Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[Cl:37][C:38]1[CH:39]=[C:40]([Mg]Br)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].CO>ClC1C=CC=CC=1.C(Cl)Cl>[Cl:37][C:38]1[CH:39]=[C:40]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)=[O:9])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc([Mg]Br)cc1Cl
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(Cl)c3)sc2c1
Yield: 61.6 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.0 g, 2.3 mmol) in chlorobenzene (10 mL) was treated with a 0.69 M THF solution of 3-chloro-4-methoxyphenylmagnesium bromide (11 mL, 7.6 mmol) (prepared from 4-bromo-2-chloroanisole, catalytic iodine, and magnesium turnings in THF) to provide, after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 760 mg (62%) of the title compound as a yellow foam: 1H NMR d 1.43 (m, 2H), 1.58 (m, 4H), 2.73 (t, J=5.9 Hz, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 4.08 (t, J=5.9 Hz, 2 ), 6.74 (d, J=9.2 Hz, 1H), 6.78 (d, J=9.2 Hz, 2H), 6.96 (dd, J=2.2 Hz, 8.9 Hz, 1H), 7.26 (dd, J=2.2 Hz, 8.7 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H); 13C NMR d 24.4, 26.1, 55.3, 55.9, 56.4, 57.9, 66.4, 104.7, 112.2, 114.6, 115.3, 122.8, 124.5, 127.1, 128.8, 130.6, 130.8, 131.7, 132.5, 134.1, 140.4, 140.9, 155.3, 158.1, 163.4, 193.2; MS (FD) m/e 535 (M+); Anal. calc'd. for C30H30ClNO4S: C, 67.22; H, 5.64; N, 2.61. Found: C, 66.94; H, 5.90; N, 2.34.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].[Br-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:27])[CH2:19][O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
2 g of sodium 3-acetoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate were dissolved in 20 ml of 35% v/v aqueous methanol, and 16 g of sodium bromide were added to the resulting solution. The mixture was stirred at 70° C. for 2 hours, after which it was diluted with 20 ml of ice-water, neutralised by the addition of a saturated aqueous solution of sodium carbonate and then extracted twice, each time with 50 ml of ethyl acetate. The aqueous phase was acidified by the addition of a saturated aqueous solution of potassium hydrogen sulphate and then again extracted twice, each time with 50 ml of ethyl acetate. All of the ethyl acetate extracts were combined and the combined extracts were washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure to give 1.4 g of 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylic acid, in the form of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N+:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5]2[O:7][N:23]=[C:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:15]=2)=[CH:3][C:2]=1[OH:1])([O-:13])=[O:12]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: N
Product: O=[N+]([O-])c1ccc(-c2nc(-c3cccnc3)no2)cc1O

Procedure:
The title compound was prepared according to Method C using 3-hydroxy-4-nitrobenzoic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=7.9, 4.8, 0.8 Hz, 1 H), 7.76 (dd, J=8.5, 1.8 Hz, 1 H), 7.92 (d, J=1.6 Hz, 1 H), 8.12 (d, J=8.3 Hz, 1 H), 8.45 (dt, J=7.9, 2.0 Hz, 1 H), 8.83 (dd, J=4.8, 1.6 Hz, 1 H), 9.26 (d, J=1.2 Hz, 1 H)) ppm; MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([OH:13])=O)[N:4]=1.S(Cl)([Cl:16])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([Cl:16])=[O:13])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)nc(C(=O)O)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)nc(C(=O)Cl)n1

Procedure:
A mixture consisting of 1.1 g (6.0 mmol) of 4,6-dimethoxypyrimidine-2-carboxylic acid, obtained in accordance with a method descibed in the specification of WO 9318012 A1, 1.1 g (9.0 mmol) of thionyl chloride, one drop of N,N-dimethylformamide and 5 ml of toluene was stirred under heating and refluxing for 3 hours. After the reaction, excess thionyl chloride and the solvent were removed under reduced pressure to obtain crystal of 4,6-dimethoxypyrimidine-2-carbonylchloride. In a separate vessel, 0.30 g (2.0 mmol) of 6,6-difluoro-5-methyl-5-hexenole and 0.61 g (3.0 mmol) of 4,6-dimethoxypyrimidine-2-carbonylchloride were dissolved in 10 ml of tetrahydrofuran, followed by the drop-wise addition of 0.40 g (4.0 mmol) of triethylamine at room temperature, followed by stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:7) to obtain 0.20 g (yield: 21%) of 6,6-difluoro-5-methyl-5-hexenyl 4,6-dimethoxypyrimidine-2-carboxylate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[C:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:37][CH:36]=[C:35]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)[N:34]=1.[CH2:54]([C@@H:59]1[O:61][C@H:60]1[CH2:62]O)[CH2:55][CH2:56][CH2:57][CH3:58]>C(Cl)(Cl)Cl>[F:32][C:33]1[C:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:37][CH:36]=[C:35]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH2:62][C@H:60]3[C@H:59]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[O:61]3)=[CH:51][CH:52]=2)[N:34]=1
Reactant: CCCCC[C@@H]1O[C@H]1CO
Reactant: CCCCCCCCc1ncc(-c2ccc(O)cc2)nc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ncc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)cc2)nc1F
Yield: 40 %

Procedure:
In an analogous reaction to Example 5a, 3.04 g (11.60 mmol) of triphenylphosphine, 1.82 ml (11.60 mmol) of diethyl azodicarboxylate, 2.00 g (7.00 mmol) of 2-fluoro-3-octyl-6-(4-hydroxyphenyl)pyrazine and 1.67 g (11.60 mmol) of (2S,3S)-3-pentyloxiran-2-ylmethanol give 1.20 g of [(2S,3S)-3-pentyloxiran-2-yl]methyl 4-(2-fluoro-3-octylpyrazin-6-yl)phenyl ether of [α]D20 (c = 0,995 in CHCl3)=-16.58. ##STR28##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[NH:8])[O:7][CH2:17][CH3:18])=[C:4]([F:11])[CH:3]=1
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1ccc(Cl)cc1F
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1ccc(Cl)cc1F

Procedure:
starting from 4-chloro-2-fluorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 4-chloro-2-fluorobenzimidate as an oil; mass spectrum: 202 (3.5), 201 (1), 200 (10), 182 (2), 173 (27), 157 (100), 156 (75);
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[CH:9]=[CH:8]1.C(N(CC)CC)C>O1CCCC1>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][N:17]([CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[NH:7][CH:8]=[CH:9]2)[C:3](=[O:4])[CH:2]([Br:1])[CH3:6]
Reactant: COc1ccc(CNCc2cccc3cc[nH]c23)c(OC)c1
Reactant: CC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2cccc3cc[nH]c23)C(=O)C(C)Br)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Add 2-bromopropionyl chloride (3.25 g, 18.96 mmol) to a solution of N-[(indol-7-yl)methyl]-2,4-dimethoxybenzylamine (5.0 g, 17.24 mmol) and triethylamine (3.49 g, 64.48 mmol) in tetrahydrofuran (100 ml). Stir for 1 hour at room temperature and quench with saturated aqueous sodium bicarbonate. Extract with ethyl acetate, concentrate under reduced pressure, and subject the residue to silica gel chromatography eluting with 1:1 ethyl acetate:hexanes to provide the desired compound (4.72 g, 63%).
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1)=O.Cl.[NH2:19][OH:20].C[O-].[Na+]>CO>[OH:20]/[N:19]=[CH:1]/[C:3]1[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: COC(=O)c1cccc(-n2cccc2C=O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-n2cccc2/C=N/O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
Methyl 3-(2-formylpyrrol-1-yl)benzoate (5.0 g) was added to a mixture of hydroxylamine hydrochloride (1.5 g) and 28% methanolic sodium methoxide (4.2 g) in methanol (50 ml) and the mixture was stirred for 4 hours at ambient temperature. The solvent was removed by concentration and the residue was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel eluting with a mixture of chloroform and ethyl acetate (19:1). The first eluted fractions containing the desired product were collected and evaporated in vacuo and the residue was triturated with a mixture of diisopropyl ether and n-hexane to give methyl 3-[(E)-2-hydroxyiminomethylpyrrol-1-yl]benzoate (Compound A) (0.8 g). The further eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-[(Z)-2-hydroxyiminomethylpyrrol-1-yl]benzoate (Compound B) (1.43 g) as an oil.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=1
Reactant: Brc1cccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reaction time: 0.17 h

Procedure:
1.45 ml of a hexane solution containing 1.54 M normal butyl lithium was added dropwise into 200 ml of diethyl solution containing 10.0 g of 3-bromopyridine at −78° C. in a nitrogen atmosphere over 10 minutes. After the dropwise addition, the mixture was stirred for 10 minutes and then 20 ml of tributyltin chloride was added dropwise thereinto over 10 minutes. Then, after stirring for 30 minutes, water was added to the reaction mixture and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to silica column chromatography and eluted with hexane and then with hexane/ethyl acetate (7:1), to give 21.9 g of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:25](=[O:27])[CH3:26])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(C)=O
Yield: 80 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10 gm, 0.3 mmoles), acetic anhydride (0.5 mL) and triethylamine (0.7 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 90 mg (80%) of 2-(p-methoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-fluorobenzofuran, mp. 85°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2cc(Br)ccc2nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (2.0 g) in N,N-dimethylformamide (20 ml) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (2.5 g) and 60% sodium hydride (682 mg) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (492 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]2[C:17]3[C:24]([Br:32])=[C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COC1CCCC(Nc2ncnc3oc(-c4ccccc4)cc23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)COC1CCCC(Nc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Suspend 1.65 g (3.9 mmol) of (+/−)-({3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-oxy)acetic acid tert-butyl ester in 4 ml of carbon tetrachloride and add 762 mg (4.3 mmol) of N-bromosuccinimide. Heat the reaction mixture under reflux for 1 h. After cooling to RT, add a further 350 mg of N-bromosuccinimide. Stir the reaction mixture under reflux again for 1 h, then cool and concentrate under reduced pressure. From the residue, after purification by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1), 0.99 g of the target product is isolated (50.6% of theory).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[C:16]([CH:21]=O)=[N:17][CH:18]=[CH:19][CH:20]=1.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:14][C:15]1[C:16]([C:21]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]3[N:9]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ncccc1F
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ncccc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.76 g), 3-fluoropyridin-2-carboaldehyde (0.50 g), sodium hydrogen sulfite (0.50 g) and DMF (3 ml) was stirred at 120° C. for 8 hours. To the cooled reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-fluoropyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.43 g), which is hereinafter referred to as “intermediate compound (M6-2)”.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CC1C=CC(S(O[CH2:23][CH:24]2[CH2:28][O:27][C:26](=[O:29])[NH:25]2)(=O)=O)=CC=1>C(#N)C>[N:7]1([CH2:23][CH:24]2[CH2:28][O:27][C:26](=[O:29])[NH:25]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1NC(CN2CCCC2)CO1
Yield: 92 %

Procedure:
Potassium carbonate (0.62 g, 4.5 mmol, 2 eq) and pyrrolidine (0.28 ml, 3.37 mmol, 1.5 eq) are added to a solution of (2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate a91 (0.62 g, 2.25 mmol, 1 eq) in acetonitrile (22 ml). The mixture is heated at reflux overnight. After cooling, the mixture is filtered and the solid is washed with acetonitrile. The acetonitrile phases are concentrated in vacuo. The residue is taken up in dichloromethane, heated, filtered and washed with dichloromethane. The dichloromethane phases are concentrated in vacuo to give 0.35 g of 4-(pyrrolidin-1-ylmethyl)-1,3-oxazolidin-2-one a92 as a yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[N:34]1([O:29][C:28](=[O:30])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:15]4[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH3:3])=[CH:17][CH:16]=4)[CH2:19][CH2:20]3)=[CH:32][CH:31]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1
Reactant: COCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)On4nnc5ccccc54)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.4 %

Procedure:
A mixture of 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acid dihydrochloride (2.00 g) and 1-hydroxybenzotriazole (0.84 g) in methylene chloride (40 ml) was treated with triethylamine (1.44 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution successively, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. To the residue was added diisopropyl ether, and the resulting precipitate was filtered, washed with diisopropyl ether and dried under reduced pressure to give 4-[4-(4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (2.30 g) as a dark yellow solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6][N:5]1[CH3:18])([OH:3])=[O:2].Cl.[CH3:20][CH2:21]O>>[C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6][N:5]1[CH3:18])([O:3][CH2:20][CH3:21])=[O:2]
Reactant: CCO
Reactant: COc1cc2c(cc1OC)CN(C)C(C(=O)O)C2
Agent: Cl
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C

Procedure:
The resulting tetrahydroisoquinoline derivative of formula 30 is then esterified with a suitable lower alkanol by standard means to produce a tetrahydroisoquinoline ester of formula 31 (step 2). For example, 3-carboxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (30) is treated with HCl in EtOH to produce 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K+].[Br-]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:3])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CN1CCN(C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-methylpiperazine, yield 81%. White crystals, m.p. 237–240° C.; 1H NMR (DMSO-d6): δ 11.67 (br s, 1H), 7.50, 7.45, 7.24, 7.20 (AB-system, d=7.47 and 7.22; J=8.84 Hz, 4H), 4.40–3.91 (br, 2H, 3.77–2.92 (br m, 6H+water), 2.77 (s, 3H); IR (KBr): ν 1717 (C═O) cm−1.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3.[H-].[Na+].[CH3:29][O:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][S:33][C:32]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][O:38][C:36]([C:35]1[C:31]([O:30][CH3:29])=[C:32]([S:40]([O:23][C:18]2[C:19]([CH2:21][CH3:22])=[CH:20][C:15]([C:14]3[C:4]4[C:3]([CH3:26])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[CH:16][C:17]=2[CH2:24][CH3:25])(=[O:41])=[O:42])[S:33][CH:34]=1)=[O:37]
Reactant: COC(=O)c1csc(S(=O)(=O)Cl)c1OC
Reactant: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1O
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1scc(C(=O)OC)c1OC
Yield: 63.3 %

Procedure:
The title compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol (0.604 g, 1.67 mmol), 60% sodium hydride/mineral oil (0.0669 g, 1.67 mmol) and 3-methoxy-4-(methoxycarbonyl)thiophene-2-sulphonylchloride (0.499 g, 1.84 mmol) to give 0.629 g (63%) of the title compound. 1H NMR (DMSO-d6) δ 1.10 (t, 6 H), 1.59 (s, 3 H), 2.42 (s, 3 H), 2.57-2.68 (m, 4 H), 3.86 (s, 3 H), 4.02 (s, 3 H), 7.20 (s, 2 H), 7.38-7.50 (m, 3 H), 7.98 (d, 1 H), 8.50 (s, 1 H), 8.81 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=1)[O:21][CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:37]=[CH:36][CH:35]=[C:20]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])[CH:19]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (509 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (753 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 96.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (809 mg, yield: 69%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).