Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:30][CH2:29]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl>[C:35]([N:1]1[CH2:4][CH:3]([CH2:5][CH2:6][N:7]([S:31]([CH3:34])(=[O:33])=[O:32])[C:8]2[C:9]([CH:28]3[CH2:29][CH2:30]3)=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH2:2]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CNC3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3CN(C(C)=O)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a solution of Compound (6) (8 mg, 0.02 mmol) in DCM (2.0 mL) was added acetic anhydride (0.1 mL) and pyridine (0.1 mL) and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between EtOAc (25 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo (32 mg). The crude material was purified by reverse phase preparative LCMS: Acetonitrile/water (0.1% formic acid) to give Compound (8) (2.14 mg, 20%). ESI-MS m/z calculated for [M+H]+: 544.2. found: 544.1. 1H NMR (400 MHz, CD3CN) δ 7.85 (s, 1H), 7.63-7.54 (m, 4H), 7.40 (s, 1H), 7.05 (br s, 1H), 4.21-4.14 (m, 1H), 3.93 (td, J=8.9, 3.2 Hz, 1H), 3.76-3.67 (m, 3H), 3.49-3.43 (m, 1H), 3.11 (d, J=1.0 Hz, 3H), 2.93 (d, J=4.8 Hz, 3H), 2.77-2.64 (m, 1H), 2.46-2.36 (m, 1H), 1.95-1.81 (m, 2H), 1.73 (d, J=2.4 Hz, 3H), 1.14-1.02 (m, 3H), 0.69-0.58 (m, 1H).
Reaction SMILES: O[CH:2]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:17]([SH:20])(S)[CH3:18].C1(C)C=CC([S:27](O)(=O)=O)=CC=1>>[CH2:3]([C:2]1[S:27][CH2:18][CH2:17][S:20][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(=O)C(O)CCCCCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(S)S
Product: CCCCCCC1=C(CCCCCC)SCCS1
Yield: 67.8 %

Procedure:
The method of Example 4 was used, using 7-hydroxytetradecan-8-one (22.8 g), ethane dithiol (9.4 g) and p-toluenesulphonic acid (0.5 g) to give 2,3-dihexyl-5,6-dihydro-1,4-dithiin as a greenish oil, bp 145°-155°/0.09 mm, yield 67.8%. NMR (CDCl3) 3.13 δ (singlet), 0.7-2.4 δ (complex series of multiplets).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[F:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[F:27])=[O:19])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: Nc1cc(O)ccc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)no1
Temperature: 50 °C
Yield: 68.2 %

Procedure:
To a stirred suspension of phenyl 5-tert-butylisoxazol-3-ylcarbamate (prepared as described in Example 270A) (260 mg, 1 mmol) and 3-amino-4-fluorophenol (127 mg, 1 mmol) in acetonitrile (15 mL) at rt, was added DBU (0.3 mL, 2 mmol). The mixture was heated at 50° C. for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue purified via silica gel column chromatography to afford 1-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (200 mg, 68%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ9.68 (m, 2H), 8.41 (m, 1H), 7.68 (m, 1H), 6.56-6.65 (m, 2H), 6.45 (s, 1H), 1.29 (s, 9H); LC-MS (ESI) m/z 294 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCC1CCNCC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.28 mmol) and diisopropylethylamine (49 mL, 0.28 mmol) in CH2Cl2 (2 mL) was added 2-fluorobenzenesulfonyl chloride (54 mg, 0.28 mmol) and the mixture was stirred at ambient temperature for 18 hr. To the resulting mixture was added trifluoroacetic acid (0.70 mL) and stirred at ambient temperature for 18 hr. The reaction mixture was concentrated and neutralized with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the organic layer was concentrated to give 2-fluoro-N-piperidin-4-ylmethyl-benzenesulfonamide as a pale yellow solid. To a solution of above solid (0.076 g, 0.28 mmol) and diisopropylethylamine (0.072 mL, 0.42 mmol) in 2-propanol (3 mL) was added (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (0.044 g, 0.21 mmol) and the resulting mixture was stirred at 100° C. for 18 hr. The mixture was concentrated, and the residue was purified by column chromatography (silica gel, 5% MeOH in CH2Cl2) to give N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-fluoro-benzenesulfonamide as a pale yellow solid (0.024 g, 26%).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[N+]([O-])=O)[C:15]([C:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])=[O:30])=[C:14]([CH3:36])[NH:13][C:12]=1[CH3:37])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:34]([CH2:33][CH2:32][O:31][C:29]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:37])[NH:13][C:14]=1[CH3:36])=[O:30])#[N:35]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(C(=O)OCc2ccccc2)=C(C)N1
Agent: [Pd]
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
The solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitronitrophenyl)pyridine (3.24 g, 7.02 mmol) in 160ml of 4.4% (w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 3.24 g) for 30 min., the reaction was quenched by addition of 10 ml of CHCl3. The mixture was filtered and concentration of filtrate give a yellow powder, which was dissolved in CHCl3, washed with water and 1N HCL. After drying and removal of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (1.94 g, 75%)
Reaction SMILES: Cl[C:2]1([CH:10]=[N:11][OH:12])[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH2:3]1.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][C:21](=[CH2:24])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:13]([O:15][C:16]([CH:18]1[CH2:19][CH2:20][C:21]2([O:12][N:11]=[C:10]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH2:24]2)[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: COC1=CC=CC(Cl)(C=NO)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CC1)CC(c1cccc(OC)c1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-chloro-1-hydroxyiminomethyl-3-methoxybenzene (31 g, 167 mmol) in DCM (50 ml) was slowly added dropwise to a solution of 4-methylenecyclohexanecarboxylic acid ethyl ester (28 g, 167 mmol) in DCM (950 ml) at 0° C. Subsequently, a solution of triethylamine (50 ml) in DCM (50 ml) was slowly added dropwise at 0° C. and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with water (500 ml). The combined organic phases were washed with 10% aq. citric acid solution (800 ml) and sat. aq. NaCl solution (500 ml), dried over sodium sulphate and the solvent was removed under vacuum. The desired product 3-(3-methoxyphenyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (51 g) was reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:12])=[CH:18][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)ccc3ncc(Br)cc32)cc1
Temperature: 35 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a stirred solution of 7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (29 g, 128.9 mmol, 1.0 eq) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 7.73 g, 193.3 mmol, 1.5 eq) in portions at RT, the mixture was stirred at 30 to 40° C. for 1 h. 1-(Chloromethyl)-4-methoxybenzene (30.28 g, 193.3 mmol, 1.5 eq) was added dropwise. The resulting mixture was stirred at 30 to 40° C. overnight and quenched with water (500 mL) and extracted with ethyl acetate (5×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/petroether) to afford the desired product, 1-(4-methoxybenzyl)-7-bromo-1,5-naphthyridin-2(1H)-one (C-5) (20.2 g, 45.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.15 (s, 1H), 8.00 (d, J=10 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.6 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 5.45 (s, 2H), 3.71 (s, 3H); ESI-MS m/z: 345.1 [M+H]+.
Reaction SMILES: CN(C)[C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9](CC)[CH:8]=[CH:7][C:6]=1NC1C=CC(C)=C(C(F)(F)F)C=1F.CC[OH:30]>[OH-].[Na+]>[C:5]1([CH2:4][C:3]([OH:26])=[O:30])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCO
Reactant: CCc1ccc(Nc2ccc(C)c(C(F)(F)F)c2F)c(CC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccccc1
Temperature: 80 °C

Procedure:
A solution of the above 5-ethyl-2-(2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide described in Example 3 (0.9 g, 2,4 mmol) in EtOH (25 mL) and 4N NaOH (12 mL) is heated to 80° C. overnight. After cooling, the reaction is concentrated under reduced pressure and diluted with ice cold EtOAc. The pH of the aqueous layer is adjusted to 1-2 with ice cold 2.5 N HCl. The separated organic layer is dried with Na2SO4 and concentrated to a solid. The solid is purified by trituration with an Et2O/hexane mixture to give the title acid, 5-ethyl-2-2′-fluoro-4′-methyl-3′-trifluoromethylanilino)phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([CH3:11])([CH3:10])[O:8][C:7](=[O:12])[C:5]=2[N:6]=1.[CH3:13][O:14][CH2:15][CH2:16][Br:17]>>[BrH:17].[NH:1]=[C:2]1[N:6]([CH2:16][CH2:15][O:14][CH3:13])[C:5]2[C:7](=[O:12])[O:8][C:9]([CH3:10])([CH3:11])[C:4]=2[S:3]1
Reactant: CC1(C)OC(=O)c2nc(N)sc21
Reactant: COCCBr
Product: Br
Product: COCCn1c2c(sc1=N)C(C)(C)OC2=O

Procedure:
A mixture of Example 249B and commercially available 2-bromoethyl methyl ether (Aldrich) was processed at 120° C. using the method described in Example 12A to afford the title compound. MS (ESI+) m/z 243 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29](O)=[O:30])[C:22]=3[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[NH:37][C:29]([C:28]1[C:22]2[N:21]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]3)[NH:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:30]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)O)cccc3[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)Nc4nccs4)cccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a solution of 2-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (31; 150 mg, 0.36 mmol), thiazol-2-amine (4; 35.5 mg, 0.36 mmol), and HATU (202 mg, 0.53 mmol) in DMF (5 mL) was added DIEA (137 mg, 1.06 mmol). The mixture was stirred at room temperature for 18 h. It was then diluted with water (20 mL) and stirred for 30 min. The precipitate was collected by filtration, and then purified by column chromatography to give 85 mg of the title compound 32 (yield: 48%). MS (ESI) calcd for C26H27N5O4S: 505.18; found: 506 [M+H].
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15]Cl>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:14]2[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc[nH]1
Reactant: Fc1cccc(Cl)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nccn1Cc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-n-butylimidazole (3.75 g, 0.03 mol) in dry dimethylformamide (4 mL) was added to sodium hydride (0.95 g) in dimethylformamide (18 mL). After the gas evolution subsided, the mixture was stirred one hour under argon and 2-chloro-6-fluorobenzylchloride (5.5. g, 0.031 mol) in dimethylformamide (7 mL) was added to produce an exotherm. The mixture was stirred for 17 hours at ambient temperature, diluted with ice water and extracted with ethyl acetate. The washed, dried, concentrated organic layer provided 7.63 (94%) of the title compound whose NMR was consistent with the structure. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[CH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.I[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][Si:22]([C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]#[C:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:15][CH:16]=1)([CH3:24])[CH3:25]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
Into a 100 ml round bottom flask was placed a mixture of 1.31 g (0.0081 mole) of 3.5-dimethoxyphenylacetylene, 2.25 g (0.0075 mole) of 4-iodophenyl-trimethylsilylacetylene, 0.016 g (0.084 mmole) of CuI, 0.155 g (0.22 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 15 ml of THF and 15 ml of triethylamine. The light brown solution turned to a suspension within a minute. After ˜40 min, the reaction mixture turned to an orange solution with some white ppt. The reaction was followed by TLC. The mixture was stirred at room temperature under nitrogen overnight. TLC showed presence of staring material still. The reaction was stirred continuously overnight at room temp. Not much further reaction had occurred. It was then stirred overnight at 50° C. TLC indicated that only a trace of starting material was present. The reaction was then terminated and the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 15 ml of chloroform and the solution was washed two times with water (15 ml each) and dried over anhydrous MgSO4, filtered and concentrated. 2.27 g (90.4% yield) of solid was obtained. 1HNMR: 0.26 ppm (s, 9H); 3.83 ppm (s, 6H); 6.49 ppm (s, 1H); 6.70 ppm (s, 2H); 7.47 ppm (s, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][OH:13])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:22]Cl.Cl>O1CCCC1>[CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][O:13][CH2:22][C:21]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=2)[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CN(C)C1(CO)CCCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(COCC2(N(C)C)CCCc3sccc32)cc(OC)c1OC
Temperature: 0 °C

Procedure:
15 ml of tetrahydrofuran containing 2.57 g of 4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophen obtained in Example 1 was added to an ice-cooled suspension of 60% sodium hydride (0.54 g) in tetrahydrofuran. 15 ml of tetrahydrofuran containing 2.90 g of 3,4,5-trimethoxybenzyl chloride was further added to the reaction mixture, followed by refluxing under heat for 24 hours. After cooling, the reaction mixture was poured into hydrochloric acid solution, and washed with ether. The aqueous phase was added with a sodium hydroxyde solution for making the system basic, followed by extracting with chloroform. After the chloroform phase was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography to obtain 2.79 g of the title compound as a pale yellow oily product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH3:18][C:19]1C=CC=C(C)[C:20]=1CN1C2C(=CC=C(C(O)=O)C=2)C(C)=C1>>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Reactant: Cc1cccc(C)c1Cn1cc(C)c2ccc(C(=O)O)cc21
Product: C=CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (5.7 g) as a colorless oil was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate (7.5 g) obtained with the method described in the document (WO 1998/43956 A) according to the method of the process (2) of Example 66.
Reaction SMILES: C(S[C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])[N:10]=1)C1C=CC=CC=1.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40](OO)=O)[CH:35]=1.[S:44]([O-:48])([O-:47])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:40]([S:44]([C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[C:11]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])[N:10]=1)(=[O:48])=[O:47])[C:36]1[CH:35]=[CH:34][CH:39]=[CH:38][CH:37]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(SCc2ccccc2)n1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(S(=O)(=O)Cc2ccccc2)n1

Procedure:
To a solution of the product of step ii) (6.8 g) in DCM (300 ml) was added m-chloroperbenzoic acid (8 g) at ambient temperature with stirring. After 6 h a concentrated solution of sodium thiosulphate (50 ml) was added and the organic phase collected. The organic phase was then washed with saturated sodium bicarbonate solution (×2) followed by brine. The organic phase was dried (MgSO4) and the solvent evaporated to leave the subtitle compound as a colourless foam. Yield: 7.0 g.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[CH:19]([C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)=[O:20].O>CCCCCC.C1COCC1>[C:21]12([CH:19]([OH:20])[CH:10]([C:9]3[CH:16]=[CH:17][CH:18]=[C:7]([Cl:6])[CH:8]=3)[N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Reactant: Clc1cccc(Cn2ccnc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(C(c1cccc(Cl)c1)n1ccnc1)C12CC3CC(CC(C3)C1)C2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
15.5 ml (23 mmol) of a 1.5 molar solution of n-butyllithium in hexane were added dropwise to a solution of 3.85 g (20 mmol) of N-(3-chlorobenzyl)-imidazole in 46 ml of absolute THF at -70° C. The mixture was stirred for 30 minutes at -70° C., after which a solution of 3.20 g (20 mmol) of 1-formyladamantane in 20 ml of absolute THF was added dropwise at -70° C. Stirring was continued for 1 hour at about -70° C. and for 2 hours at about -70° C. to room temperature, 120 ml of water were added at about 10° C., while cooling, and the suspension formed was stirred for 1.5 hours at 5°-8° C. Thereafter, the crystalline substance (crude product) was filtered off under suction and rinsed with water and hexane, and the crystalline product, dissolved in CH2Cl2, was filtered over a silica gel/CH2Cl2 column (diameter 2.0 cm, height 20 cm). The filtered solution was evaporated down in vacuo and the residue (2.36 g) was crystallized from acetone. 2.15 g (=30.1% yield) of pure 1-(1-adamantyl)-2-(3-chlorophenyl)-2-(1-imidazolyl)-ethanol of melting point 115° C. were obtained.
Reaction SMILES: O[CH:2]([C:4]1([O:13]C)[C:8]([O:9]C)=[CH:7][CH:6]([O:11]C)O1)[CH3:3]>OS(O)(=O)=O>[CH3:3][C:2]1[O:11][CH:6]=[CH:7][C:8](=[O:9])[C:4]=1[OH:13]
Reactant: COC1=CC(OC)OC1(OC)C(C)O
Agent: O=S(=O)(O)O
Product: Cc1occc(=O)c1O

Procedure:
2(1-hydroxy ethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (2.30 g, 0.012 moles) was stirred at room temperature for 4 hours in 50 ml of 1 N H2SO4. Isolation as described in Example 9 gave 67% assayed yield of pure maltol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[CH3:17])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[CH3:17])[CH2:6][CH2:7]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1N1CCN(C)CC1
Yield: 86 %

Procedure:
A heterogeneous mixture of 4-(4-methylpiperazinyl)-3-methylnitrobenzene 5 (20 g, 85 mmol), 10% Pd/C (1.3 g) in methanol (1.2 liter) was hydrogenated [H2] at 40 PSI for 3 hours. The palladium catalyst was filtered through a pad of celite, washed with methanol (3×50 mL) and the combined filtrate was concentrated to afford 4-(4-methylpiperazin-1-yl)-3-methylaniline 7 (15 g, 86%). 1H NMR (CD3OD): δ 6.83 (d, 1H, J=8.7 Hz), 6.59 (d, 1H, J=2.7 Hz), 6.54 (dd, 1H, J=8.4 and 2.7 Hz), 2.84 (t, 4H, J=4.8 Hz), 2.60 (bm, 4H), 2.34 (s, 3H), 2.20 (s, 3H); LCMS: purity: 99.9%, MS (m/e): 206 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15](O)=[O:16].S(Cl)([Cl:22])=O>CN(C)C=O>[F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([Cl:22])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2ccccc2c1OCC(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ccccc2c1OCC(F)(F)F

Procedure:
A mixture of 10 g. (37 mmoles) of 1-(2,2,2-trifluoroethoxy)-2-naphthoic acid, 21.8 ml. (35.7 g., 300 mmoles) of purified thionyl chloride and 3 drops of dimethylformamide is refluxed for one hour. Excess thionyl chloride is removed in vacuo at water aspirator pressure while heating on a steam bath. Last traces of thionyl chloride are removed by vacuum distillation with added benzene. The product is 1-(2,2,2-trifluoroethoxy)-2-naphthoyl chloride according to infrared spectral measurement.