Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3cc(-c4ccc(Cl)cc4)[nH]n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(-c2cc(-c3ccc(C4CNCCO4)cc3)n[nH]2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 169.8 %

Procedure:
tert-Butyl 2-(4-(5-(4-chlorophenyl)-1H-pyrazol-3-yl)phenyl)morpholine-4-carboxylate (180 mg, 0.41 mmol) was dissolved in dioxane (5.5 ml) and a solution of HCl in dioxane (4M, 1.53 ml, 6.15 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. and overnight at room temperature. The solid was filtered off, washed with ether and dried in vacuo to afford 2-(4-(5-(4-chlorophenyl)-1H-pyrazol-3-yl)phenyl)morpholine hydrochloride (131 mg, 85%) as a white solid. MS (ISP): 340.1 ([{35Cl}M+H]+), 342.1 ([{37Cl}M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[CH2:13][CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].C(O)(=O)C>CO>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[CH2:13][CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCc1c(O)c2ccccc2oc1=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1oc2ccccc2c(O)c1CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A rapidly stirred suspension of the product obtained in Example 16 (0.21 g, 0.71 mmol) in 10 mL of methanol was treated portionwise with 0.08 g (2.1 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature for 36 hours. Glacial 30 acetic acid (3 mL) was added, and the mixture was concentrated. The residue was partitioned between ethyl acetate and water, and the organic layer was dried and concentrated. The product was chromatographed on silica gel, eluting with 4:1 chloroform: ethyl acetate, to give the title compound, m.p. 138°-140° C. NMR (CDCl3) δ1.25 (m, 2H), 2.88 (m, 2H), 4.66 (dd, 1H), 7.32 (m, 7H), 7.52 (t, 1H), 7.90 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:23])[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2sc(-c3ccccc3)nc2c1O
Temperature: 130 °C
Reaction time: 1.67 h
Yield: 41.8 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (217 mg, 0.80 mmole), tetramethyltin (318 μl, 2.30 mmole) and bis(triphenylphosphine)palladium(II) dichloride (52 mg, 0.07 mmole) in dimethylformamide (3 ml) was stirred at 130° C. for 100 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (105 mg). MS: (+) m/z 315.29 (M+1)
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[CH:14]([CH3:33])[C:15]([C:21]1[CH:32]=[CH:31][C:24]2[N:25]([CH3:30])[C:26](=[O:29])[N:27]([CH3:28])[C:23]=2[CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[CH:14]([CH3:33])[C:15]([C:21]1[CH:32]=[CH:31][C:24]2[N:25]([CH3:30])[C:26](=[O:29])[N:27]([CH3:28])[C:23]=2[CH:22]=1)([OH:20])[C:16]([F:17])([F:18])[F:19]
Reactant: COc1ccc(C(C)C(O)(c2ccc3c(c2)n(C)c(=O)n3C)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
A 1M solution of boron tribromide in DCM (3.7 ml) was added to a solution of 5-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (300 mg) in DCM (10 ml). at −65° C. The mixture was allowed to warm to room temperature and then stirred for 4 h. MeOH (1.4 ml) and saturated aqueous NaHCO3 solution were added and stirred for 30 min. The mixture was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 30 to 100% EtOAc/heptane) to give the title compound (259 mg) as a light yellow oil. MS (m/e)=415.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 100 mL round-bottom flask was charged tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate (1.90 g, 5.14 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (2.12 g, 15.6 mmol, 3.00 equiv), potassium carbonate (2.15 g, 15.6 mmol, 3.00 equiv), Pd(PPh3)4 (0.600 g, 0.520 mmol, 0.10 equiv), dioxane (25 mL), water (2.5 mL) with an inert atmosphere of nitrogen. The resulting solution was stirred overnight at 80° C., diluted with water (50 mL), extracted with dichloromethane (3×40 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide in 2.00 g (95% yield) of tert-butyl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 381 [M+H]+.
Reaction SMILES: [Br:1][CH:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][C:8]2[CH:7]=[N:6][N:5]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[CH:3]1[OH:30].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][CH:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][C:8]2[CH:7]=[N:6][N:5]([C:26]([CH3:28])([CH3:27])[CH3:29])[C:4]=2[C:3]1=[O:30]
Reactant: CC(C)(C)n1ncc2c1C(O)C(Br)C1(CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)(C)n1ncc2c1C(=O)C(Br)C1(CCN(C(=O)OCc3ccccc3)CC1)C2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.1 %

Procedure:
Benzyl 6-bromo-1-tert-butyl-7-hydroxy-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (57.9 g, 122 mmol) was dissolved in acetone (1 L) and cooled to 0° C. in an ice bath. To the solution was added Jones Reagent (122 mL) (Fillion, E. Tetrahedron Letters 2004, 46, 1091-1094). The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 45 minutes. Saturated aqueous sodium bicarbonate was added until gas evolution ceased and the pH reached 7. The resulting mixture was filtered through a pad of Celite®, rinsing with ethyl acetate. The filtrate layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed twice with water, once with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was crystallized from ethyl acetate/heptanes to afford the title compound (50.4 g, 87%). +ESI (M+H) 474.5; 1H NMR (400 MHz, CDCl3, δ): 7.32 (d, J=9.38 Hz, 6 H), 5.11 (s, 2 H), 4.24 (s, 1 H), 3.58-3.84 (m, 2 H), 3.16-3.41 (m, 2 H), 2.67-2.91 (m, 2 H), 1.80 (br. s., 1 H), 1.61-1.76 (m, 11 H), 1.52-1.61 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@H:13]1[CH2:15][C@@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[CH:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:24][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: O=C(N(CC1CCNCC1)[C@H]1C[C@@H]1c1ccccc1)C(F)(F)F
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (243 mg, 0.745 mmol) in 1,2-dichloroethane (DCE) (4 mL) were added 4-formylbenzoic acid (134 mg, 0.894 mmol) and sodium triacetoxyborohydride (252 mg, 1.191 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (4 mL) and extracted with CH2Cl2 (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 5% MeOH/EtOAc) to give 180 mg of product as pale yellow solid. MS: (M+H)+=461.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.32 (m, 2H), 1.35-1.47 (m, 1H),1.53-1.82 (m, 3H), 1.88-2.05 (m, 2H), 2.81 (br. s., 2H), 3.09-3.22 (m, 2H), 3.26-3.41 (m, 2H), 3.27-3.43 (m, 2H), 7.09-7.35 (m, 5H), 7.39-7.50 (m, 2H), 7.86-7.94 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])=[CH:5][C:4]=1[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:21]1)#[N:2].[H][H]>[Pd].C(OCC)(=O)C.CO>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[NH:19][C@H:20]1[CH2:21][CH2:22][C@H:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:25]1)#[N:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(C(=O)OCc3ccccc3)ccc2C#N)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(C(=O)O)ccc2C#N)CC1

Procedure:
Palladium on carbon 10% by weight Degussa type (50 mg) was added to a solution of phenylmethyl 4-cyano-3-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}benzoate (71.8 mg, 0.16 mmol) in ethyl acetate (3 mL) and methanol (400 uL). The mixture was subjected to 1 atm of hydrogen for 70 min. The catalyst was then removed by filtration through celite. The resulting filtrate was concentrated to provide 4-cyano-3-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclohexyl]amino}benzoic acid (55.8 mg, 0.16 mmol) which was carried into the subsequent step without further purification. 1H NMR (400 MHz, CD3OD): 7.47 (d, 1H), 7.37 (s, 1H), 7.24 (d, 1H), 3.47-3.21 (m, 2H), 2.09 (m, 2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.43 (s, 9H), 1.24 (m, 2H); MS (EI) for C19H25N3O4: 304 (MH+-tert-butyl).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:40]1[S:41][CH:42]=[CH:43][N:44]=1.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:40]3[S:41][CH:42]=[CH:43][N:44]=3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3nccs3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General Procedure U. To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 12 mg, 0.028 mmol) in DMF (1 ml) was added K2CO3 (19 mg, 0.14 mmol) and 2-bromothiazole (23 mg, 0.14 mmol). The mixture was stirred at room temperature overnight and a small amount of NaOH was added. The reaction was kept stirring for 72 h, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])=[CH:6][CH:7]=1)=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(CCCl)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of 3.95 g of p-aminobenzophenone in 100 ml of chloroform was treated with 2.6 g of 3-chloropropionyl chloride and, after the addition of 26 ml of 1N sodium hydroxide solution, stirred at room temperature. The organic phase was separated, washed in sequence with water, 1N HCl and water, dried and evaporated. After recrystallization from methanol of the oil obtained there was obtained 4-(3-chloropropionamido)benzophenone, m.p. 135°-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Se]C3C=CC=CC=3)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2[Se]c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCC=C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of the crude product of Step 1 (4.2 g, 13.9 mmol) in dichloromethane (100 ml) at -40° was treated portionwise with 86% 3-chloroperoxybenzoic acid (3.0 g, 14.9 mmol). After 30 min, the mixture was warmed to room temperature, washed with 2N-NaOH (2×100 ml), dried (MgSO4), and evaporated in vacuo. The residue was dissolved in 1N-H2SO4 (100 ml) and the solution washed with ether (3×100 ml), basified with sodium carbonate, and extracted with dichoromethane (3×100 ml). The chlorinated extracts were dried (MgSO4) and evaporated in vacuo. The residue was distilled to give the product (1.79 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH2:24])[CH2:16][CH3:17]>C(Cl)(Cl)Cl>[CH2:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][NH:24][C:5](=[O:7])[C:4]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:2]([Br:1])[C:3]=1[O:13][CH3:14])[CH2:16][CH3:17]
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: CCCN1CCCC1CN
Solvent: ClC(Cl)Cl
Product: CCCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Yield: 79 %

Procedure:
The title compound was prepared from 3-bromo-2,6-dimethoxybenzoic acid via the acylchloride and (-)-1-n-propyl-2-(aminomethyl)pyrrolidine in the same manner as described in Example 8. Yield 79%. M.p. 103°-104° C. [α]D20 =-85.4° (c=0.5; CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH:12]=NN=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[CH:5][CH:4]=1.N([O-])=[O:35].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([CH:12]=[O:35])=[O:11])=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: COc1ccc(CC(=O)C=NN=P(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)C=O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.82 g of 1-(4-methoxyphenyl)-3-(triphenylphosphoranylidene-hydrazono)-acetone in 12 ml of tetrahydrofuran is mixed with 0.84 g of pulverized sodium nitrite and the mixture is diluted with 5 ml of water. The resulting suspension is cooled to 0°-5°, treated dropwise over the course of 7 minutes with 8.8 ml of 2N hydrochloric acid and then kept for a further 30 minutes at 0°-5°. The aqueous phase is twice washed with methylene chloride; the combined organic solutions are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The oily residue is chromatographed on 40 g of acid-washed silica gel. A small quantity of a by-product is eluted with benzene and, using 1200 ml of a 95:5-mixture of benzene and ethyl acetate, the 4-methoxybenzylglyoxal is obtained in the form of the hydrate, which is an oily product; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.79-5.84μ, 6.23μ and 6.63μ. The anhydrous product melts at 139°-140° after recrystallisation from a mixture of chloroform and hexane; ultra-violet absorption spectrum:λmax 333 mμ (in ethanol or hydrochloric acid/ethanol) and λmax 367 mμ (in potassium hydroxide/ethanol); ethanol); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.00μ, 5.97μ, 6.09μ, 6.24μ, 6.61μ and 7.15μ.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1ccc2c(Br)nn(-c3ccc(C)cc3)c2c1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3ccccc3Cl)nn(-c3ccc(C)cc3)c2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a mixture of methyl 3-bromo-1-(4-methylphenyl)-1H-indazole-6-carboxylate (0.30 g, 0.87 mmol), 2-chlorophenylboronic acid (0.21 g, 1.34 mmol), cesium carbonate (0.86 g, 2.64 mmol), copper(I) chloride (91.6 mg, 0.93 mmol), 1,1′-bis(diphenylphosphino)ferrocene (51.6 mg, 0.09 mmol) and palladium(II) acetate (9.8 mg, 0.04 mmol) under argon was added N,N-dimethylformamide (4.3 mL). The mixture stirred in a sealed tube at 90° C. for 30 min. The mixture was cooled to ambient temperature and quenched with saturated sodium bicarbonate (15 mL). The mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (100% hexanes→95% hexanes/ethyl acetate) gave the title compound (0.25 g): LC-MS [M+1]=377.2.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.C(C(CCCC)C([O-])=O)C.[Na+:21]>O1CCCC1.CO.C(O)(C)C>[S-:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[Na+:21].[Na+:21]
Reactant: O=C(O)c1ccnc(S)c1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C([O-])c1ccnc([S-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-mercapto-4-pyridinecarboxylic acid (7.65 g) in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was added a solution of sodium 2-ethylhexanoate in isopropyl alcohol (27.5%) and the mixture was stirred for 2 days at room temperature. The reaction mixture was evaporated and the residue was washed with a mixture of acetone and ethanol. The crystals were collected by filtration dried over phosphorus pentoxide to give disodium 2-sulfido-4-pyridinecarboxylate (8.5 g).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH2:3]O.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:49]([O:51][C:52](=[O:68])[C:53]([O:56][C:57]1[CH:62]=[CH:61][C:60]([S:63]C(=O)C)=[CH:59][C:58]=1[CH3:67])([CH3:55])[CH3:54])[CH3:50].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.C(#N)C.CO>[CH2:49]([O:51][C:52](=[O:68])[C:53]([O:56][C:57]1[CH:62]=[CH:61][C:60]([S:63][CH2:3][C:2]([CH3:19])([CH3:1])[CH2:5][C:6]#[C:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:59][C:58]=1[CH3:67])([CH3:54])[CH3:55])[CH3:50]
Reactant: CC(C)(CO)CC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(SCC(C)(C)CC#Cc2ccc(OC(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
A solution of 0.109 g (0.40 mmol) 2,2-dimethyl-5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (example 24E]) in 0.4 ml CH2Cl2 was treated at 0° C. with 0.11 ml (0.48 mmol) 2,6-di-tert-butylpyridine and 0.07 ml (0.44 mmol) trifluoromethanesulfonic anhydride. After 1.5 h at 0° C. the solution was evaporated, dissolved in 1.5 ml acetonitrile and added to a suspension of 0.142 g (0.48 mmol) of 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 1C]) and 0.274 g (0.84 mmol) of Cs2CO3 in 2.5 ml of acetonitrile and 0.1 ml of MeOH. After vigorous stirring for 20 h at ambient temperature and filtration, the solvent was evaporated and the residue re-dissolved in dichloromethane and filtered again and evaporated. Purification by flash chromatography (SiO2, n-heptane/EtOAc 2.5%) yielded 0.18 g of the title compound as colorless viscous oil.