to 30° C. After decantation, the supernatant solution is discarded. Ethanol (400 cc) is added to the remaining gummy solid and the mixture is stirred for 63 hours at a temperature of about 20° C. The resulting crystals are filtered off, washed twice with ethanol (60 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Pyrid-3-yl-methyl)isothiourea monohydrochloride (100 g), melting at 220° C. is thus obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: COC1CN(Cc2ccccc2)CCC1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Temperature: -70 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
a') A solution of 3-methoxy-1-(phenylmethyl)-4-piperidinone (4.4 g) in tetrahydrofuran was cooled to -75° C. Lithium tris-sec-butylborohydride was added dropwise and the reaction mixture was stirred for 2 hours at -70° C. Acetic acid 10% (100 ml) was added dropwise at room temperature. The organic solvent was evaporated. The aqueous residue was alkalized with NH4OH, then extracted twice with diisopropylether. The separated organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated. The residue was purified by short column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5 upgrading to 98/2), yielding 1.3 g (29.4%) of cis-3-methoxy-1-(phenylmethyl)-4-piperidinol (intermediate 2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]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]>>[CH3:13][S:12][C:11]1[C:2]([NH:1][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])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CSc1ccc2ncccc2c1N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(SC)ccc2ncccc12

Procedure:
5-Amino-6-methylthioquinoline, prepared as described in Example 34, and commercially available oleoyl chloride were coupled to give the title compound according to the procedure described in Example 25. Mass spectrum m/e: 454.3 (M+).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:13]1[O:15][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20][OH:21]>>[CH3:20][O:21][CH2:14][CH:13]([OH:15])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:16][CH:17]([CH3:18])[CH3:19]
Reactant: CO
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Product: COCC(O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
To a solution of 176 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane in 10 ml of methanol was added 2 g of dry neutral alumina, and the mixture was heated under reflux for 16 hours. After filtration of the alumina, the filtrate was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 96 mg of (2RS, 3S)-3-carbobenzoxyamino-2-hydroxy-5-methylhexyl methyl ether as a colorless viscous oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH2-].[Na+].[O:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>C1COCC1>[O:18]1[CH:22]2[C:2]3[C:3]4[C:8]([C:9]5[C:14]([C:15]=3[CH:19]1[CH:20]=[CH:21]2)=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: c1ccoc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CC2OC1c1c2c2ccccc2c2ccccc12
Temperature: 70 °C

Procedure:
9-Bromophenanthrene (18.6 g, 72.3 mmol), sodium amide (8.47 g, 217.0 mmol) were charged in a two-necked bottle. The bottle was then vacuumed and purged with nitrogen, and dried THF (120 mL) and furan (78.1 mL, 1.07 mmol) were added to the bottle. The mixture in the bottle was heated to 70° C. for reaction for 24 hours, and the resulting was filtered to remove metal. The filtrate was condensed to remove the solvent, and then purified by chromatography with hexanes to yield A (14.7 g, 83%) as white solid powder.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH:12]1[CH2:18][O:19][CH3:20])=O)C1C=CC=CC=1.I[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1.Br>C(O)(=O)C>[NH2:28][C:23]1[C:22]2[C:23](=[CH:22][C:27]([CH2:26][N:14]3[CH2:15][CH2:16][NH:11][CH:12]([CH2:18][O:19][CH3:20])[C:13]3=[O:17])=[CH:26][CH:27]=2)[N:24]=[CH:25][N:24]=1
Reactant: COCC1C(=O)NCCN1C(=O)OCc1ccccc1
Reactant: Nc1ncccc1I
Agent: Br
Solvent: CC(=O)O
Product: COCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 1 h

Procedure:
To a solution of 2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (5.8 g, 13.3 mmol) in 50 mL of acetic acid is added dropwise, 20 mL of a 30%HBr in AcOH solution. The solution is stirred for 1 hour. After this time, the solution is concentrated. The resulting crude product is purified by column chromatography eluting with CH2Cl2:MeOH:NH4OH (20:5:1). The title compound (2.0 g, 6.6 mmol) is obtained as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ8.60 (s, 1H), 7.72 (m, 2H), 7.48 (d, 1H), 5.60 (bs, 2H), 4.72 (AB, 2H), 3.87 (m, 2H), 3.71 (m, 1H), 3.42 (m, 1H), 3.40 (s, 3H), 3.19 (m, 2H), 3.02 (m, 1H). MS (ion spray) m/z 302, (M+H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2C=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH2:12][C:11]2=[O:30])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cccnc32)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C(=O)Cc3cccnc32)cc1
Reaction time: 6 h
Yield: 50.2 %

Procedure:
A solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (24.3 g, Reference Example 73) in dichloromethane (700 mL), under nitrogen and at 5° C., was treated with 3-chloroperbenzoic acid (26.7 g, 70%). After stirring at 5° C. for 16 hours a further aliquot of 3-chloroperbenzoic acid (15 g, 70%) was added and stirring was continued for a further 6 hours at 5° C. The reaction mixture was then treated with sodium sulfite solution (1 L, 10%), the organic phase was separated and the aqueous phase was extracted twice with dichloromethane (200 mL). The combined organic phase and extracts were washed with water (400 mL), dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:3, v/v) and then with a mixture of dichloromethane and methanol (95:5, v/v) to give the title compound (11.7 g) as an orange solid.