Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH3:18][O-:19].[Na+]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:19][CH3:18]
Reactant: C[O-]
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-Chloro-6-fluoro-5-nitroquinoxaline-2(1H),3(4H)-dione (0.100 g, 0.385 mmol, as prepared above) in DMSO (1.0 mL) at room temperature, sodium methoxide (0.125 g, 2.31 mmol, Mallinckrodt) was added in one portion. The resulting dark red solution was stirred overnight at room temperature. It was then diluted with water (5.0 mL) and acidified with concentrated HCl (6 drops) to pH ~2. The precipitated solid was filtered, washed with water (5.0 mL), and dried under vacuum to obtain 0.116 g (110%) of pure (1H NMR) title compound as a yellow powder; m.p. darkens at 316° C.; 1H NMR (DMSO-d6): δ3.821 (s, 3H), 7.275 (s, 1H), 12.079 (s, 1H) 12.121 (s, 1H). The NMR also indicates the presence of DMSO (reaction solvent).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=2)=[CH:2]1.N1C2C(=CC=CC=2)C=CC=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]\[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:19]=2)=[CH:2]1
Reactant: N[C@H](COc1cncc(C#Cc2ccncc2)c1)Cc1c[nH]c2ccccc12
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: N[C@H](COc1cncc(/C=C\c2ccncc2)c1)Cc1c[nH]c2ccccc12
Yield: 73.6 %

Procedure:
A mixture of Example 14D (40 mg, 0.11 mmol), 5% Pd/BaSO4 (8.1 mg) and quinoline (8.1 μL) in methanol (3 mL) was stirred under hydrogen (20 psi) at room temperature for 12 minutes and filtered. The filtrate was concentrated and the residual oil was purified by HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide the desired product (30 mg, 75%). MS (APCI) m/e 369 (M−H)−; 1H NMR (300 MHz, CD3OD) δ 8.57 (d, J=6.8 Hz, 2H), 8.29 (d, J=2.4 Hz, 1H), 8.04 (s, 1H), 7.69 (d, J=6.4 Hz, 2H), 7.57 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.33 (t, J=1.7 Hz, 1H), 7.21 (s, 1H), 7.14 (m, 2H), 7.02 (td, J=8.1, 1.0 Hz, 1H), 6.95 (d, J=12.2 Hz, 1H), 4.24 (dd, J=10.5, 3.0 Hz, 1H), 4.08 (dd, J=10.5, 5.6 Hz, 1H), 3.92 (m, 1H), 3.26 (m, 2H); Anal. Calcd for C23H22N4O. 3.6 TFA: C, 46.45; H, 3.30; N, 7.17. Found: C, 46.56; H, 3.35; N, 7.34.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(OC)C=CC=CC=1.[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:49]/[O:50][CH3:51])/[C:20]([NH:22][C@@H:23]2[C:47](=[O:48])[N:25]3[C:26]([C:35]([O:37]CC4C=CC(OC)=CC=4)=[O:36])=[C:27]([C@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+:65].[Na+].[Na+]>ClCCl>[NH2:13][C:14]1[S:15][CH:16]=[C:17](/[C:19](=[N:49]/[O:50][CH3:51])/[C:20]([NH:22][C@@H:23]2[C:47](=[O:48])[N:25]3[C:26]([C:35]([O-:37])=[O:36])=[C:27]([C@H:30]4[CH2:34][CH2:33][CH2:32][O:31]4)[CH2:28][S:29][C@H:24]23)=[O:21])[N:18]=1.[Na+:65]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
Aluminium chloride (740 mg, 5.55 mmol) was added to anisole (32 ml) and dry dichloromethane (15 ml) at -20° C. and stirred for 15 min. The temperature of the cooling bath was then lowered to -40° C. before addition of a solution of 4-methoxybenzyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (1.06 g, 1.85 mmol) in dichloromethane (10 ml). After 1 min., the solution was treated with trisodium citrate (0.5M, 54 ml) and then vigorously stirred for 10 min. at room temperature. The aqueous phase was separated, washed with dichloromethane (×2) and concentrated in vacuo. The residue was chromatographed on HP20SS eluting with water, then 1% THF in water. Fractions containing the product, (h.p.l.c. analysis), were combined and freeze-dried to give the title compound (560 mg, 64%); νmax (KBr) 3399, 1762, 1669, 1603, 1529, 1038 cm-1 ; δH (d6 -DMSO, 250 MHz) 1.50-1.91 (4H, m), 3.25 and 3.38 (2H, ABq, J 16.8 Hz), 3.60-3.82 (2H, m), 3.84 (3H, s), 4.96 (1H, d, J 4.7 Hz), 5.20 (1H, dd, J 8.6, 6.0 Hz), 5.48 (1H, dd, J 8.1, 4.7 Hz), 6.76 (1H, s), 7.23 (2H, br. s, exch.), 9.50 (1H, d, J 8.1 Hz, exch.). [Mass spectrum: +ve ion (thioglycerol) MH+ (476), MNa+ (498)].
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[O:8]1.[S:19](=[O:21])=[O:20].[Li].C[O-].[Na+:25]>CCCCCC.[Na]>[CH3:6][C:7]1([CH3:18])[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:19]([O-:21])=[O:20])[CH:13]=2)[O:8]1.[Na+:25]
Reactant: O=S=O
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: C[O-]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC1(C)C=Cc2cc(S(=O)[O-])ccc2O1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
A 1.5M solution of butyllithium in hexane (5.2 ml) was added to a stirred solution of 2,2-dimethyl-6-bromochromene [prepared by the procedure described in Bull. Chem. Soc. Jap., 1982, 55(4) 1153] (2.0 g, 8.4 mM) in sodium dried ether (24 ml). The mixture was stirred for 3 hours, then cooled to -20° C. and treated with excess gaseous sulphur dioxide, whereupon the lithium sulphinate salt immediately began to separate out as a solid. The resultant suspension was stirred rapidly for one hour and then allowed to attain ambient temperature. The solid precipitate of lithium 2,2-dimethylchromene-6-sulphinate was collected by filtration and washed with dry acetone and sodium dried ether. The lithium salt was then dissolved in water and the solution acidified to pH 1 and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and evaporated. The resultant 2,2-dimethylchromene-6-sulphinic acid was dissolved in methanol (10 ml) containing sodium methoxide (400 mg, 7.3 mmol). After 10 minutes, the methanol was removed in vacuo to leave a solid residue of sodium 2,2-dimethylchromene-6-sulphinate, which was dried by azeotropic distillation with toluene in vacuo and used directly in the above reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@@H](Oc1ccc(F)cc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In analogous manner to that described in example 5a), the reaction of (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-butyric acid and 2,5-difluoro-nitrobenzene yielded (72% of theory) the title compound as a brown oil, MS m/e (%): 357.1 (M−H+, 100).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:4]=1)[NH2:2].[N:21]([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.O>[N:1]([C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([O:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH:4]=1)=[N+:2]=[N-:21]
Reactant: CC(C)(O)COc1cc(NN)nc(N2CCOCC2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(O)COc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1

Procedure:
1-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol was dissolved in glacial acetic acid (30 mL). To this solution was added a solution of sodium nitrite (700 mg) in water (4 mL). The reaction was stirred for ten minutes, and poured into ethyl acetate (100 mL). The organic layer was then washed with water (100 mL) and 10% sodium carbonate (2×100 mL). The organic layer was dried over magnesium sulfate and evaporated to give 1-(6-Azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-2-methyl-propan-2-ol, which was used without purification in the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:8][CH2:7]2)[O:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:12][C:3]1=2.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8]2)[O:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:12][C:3]1=2
Reactant: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)C(=O)C3(CC3)O4)CC2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)C(O)C3(CC3)O4)CC2)cc(OC)c1OC
Yield: 95.6 %

Procedure:
In a mixture of methylene chloride (2 ml) and methanol (10 ml) is dissolved 1-[3-oxospiro[benzofuran-2(3H), 1'-cyclopropan]-5-ylcarbonyl]-4-(3,4,5-trimethoxybenzyl)piperazine (0.5 g). To the solution is added, while stirring under ice-cooling, sodium borohydride (0.2 g). The reaction mixture is concentrated under reduced pressure. After addition of water (50 ml), the residue is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give 1-[3-hydroxyspiro[benzofuran-2(3H), 1'-cyclopropan]-5-ylcarbonyl]-4-(3,4,5-trimethoxybenzyl)piperazine (0.48 g) as a colorless oily product. This product (0.15 g) and fumaric acid (0.04 g) are dissolved in methanol (3 ml). The mixture is concentrated under reduced pressure. To the concentrate is added ether to give 1-[3-hydroxyspiro[benzofuran-2(3H), 1'-cyclopropan]-5-ylcarbonyl]-4-(3,4,5-trimethoxybenzyl)piperazine-fumarate (0.13 g) as a powdery product.
Reaction SMILES: Cl.[C:2]([OH:33])(=[O:32])[CH2:3][CH2:4][C@H:5]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]([NH:16][CH2:17][C@H:18]2[NH:29][C:28]3[C:26](=[O:27])[NH:25][C:23]([NH2:24])=[N:22][C:21]=3[NH:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:11])[C:6]([OH:8])=[O:7]>>[C:2]([OH:33])(=[O:32])[CH2:3][CH2:4][C@H:5]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:16][CH2:17][CH:18]2[NH:29][C:28]3[C:26](=[O:27])[NH:25][C:23]([NH2:24])=[N:22][C:21]=3[NH:20][CH2:19]2)=[CH:30][CH:31]=1)=[O:11])[C:6]([OH:8])=[O:7]
Reactant: Nc1nc2c(c(=O)[nH]1)N[C@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: Cl
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2

Procedure:
After subsequently slowly bringing the pH to 4.4 using hydrochloric acid and maintaining this value, 42.0 g of crystalline (6R)-tetrahydrofolic acid with a chemical content of 96.2% and a (6R) percentage of 99.5 are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[CH2:18]([CH2:20][NH2:21])[OH:19]>O>[N:13]1([C:4]2[N:3]=[C:2]([NH:21][CH2:20][CH2:18][OH:19])[CH:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: NCCO
Solvent: O
Product: OCCNc1cc(N2CCCC2)nc(N2CCCC2)n1

Procedure:
A mixture of 4-chloro-2,6-di-1-pyrrolidinyl-pyrimidine (II, J. Med. Chem., 33, 1145 (1990), 300 g) in ethanolamine (1000 mL) is heated at 140° for 66 hr. The reaction mixture is cooled, diluted with water (1700 mL) and the product is isolated by filtration, to give the title compound, mp=150.5-151.50°; NMR (CDCl3) 6.55, 4.83, 4.75, 3.75-3.72, 3.54-3.38 and 1.93-1.85 δ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][C@H:13]3[C@H:8]([CH2:9][N:10]([CH3:16])[CH2:11][CH2:12]3)[C:6]=2[CH:7]=1.[CH2:17](O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:15][CH2:14][C@H:13]4[C@H:8]([CH2:9][N:10]([CH3:16])[CH2:11][CH2:12]4)[C:6]=3[CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCc1ccccc1
Reactant: CN1CC[C@H]2COc3ccc(O)cc3[C@H]2C1
Product: CN1CC[C@H]2COc3ccc(OCCc4ccccc4)cc3[C@H]2C1

Procedure:
A mixture of 0.2 g (±)-[4aR*,10bS*]-1,3,4,4a,5,10b-hexahydro-9-hydroxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine (m.p. of HCl salt 268°-269° ), 0.215 ml phenethyl alcohol and 0.3 g dicyclohexylcarboddiimide is heated under nitrogen for 18 hours at 130°. The cooled reaction mixture is flash chromatographed with CH2Cl2 /methanol (20:1) to yield the title compound; m.p. HCl salt 204°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=2[N+:20]([O-])=O)=[N:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:5])[CH3:2].[Cl-].[NH4+].O1CCC[CH2:33]1>[Zn]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:12]3[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=3[N:20]=[CH:33]2)=[N:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CCOC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To mixture of 3.0 g of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41b), 40 mL of tetrahydrofuran and 20 mL of saturated ammonium chloride solution, was added in three equal portions, at 30 minute intervals, 9 g of zinc powder. After the third portion of zinc powder was added, the orange color disappeared and the mixture turned clear. The solid was removed by filtration. The organic layer was separated. The aqueous layer was extracted twice with 30 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with 30 mL of acetic acid and 3 mL of trimethyl orthoformate for 1 hour. The mixture was concentrated under reduced pressure, 100 mL of water was and the pH adjusted to 9 by addition of 15% sodium hydroxide solution. The precipitate was collected by filtration and purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-2:98) to give 2.3 g of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid ethyl ester (I.41a) as an off-white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:21])[CH2:10][C:11]([C:13]2[C:18](OC)=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:5][CH:4]=1.Br.C([O-])(O)=O.[Na+]>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:21][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ncccc2OC)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccc(O)cc2)oc2cccnc12
Temperature: 25 °C
Yield: 3.3 %

Procedure:
In 50 mL round-bottom flask fitted with magnetic stirrer were placed 1-(4-methoxyphenyl)-3-(3-methoxypyridin-2-yl) propane-1,3-dione (4.68 g, 16 mmol) and 45% aqueous solution of HBr (25 mL). The reaction mixture was refluxed for 3 h, then cooled down to rt. Solid NaHCO3 was used to adjust pH to 7, followed by EtOAc (30 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, concentrated to give the crude product, which was purified by column chromatography using 30% MeOH in EtOAc to give 125 mg of 2-(4-hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one (3.2%). MS (ES) m/z: 240.09 (M+1), and 149.06.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[C:24]([O:41][CH3:42])=[C:25]([CH:39]=[O:40])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:28]=1>O>[F:22][C:23]1[C:24]([O:41][CH3:42])=[C:25]([C:39]([OH:2])=[O:40])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:28]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Agent: c1cc[nH+]cc1
Solvent: O
Product: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Reaction time: 12 h
Yield: 57 %

Procedure:
Pyridinium dichromate (0.25 g, 0.67 mmol ) was added to a solution of 5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carbaldehyde (0.2 g, 0.67 mmol) DMF (2 mL) and stirred for 12 h, to complete the reaction more pyridinium dichromate (0.2 g , 0.53 mmol) was added and stirred for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc(10 mL). Solvent was removed under reduced pressure to get 5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.12 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50]O)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:58])CC)C>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][F:58])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CF)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
To a solution of {(1S,2S,3S,4R,5S)-2,3,4-Tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-1-yl}-methanol (616 mg, 0.871 mmol) in dichloromethane (3 mL) at 0 degrees Celsius was added diethylaminosulfur trifluoride (170 microL, 1.3 mmol) and the resulting mixture was slowly warmed to room temperature and stirred at this temperature for 16 hours. The mixture was diluted with dichloromethane and washed with a saturated solution of aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using a 40 g redisep silica cartridge (eluting with a gradient of 0 to 20% ethyl acetate in heptane) to afford (1S,2S,3S,4R,5S)-2,3,4-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-fluoromethyl-6,8-dioxa-bicyclo[3.2.1]octane as a colorless oil (40 mg, 7% yield). (LCMS) 753.4 (M+HCOO−: negative mode).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](Br)[C:23]#[CH:24]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:24][C:23]#[CH:22])(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Product: C#CCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 1.43 g (0.012 mol) of propargylbromide the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising, extremely viscous oil in a yield of 2.33 g (71.4% of theory) and with an Rf value of 0.66 (solvent mixture as specified in 4.7.1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)(=[O:30])=[O:31])=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)s2)c(F)c1

Procedure:
5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}thiophene-3-carboxamide was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.480 mmol) and 4-[(4-bromophenyl)sulfonyl]morpholine (147 mg, 0.480 mmol) as the starting materials.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[C:21]2[C:22]([CH3:30])=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[C:21]2[C:22]([CH3:30])=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: Cc1cc(C(N)=O)ncc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 336 h
Yield: 59.2 %

Procedure:
3-Chloroperbenzoic acid (259 mg, 0.98 mmol) was added to a solution of 5-[[(4-chlorophenyl)thio](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxamide (395 mg, 0.98 mmol) in methylene chloride (10 ml) at 0° C. After stirring for 14 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and collected by filtration, thus to obtain the title compound (243 mg, 0.58 mmol, 59%) as a white solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].C1(CNC([C:18]2[CH:35]=[CH:34][C:21]3[NH:22][C:23]([C:25]4[C:33]5[C:28](=CC=CC=5)[NH:27][N:26]=4)=[N:24][C:20]=3[CH:19]=2)=O)CCCCC1>>[CH2:3]([O:4][C:28]1[NH:27][N:26]=[C:25]([C:23]2[NH:22][C:21]3[CH:34]=[CH:35][CH:18]=[CH:19][C:20]=3[N:24]=2)[CH:33]=1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(NCC1CCCCC1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Product: CCOc1cc(-c2nc3ccccc3[nH]2)n[nH]1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A mixture of trifluoroacetic acid (6 mL) and 2-(5-ethoxy-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (300 mg, Reference Example 11) was stirred at 50° C. for 1.5 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water (pH 10). The organic layer was dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) and then recrystallised from toluene to give 2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole (0.1 g) as a colourless solid, mp 217-219.5° C. [Elemental analysis: C, 62.26%; H, 5.23%; N, 23.44%. Calculated for C12H12N4O: C, 63.15%; H, 5.30%; N, 24.55%].