Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](ON3C(=O)CCC3=O)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C.O>[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (“soln.”) of 6-aminohexanoic acid (1; 144 mg, 1.1 mmol) in 9% aq. Na2CO3 soln. (2.4 ml) was added a soln. of (9H-fluoren-9-yl)methyl succinimidyl carbonate (2; 337 mg, 1 mmol) in DMF (2.5 ml). After stirring for 1 h at room temperature (“r.t.”), the mixture was diluted with H2O (50 ml) and extracted twice with Et2O (2×20 ml). Then, the H2O phase was acified with conc. HCl soln. to pH 2 and extracted with AcOEt (5×30 ml). The organic (“org.”) layer was dried (MgSO4) and evaporated. The residue was crystallized in CHCl3/petroleum ether: 306 mg (86%) of 3. Colorless crystals. M.p. 116°. 1H-NMR (CDCl3): 7.80-7.55 (2m, H—C(1)(fmoc), H—C(4)(fmoc), H—C(5)fmoc, H—C(8)(fmoc); 7.45-7.25 (m, H—C(2)(fmoc), H—C(3)(fmoc), H—C(6)(fmoc), H—C(7)(fmoc); 4.45 (m, CH2O)(fmoc)); 4.2(m, H—C(9)(fmoc)); 3.25-3.0, 2.4, 1.8-1.3 (3m, NH(CH2)5CO). Anal. calc. for C21H23NO4 (353.42): C 71.37, H 6.56, N 3.96; found: C 71.35, H 6.65, N 3.93.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:8]2[C:21]([Br:24])=[CH:22][S:23][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>CO.C1COCC1>[Br:24][C:21]1[C:8]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[S:23][CH:22]=1
Reactant: COC(=O)c1cc2scc(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2scc(Br)c2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product of Step 3 (4 g) in 50 ml of 1:1 MeOH/THF was added 25 ml of 1N aqueous LiOH solution. The reaction mixture was stirred at 55° C. for 4 h and the concentrated under reduced pressure to move the volatile solvent. The resulting aqueous solution was treated with 5 ml of AcOH and stirred for 2 h. The solid was collected by filtration to give 3.2 of the title compound as a white powder.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[CH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2].[BH4-].[Na+]>CO>[C:1]([CH:3]([C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#CC(=Cc1cccnc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CC(Cc1cccnc1)c1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
The thus obtained 1-cyano-1-(4-bromophenyl)-2-(pyridin-3-yl)-ethene (m.p. 126°) is dissolved in 800 ml of CH3OH, and then 10 g of NaBH4 are added, with stirring, within 20 minutes at 20°-30°. The mixture is stirred for 12 hours at room temperature and the solvent evaporated at the water jet. The residue is suspended in 1000 ml of water, sucked off, dried and recrystallised in toluene (m.p. 111°).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:14]([NH2:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C([O-])(O)=O.[Na+].[CH3:22][N:23]([CH3:37])[C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.C(O)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O1CCCC1.ClCCCl>[ClH:1].[ClH:1].[CH3:22][N:23]([CH3:37])[C:24]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([NH:2][CH:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:14]([NH2:16])=[O:15])[CH2:28][CH2:29]1
Reactant: NC(=O)C(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NC(Cc2c[nH]c3ccccc23)C(N)=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
D,L-tryptophanamide hydrochloride (1.49 g, 6.25 mmol) was vigorously stirred with 1,2-dichloroethane (30 ml), tetrahydrofuran (20 ml) and saturated NaHCO3 solution (40 ml) for 15 min and the aqueous phase was then immediately extracted with a tetrahydrofuran/ethyl acetate mixture (1:3.5×40 ml). After drying with Na2SO4 the organic phase was concentrated to low volume. The released base (1.03 g, 5.06 mmol) and 4-(dimethylamino)-4-phenylcyclohexanone (1.09 g, 5.06 mmol) were dissolved in tetrahydrofuran (40 ml) and 1,2-dichloroethane (30 ml) in argon. Glacial acetic acid (0.291 ml, 5.06 mmol) and Na2SO4 (2.53 g) were added to the clear solution. After a reaction time of 15 min the reaction mixture was mixed with NaBH(OAc)3 (1.52 g, 7.08 mmol) and stirred for 2 d at room temperature. For work up of the batch the mixture was mixed with saturated NaHCO3 solution (60 ml) and stirred for 15 min. The aqueous phase was extracted with dichloromethane (2×40 ml). The combined organic phases were concentrated to low volume after drying, and a light brown oil was obtained. The chromatographic separation of the substance mixture on silica gel 60 (150 g) was conducted with ethyl acetate/methanol (1:1).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8][NH2:9].C([O:14][C:15]([C:17]1[NH:18][N:19]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)=O)C>C1COCC1>[CH3:5][O:6][CH:7]([O:10][CH3:11])[CH2:8][NH:9][C:15]([C:17]1[NH:18][N:19]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)=[O:14]
Reactant: COC(CN)OC
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COC(CNC(=O)c1cc(COc2ccccc2)n[nH]1)OC
Temperature: 130 °C
Yield: 144.2 %

Procedure:
Trimethylaluminum (1.7 mL, 3.4 mmol) was added to a stirred solution of aminoacetaldehyde dimethyl acetal (0.37 mL, 3.4 mmol) in THF (2 mL) at 0° C. under nitrogen atmosphere. To this solution 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.7 g, 2.84 mmol) in THF (5 mL) was added at 0° C. The reaction was heated at 130° C. for 2 minutes under microwave irradiation. Then mixture was quenched with a 2N solution of HCl (pH-3) and diluted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid (2,2-dimethoxy-ethyl)-amide (1.25 g, quantitative) as a brown oil that was used in the next step without further purification.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([NH2:17])[C:7]2[C:13]([CH3:14])=[C:12]([CH:15]=[O:16])[CH:11]=[N:10][C:8]=2[N:9]=1.C([O-])(=O)C>CO>[NH2:3][C:4]1[N:5]=[C:6]([NH2:17])[C:7]2[C:13]([CH3:14])=[C:12]([CH2:15][OH:16])[CH:11]=[N:10][C:8]=2[N:9]=1
Reactant: Cc1c(C=O)cnc2nc(N)nc(N)c12
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)cnc2nc(N)nc(N)c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
NaBH4 (500 mg, 13.2 mmol) was added in portions during a 10 minute interval to a stirred suspension of crude 13 (2.73 g), in MeOH (500 mL) at 20°-23° C. Stirring was continued for two hours, then NaBH4 (500 mg) was again added as before. After the mixture had been stirred overnight, HPLC (acetate buffer of pH 3.6-MeOH, 9:1) showed the conversion of 13 to the more polar 14 was complete. After removal of the MeOH by evaporation, the residue was stirred with H2O (90 mL) and treated with 1N HCl to lower the pH to 8.0 (from 11.3 initially). This mixture was stirred while being heated at about 70° C. (bath temperature) for 20 minutes. The solid filtered from the cooled mixture amounted to 2.63 g and was used without further purification in the conversion to crude 15 described below. Spectral data: mass, m/e 206 (M+1)+ ; 1H NMR (Me2SO-d6) δ2.68 (s, CH3), 4.52 (s, CH2), 8.48 (s, C7 --H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[S:24]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:29][C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: OCc1ccsc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(OCc4ccsc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a suspension of methyl 3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (240 mg), 3-thiophenemethanol (68 mg) and triphenylphosphine (218 mg) in dry dichloromethane were added to diethyl azodicarboxylate (139 mg) under ice-cooling. After 2 hr, the reaction mixture was stirred at room temperature. After 6 hr, to a suspension of 3-thiophenemethanol (34 mg) and triphenylphosphine (109 mg) in dry dichloromethane was added diethyl azodicarboxylate (69 mg) under ice-cooling. After 20 hr, the reaction mixture was subjected to flash silica gel chromatography (silica gel 60 ml, eluent: chloroform). The eluate was recrystallized from ethyl acetate to give the objective compound (143 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>C(O)C.O1CCCC1>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 140 °C

Procedure:
To a solution of 1 g of 5-bromo-2-nitropyridine in 5 mL of ethanol are added 6 mL of a 2 M solution of dimethylamine in tetrahydrofuran. The reaction mixture is heated for 2 hours at 140° C. in a microwave machine. After cooling, the solid formed is separated off and washed with ethyl ether to give 850 mg of N,N-dimethyl-6-nitropyridine-3-amine in the form of a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][N:50]=1>C(Cl)Cl>[Br:55][C:52]1[CH:53]=[CH:54][C:49]([NH:48][C:36](=[O:38])[CH:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[C:30]([N+:45]([O-:47])=[O:46])[CH:31]=2)[CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:50][CH:51]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A solution of triphenylphosphine (241 mg, 0.92 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (164 mg, 0.92 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 64, 250 mg, 0.84 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (320 mg, 1.85 mmol). The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford N-(5-bromo-pyridin-2-yl)-2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide (216 mg, 57%) as a pale yellow solid: mp 128-130° C.; EI-HRMS m/e calcd for C19H19BrClN3O3 (M+) 451.0298, found 451.0300.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+].[Cl:24][CH:25]=[CH:26][CH2:27]Cl>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:14]([CH2:27][CH:26]=[CH:25][Cl:24])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: ClC=CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(C#N)cc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(C#N)cc2c1Br
Temperature: 25 °C
Yield: 107.9 %

Procedure:
A solution of 194 (2.50 g, 7.21 mmol) in DMF (20 mL) was added to a suspension of NaH (350 mg, 8.65 mmol, 60% in oil) in DMF (20 mL) at 0° C. 1,3-Dichloropropene (1.60 g, 14 mmol) was added and the mixture was allowed to warm to room temperature over 2 h. The DMF was removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with water (×2), brine (×2) and dried. Filtration through silica gel gave tert-butyl 1-bromo-7-cyano-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (195) (3.28 g, 100%) as a pale yellow oil; 1H NMR (CDCl3) (mixture of rotamers and E and Z forms) δ 8.73 (s, 1H), 7.93-7.96 (m, 1H), 7.83-7.87 (m, 1H, 7.68-7.70 (m, 1H), 7.39-7.46 (m, 1H), 6.00-6.11 (m, 2 H), 4.49-4.62 (m, 1H), 4.33-4.43 (m, 1H), 1.33, 1.32 (2's, 9 W. HRMS (FAB) calcd. for C19H1879Br35ClN2O2 (MH+) m/z 421.0318, found 421.0330.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[CH:4][CH:3]=1.[NH:27]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:23]([O:22][C:20]([C:9]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2[C:6](=[N:7][C:2]([N:27]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:3][CH:4]=2)[CH:8]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OC(C)(C)C)n2S(=O)(=O)c2ccccc2)n1
Temperature: 110 °C

Procedure:
tert-Butyl 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (0.500 g, 1.27 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (0.32 g, 1.4 mmol) and Cs2CO3 (0.41 g, 1.3 mmol) were combined in toluene (6 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.10 g, 0.13 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes and was heated to 110° C. for 4 hours. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water, the aqueous phase was extracted a total of three times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded purified product (0.43 g, 57%).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]=C(Br)C2C=C(C3C=CC(F)=CC=3)SC=2C=1O)=[O:7])CCC.C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)SC2=C(Br)N=1)=O)CCC.C(O[C:56]([C:58]1[N:63]=[C:62]([CH3:64])[C:61]2[CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][CH:69]=3)[S:67][C:60]=2[C:59]=1[OH:75])=[O:57])CCC.C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)SC2=C(C)N=1)=O)CCC>>[F:74][C:71]1[CH:70]=[CH:69][C:68]([C:66]2[S:67][C:60]3[C:59]([OH:75])=[C:58]([C:56]([NH:13][CH2:8][C:6]([OH:7])=[O:5])=[O:57])[N:63]=[C:62]([CH3:64])[C:61]=3[CH:65]=2)=[CH:73][CH:72]=1
Reactant: CCCCOC(=O)c1nc(Br)c2cc(-c3ccc(F)cc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(C)c2cc(-c3ccc(F)cc3)sc2c1O
Agent: CCCCOC(=O)c1nc(Br)c2sc(-c3ccc(F)cc3)cc2c1O
Agent: CCCCOC(=O)c1nc(C)c2sc(-c3ccc(F)cc3)cc2c1O
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccc(F)cc3)cc12

Procedure:
The title compound was prepared from 4-bromo-2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester and 7-bromo-2-(4-fluoro-phenyl)-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 34-c, under conditions analogous to experimental example 32-b. MS for 2-(4-fluoro-phenyl)-7-hydroxy-4-methyl-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester: (+) m/z 360.0.0 (M+1). MS for 2-(4-fluoro-phenyl)-4-hydroxy-7-methyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester: (+) m/z 360.0.0 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH2:13][C:14]([OH:16])=[O:15])[N:11]=[N:10][N:9]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][O:15][C:14](=[O:16])[CH2:13][N:12]1[C:8]([C:7]2[CH:6]=[CH:5][S:4][C:3]=2[S:2][CH3:1])=[N:9][N:10]=[N:11]1
Reactant: OCCO
Reactant: CSc1sccc1-c1nnnn1CC(=O)O
Agent: O=S(=O)(O)O
Product: CSc1sccc1-c1nnnn1CC(=O)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.1 %

Procedure:
To a solution of 920 mg (3.6 mM) of [5-(2-methylthio-3-thienyl)tetrazol-1-yl]acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=50/1) for separation and purification, to give 950 mg (yield 88.1%) of [5-(2-methylthio-3-thienyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=2)[OH:14])=[O:12])=[CH:7][CH:6]=1.Cl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O.C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[OH:14])=[O:12])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(=O)C(O)c2ccc(OCOC)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(O)cc1)C(O)c1ccc(O)cc1
Reaction time: 0.75 h

Procedure:
4,4'-Di(methoxymethoxy)benzoin (26 g) was dissolved in a mixture of water (250 ml) and ethanol (250 ml) at 80°. Concentrated hydrochloric acid (2.6 g) was added, and the solution was stirred at 80° for 45 minutes. Then it was cooled and a solution of sodium bicarbonate (2.6 g) in water (50 ml) was added. The reaction mixture was poured into water (600 ml) saturated with ammonium sulphate, and the resulting mixture was extracted with ether. The ethereal solution was dried over anhydrous MgSO4, and removal of the ether by distillation left 19 g of a dark red solid. Thin layer chromatography of this showed it to be substantially 4,4'-dihydroxybenzoin by comparison with an authentic sample (see later), and the material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC2CCCC2Nc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCC2CCCC2Nc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
Methyl 4-[2-[N-(4-chlorophenyl)amino]cyclopentan-1-ylmethoxy]benzoate (2.57 g) was dissolved in methanol (40 ml) and thereto was added a solution of sodium hydroxide (0.86 g) in water (8 ml), and the mixture was heated with stirring at 60° C. for 14 hours. The reaction mixture was cooled and thereto was added conc. hydrochloric acid (1.87 ml), then, the mixture was concentrated under reduced pressure. The residue was washed with water and about 50 % aqueous methanol was added thereto, and the mixture was heated. The mixture was allowed to stand, and the resulting crystal was collected by filtration to give the desired product (1.72 g). mp. 153°-156° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C>C1COCC1>[S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:10])=[O:9]
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Yield: 91.2 %

Procedure:
A mixture comprising 50 g of (tetrahydro-3-furanyl)methanol, 95 g of tosyl chloride, 52 g of triethylamine and 450 ml of THF was refluxed for 8 hours. After separation of insolubles by filtration, the reaction fluid was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/7) to obtain 114.5 g of (tetrahydro-3-furanyl)methyl tosylate.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[C:5]=2[N:6]=1.Cl.N([O-])=[O:15].[Na+]>O>[Cl:12][C:7]1[C:5]2[NH:6][C:2](=[O:15])[S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: Nc1nc2c(Cl)c(Cl)ccc2s1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2c(Cl)c(Cl)ccc2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
33 g of 2-amino-4,5-dichlorobenzothiazole, 241 g of 30% hydrochloric acid and 33.9 g of water are introduced into a 750 ml pressure vessel at room temperature and subsequently heated to 50° C. After the mixture has been stirred for 30 minutes, 58.3 g of aqueous, 40% sodium nitrite solution are metered in at a uniform rate in the course of 3 hours at 50° C., with vigorous stirring. After metering in has ended, stirring is continued for 4 hours at 50° C. Excess nitrite is then removed by adding approximately 15 g of 18% aqueous urea solution. The reaction vessel is subsequently sealed, and the reaction mixture is heated for 4 hours at 140°-150° C. (pressure approximately 6 bar). After the mixture has cooled to 20° C., the crystalline product is filtered off with suction, washed with water and dried at 60° C. to constant weight. 27.9 g of 4,5-dichlorobenzothiazol-2-one with a pure substance content of 97.2% are obtained (corresponding to 81.8% yield) with a DSC melting point of 229.1° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([CH3:9])=[N:8][C:4]=2[C:3]=1[N+:12]([O-:14])=[O:13].[F-].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24].C1OCCOCCOCCOCCOCCOC1>CS(C)=O.O.Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:22][C:23]=1[O:24][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([CH3:9])=[N:8][C:4]=2[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1nc2c([N+](=O)[O-])c(F)ccc2[nH]1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)cc3Cl)ccc2[nH]1
Temperature: 80 °C

Procedure:
Under an N2 atmosphere, 5-fluoro-2-methyl-4-nitro-1H-benzo[d]imidazole (0.233 g, 1.19 mmol) was treated with Al2O3 supported potassium fluoride (0.583 g, 40 wt. %), 3-chloro-4-hydroxyphenylacetic acid (0.223 g, 1.19 mmol) and 18-crown-6 (0.031 g, 0.119 mmol) in DMSO (1 mL). The reaction was heated 80° C. for 20 h. Upon cooling to room temperature, the reaction was diluted with water and 1N HCl was added to pH 5. The reaction was extracted with ethyl acetate (3×). The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 10% methanol in dichloromethane, afforded the title compound. LC-MS ESI (pos.) m/z: 362.0 (M+H).