Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13](=[O:15])[CH3:14])[O:8][CH:7]=[C:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)[C:5]2=[O:26]>O=[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13](=[O:15])[CH3:14])[O:8][CH2:7][CH:6]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)[C:5]2=[O:26]
Reactant: CC(=O)Oc1ccc(-c2coc3cc(OC(C)=O)c(Cl)cc3c2=O)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C2COc3cc(OC(C)=O)c(Cl)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
Adam's catalyst (0.045 g) was added to a solution of 6-chloro-4′,7-diacetoxyisoflavone (0.25 g, 0.7 mmol) in ethyl acetate (30 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 h. The catalyst was removed by filtration through Celite and the resulting filtrate was evaporated in vacuo. The residue was recrystallised from ethanol to yield 6-chloro-4′,7-diacetoxyisoflavan4-one (0.15 g, 60%) as colourless plates. 1H NMR (CDCl3): δ 2.29 (s, 3H, OCOCH3), 2.37 (s, 3H, OCOCH3), 3.98 (dd, 1H, J 6.0 Hz, 7.5 Hz, H3), 4.68 (m, 2H, H2), 6.87 (s, 1H, H8), 7.07 (d, 2H, J 8.6 Hz, ArH), 7.27 (d, 2H, J 8.6 Hz, ArH), 8.01 (s, 1H, H5).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=O.CC(C[AlH]CC(C)C)C.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]1[CH:3]=[O:2])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C=O
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To the title compound of Example 1.1 (5.4 g, 22.1 mmol) in toluene (50 mL) at −78° C. was added 1.5 M DIBAL in toluene (33.8 mL, 50.7 mmol) drop-wise over 40 minutes. Methanol (120 mL) was then added drop-wise at −78° C. over 10 minutes. The reaction mixture was moved to an ice-bath where 10% wt citric acid (500 mL) was added and then mixture was stirred for an additional 1 hour. After the resulting mixture was extracted with ethyl acetate (2 times), the organic layer washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil (3.0 g, 64%).
Reaction SMILES: [ClH:1].[C:2]([C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)#[N:3]>CCOC(C)=O>[ClH:1].[C:2]([C:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3]
Reactant: Cc1ccccc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1(C#N)CCNCC1

Procedure:
A solution of EtOAc saturated with HCl (200 ml) was added to 4-cyano-N-(1,1 -dimethylethoxy)carbonyl-4-(2-methylphenyl)piperidine (31 mg, 0.097 mmol). The resulting mixture was allowed to react for 1 hour at room temperature. The EtOAc was removed in vacuo affording 4-cyano-4-(2-methylphenyl)piperidine hydrochloride (4i) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C:14]2([C:16]#[N:17])[CH:10]([CH2:11][CH2:12][O:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[NH2:17][CH2:16][C:14]12[CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH:10]1[CH2:11][CH2:12][O:13]2
Reactant: N#CC12CN(Cc3ccccc3)CC1CCO2
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NCC12CN(Cc3ccccc3)CC1CCO2

Procedure:
10.2 g (40 mmol, 90% pure) of 7-benzyl-1-cyano-2-oxa-7-aza-bicyclo[3.3.0]octane are added dropwise to 2 g of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran and the mixture is subsequently stirred under reflux for 15 hours. 2 ml each of water, 15% strength potassium hydroxide solution, and again water, are added dropwise, the inorganic salts are filtered off with suction, and the filtrate is concentrated and distilled.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=2)[CH:8]=1)(=O)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:11]2[CH:12]=[CH:7][CH:8]=[C:9]([C:13]3[CH:30]=[CH:29][C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15]=4[CH:14]=3)[CH:10]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S(=O)(Oc1cccc(-c2ccc3c4ccccc4c4ccccc4c3c2)c1)C(F)(F)F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2cccc(-c3ccc4c5ccccc5c5ccccc5c4c3)c2)c1
Yield: 98.2 %

Procedure:
12.9 g (28.5 mmol) 3-(triphenylen-2-yl)phenyl trifluoromethanesulfonate, 6.5 g (42.8 mmol) 3-methoxyphenylboronic acid, 0.47 g (1.1 mmol) 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos) and 18.2 g (85.5 mmol) potassium phosphate tribasic (K3PO4) were weighed in a round bottom flask. 150 mL toluene and 80 mL water were added to the flask as solvent. The solution was purged with nitrogen and 0.26 g (0.28 mmol) of tris(dibenzylideneacetone)dipalladium (0) [Pd2(dba)3] was added. The solution was heated to reflux for twelve hours. Upon cooling, the organic layer was separated, and dried with MgSO4. The product was readily separated by column chromatography using hexane/dichloromethane as eluent (1/0 gradient to 3/2). The solvent was removed by rotary evaporation resulting in 11.7 g (28 mmol) of the product, 2-(3′-methoxybiphenyl-3-yl)triphonylene.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[CH2:29]([O:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH3:40])[N:35]=[C:34]([CH2:41][C:42](O)=[O:43])[N:33]=1)[CH3:30]>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:42](=[O:43])[CH2:41][C:34]2[N:35]=[C:36]([O:38][CH2:39][CH3:40])[CH:37]=[C:32]([O:31][CH2:29][CH3:30])[N:33]=2)[CH2:26][CH3:27])[CH:13]=1)[CH3:4]
Reactant: CCOc1cc(OCC)nc(CC(=O)O)n1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2nc(OCC)cc(OCC)n2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and (4,6-diethoxy-pyrimidin-2-yl)-acetic acid were reacted as described in Example 8, Step 6 to provide {5-[2-({N-[2-(4,6-diethoxy-pyrimidin-2-yl)-acetyl]-N-ethyl-amino}-methyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:30])=[C:16]([C@:18]2([CH3:29])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH2:28])=[N:19]2)[CH:17]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[O:39])=[N:36][CH:37]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[O:39])=[N:36][CH:37]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([NH:28][C:20]2[O:21][C@H:22]([C:24]([F:26])([F:27])[F:25])[CH2:23][C@:18]([C:16]3[CH:17]=[C:12]([NH:11][C:8](=[O:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)[CH:13]=[CH:14][C:15]=3[F:30])([CH3:29])[N:19]=2)=[O:39])=[N:36][CH:37]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: O=C([O-])O
Agent: O=C(c1ccc(Cl)cn1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccc(Cl)cn2)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stock solution of (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone was prepared by adding N,N′-carbonyldiimidazole (Aldrich; 278 mg, 1.72 mmol) to a solution of 5-chloropicolinic acid (Shao Yuan; 280 mg, 1.78 mmol) in THF (5.0 mL) and heating the reaction mixture to 60° C. for 2 h. (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (4i, 50 mg, 0.172 mmol) was added to a flask containing 0.55 mL (1.1 equiv.) of the (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone stock solution. The reaction mixture was allowed to stir for 30 min at ambient temperature, after which a second aliquot of (5-chloropyridin-2-yl)(1H-imidazol-1-yl)methanone solution (0.55 mL, 1.1 equiv.) was added. After 16 hs, saturated aqueous NaHCO3 (50 mL) was added to the reaction mixture and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→50% EtOAc/hexane) to give 5-chloro-N-((4S,6S)-4-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)picolinamide (85.3 mg, 0.150 mmol) as a colorless glass. MS m/z=570 M+. Calculated for C24H17Cl2F4N5O3: 570.3
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH2:22]>>[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[NH:22][C:13](=[O:15])[CH2:12][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene4-sulfonyl)sarcosine was coupled to Nε-Boc-L-lysine methyl ester hydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-Nε-Boc-L-lysine methyl ester. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[NH:6][C:5](=O)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Cl)n2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (51.5 g, 168 mmol) and phosphoryl chloride (50 mL) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (53.4 g, 98%). MS (ISN) 384.1 [(M+OAc)−], 386.0 [(M+2+OAc)−]; mp 39-40° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(O)(=O)CCCCCCCCCCC>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: CCCCCCCCCCCC(=O)O
Agent: [H+]
Solvent: CC(C)O
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 23 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.0014 mg of lauric acid was added. Next, 0.01 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.02 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 35% and phenethyltriethoxysilane was produced at a yield of 23%. The yield of (α-methylbenzyl)triethoxysilane was 0.4%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1
Reactant: COC(=O)C[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Temperature: 40 °C
Yield: 52.6 %

Procedure:
To a round 25 ml bottomed flask containing cis-methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (10 mg, 0.038 mmol) and water (4 ml) was added sodium hydroxide (5 mg, 0.13 mmol) and the solution heated to 40° C. for 1 hr. The solution was poured into a separating funnel containing ethyl acetate (15 ml) and water (10 ml). To the aqueous layer was then added aqueous hydrochloric acid (10 ml, 1.0M) and ethyl acetate (20 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (5 mg, 55%) as a solid. m/z (ES+) 251 (M+H+); δH(CD3OD) 1.61-1.77 (8H, m), 2.30 (1H, m), 2.49 (2H, d), 2.84 (1H, m), 6.27 (2H, m), 6.96 (1H, d).
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22]CC)=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)/C=C/c1sc(-n2cnc3ccccc32)nc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1nc(-n2cnc3ccccc32)sc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of ethyl(2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoate (1.00 g), 2N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL), ethanol (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid and the precipitated solid was collected by filtration, washed with water and dried to give (2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoic acid (0.90 g, 98%) as crystals. Recrystallization from acetone-hexane gave pale-yellow prism crystals. melting point: 262–264° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][C:4](=O)[CH:3]=1.S(O)(O)(=O)=O.[NH2:20][OH:21].N1C=CN=C1>>[OH:21][N:20]1[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: Cc1cc(C2CCCCC2)oc(=O)c1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Product: Cc1cc(C2CCCCC2)n(O)c(=O)c1
Yield: 93.3 %

Procedure:
20 g of 4-methyl-6-cyclohexyl-2-pyrone, 8 g of hydroxylamine sulfate and 50 g of imidazole were heated to 90° C. Further 10 g of hydroxylamine sulfate were added portionwise in the course of 3 hours. After a reaction time of 5 hours, the mixture was worked up. 11.8 g of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone melting at 143° C were obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>O1CCCC1>[N:1]1([C:8](=[O:9])[CH2:7][C:6](=[O:10])[CH3:5])[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A solution of 18.00 g (0.31 mol) azetidine in 50 ml tetrahydrofuran was added dropwise to a solution of 25.00 g of diketene (0.30 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 26.45 g (0.19 mol, 63% yield) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:5]([C:6](N)=[O:7])=[C:4]([OH:14])[N:3]=1.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[C:10]([CH:11]([F:13])[F:12])=[CH:9][C:5]([C:6]([OH:16])=[O:7])=[C:4]([OH:14])[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1cc(C(F)F)c(Cl)nc1O
Product: O=C(O)c1cc(C(F)F)c(Cl)nc1O
Yield: 98 %

Procedure:
6-Chlorodifluoromethyl-2-hydroxynicotinamide (48.5 g) was heated in dilute sulphuric acid (36 ml in 250 ml water) for 12 hours. The reaction was concentrated to about half the volume and cooled in ice. The precipitate was filtered, washed with water and air dried to give 6-chlorodifluoromethyl-2-hydroxynicotinic acid (48.1 g, 98% yield) as a pale brown solid mp.131-3° C.; 1H NMR (270 MHz): δ 7.36(1H,d), 8.33(1H,d) ppm.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>ClCCCl>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in 1,2-dichloroethane (EDC, 0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in EDC was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 159.8 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [N:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24])=[N+]=[N-].C(O)C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:23])[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:11]2[CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:5]=1[F:24]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N=[N+]=[N-])c(F)cc2c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N)c(F)cc2c1=O
Temperature: 5 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
A slurry of 1.20 kg of ethyl 7-azido-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 12 L of dimethylformamide was charged to a five gallon autoclave. After placing the vessel under nitrogen, a slurry of 76 g of 10% palladium-on-carbon in 700 ml of dimethylformamide was added. The mixture was hydrogenated at 49-50 p.s.i. and 600 r.p.m. for four hours. The reaction mixture was filtered and concentrated under aspirator pressure to give a thick but stirrable dark residue. Ethanol (3 L) was added and the suspension was briefly refluxed before allowing to cool. After cooling to 5° C., the product was collected, washed with 2×500 ml of cold ethanol and then dried at 65°-70° C. in vacuo overnight to give 962 g (86.7%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][N:3]=1.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:10]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(OCC)c1ccc(Br)nc1
Reaction time: 3 h
Yield: 91 %

Procedure:
In ethanol (50 mL) was dissolved 6-bromonicotinaldehyde (6.00 g, 32.3 mmol). Triethyl orthoformate (10.74 mL, 64.5 mmol) and p-toluenesulfonic acid mono-hydrate (307 mg, 1.613 mmol) were added and the mixture was reflexed for 3 hours. The solvent was evaporated from the mixture under reduced pressure. A saturated sodium bicarbonate solution and water were added and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give compound BC1 (7.60 g, 91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22](/C=C/C)=[CH:21][CH:20]=[CH:19][C:18]=2[C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])[CH:14]=[CH2:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClC(Cl)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:15][C:22]3[C:17](=[C:18]([C:26]4[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=4[Cl:32])[CH:19]=[CH:20][CH:21]=3)[O:16]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(/C=C/C)cccc1-c1c(Cl)cccc1Cl
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
To a solution of (2R)-2-({2′,6′-dichloro-3-[(1E)-prop-1-enyl]-1,1′-biphenyl-2-yl}oxy)but-3-enyl 4-methylbenzenesulfonate (2.02 g, 4.01 mmol) in anhydrous dichloroethane (50 mL) at room temperature under nitrogen was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.33 g, 0.401 mmol) and the reaction mixture stirred at room temperature for 20 hours and then heated to 50° C. for 45 hours. The cooled reaction mixture was concentrated to a small volume under reduced pressure and then directly pre-adsorbed onto silica gel. Purification by flash chromatography using a solvent gradient of 5 to 15% ethyl acetate in hexane afforded 1.52 g (82%) of [(2R)-8-(2,6-dichlorophenyl)-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a brown foam. MS (ESI) m/z 478 ([M+NH4]+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:16][O:15]2)=[CH:8][CH:7]=1.N1C=[C-]N=N1.[Na+].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.[H-].[Na+]>CN(C)C=O>[CH3:18][C:17]([CH3:20])([CH3:19])[C:14]([CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1)([OH:15])[CH2:16][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CC(C)(C)C1(C=Cc2ccc(C3OCCO3)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Agent: [c-]1c[nH]nn1
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)(C=Cc1ccc(C2OCCO2)cc1)Cn1cncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.3 %

Procedure:
25.6 g (0.093 mol) of 2-{2-[4-(1,3-dioxolan-2-yl)-phenyl]-ethenyl}-2-tert.-butyl-oxirane in 47 ml of absolute dimethylformamide are added dropwise, at room temperature, to a solution of sodium triazolide, prepared by slowly introducing 12.9 g (0.187 mol) of 1,2,4-triazole into a suspension of 5.6 g (0.187 mol) of sodium hydride (80% strength in paraffin oil) in 187 ml of absolute dimethylformamide. The reaction mixture is stirred at 80° C. for 4 hours and left to stand overnight at room temperature. Thereafter, the reaction mixture is poured onto ice water and extracted several times with ethyl acetate. The combined ethyl acetate phases are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed over a silica gel column (methylene chloride/ethyl acetate=2:1) and the product is recrystallized from n-hexane/ethyl acetate. 7.75 g (24% of theory) of 3,3-dimethyl-2-{2-[4-(1,3-dioxolan-2-yl)-phenyl]-ethenyl}-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 109.5°-110° C. are obtained.