Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenol (0.410 g, 1.36 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.644 g, 2.72 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.571 g (85%) of the tide compound as a light brown solid, mp 93-95° C. 1H NMR consistent. mass spectrum (−ESI) m/z 493 (M−H).
Reaction SMILES: C([C@H]([C@@H](C(O)=O)O)O)(O)=O.C([O:19][C@H:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>>[N:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[C@H:20]([OH:19])[CH2:21]2
Reactant: O=C(O[C@@H]1CN2CCC1CC2)c1ccccc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H]1CN2CCC1CC2

Procedure:
The product of Example 6C (7.0 g, 18.4 mmol) was treated with NaOH (aqueous) according to the procedure of Example 1B. The title product was obtained as white a solid (2.0 g, yield, 86%). MS (DCl/NH3) m/z 128 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1cccs1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccs1)O2
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 6.3 g (30 mmol) of 2-iodothiophene, 0.8 g of triphenylphosphine, 0.19 g of cuprous iodide, 6 ml of triethylamine and 200 ml of acetonitrile was stirred and degassed with argon for 15 minutes. Palladium acetate, 220 mg, was then added and stirring under argon was continued for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried and evaporated. The residue was chromatographed over 200 g of silica gel (Merck 70-230 mesh) using methylene chloride. Crystallization of the combined clean fractions from ether/hexane yielded 3.5 g (56%) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-[(2-thienyl)ethynyl]-2H-1-benzopyran-6-ol with m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].ClNC(=O)CCC(N)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:48]=[C:49]1[CH2:54][CH2:53][CH:52]([C:55](O)=[O:56])[CH2:51][CH2:50]1>ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:55]([CH:52]1[CH2:53][CH2:54][C:49](=[O:48])[CH2:50][CH2:51]1)=[O:56])=[O:4]
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Agent: NC(=O)CCC(=O)NCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(=O)CC1)C(C)C

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.5 g, 5.45 mmol) in 1,2-dichloroethane, N-chlorosuccinamide (0.940 g, 7.091 mmol), triphenylphosphine (1.9 g, 7.091 mmol) and 4-oxo-cyclohexanecarboxylic acid (800 mg, 5.455 mmol) were added. The reaction mixture was stirred at reflux for overnight under an atmosphere of N2. The reaction mixture was diluted with CH2Cl2 and extracted with saturated solution oh NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified using silica gel column chromatography using ethyl acetate:hexane (1:4) as eluent to obtain 3-[Isopropyl-(4-oxo-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. (1.2 g, 55%) as syrup. 1H NMR (CDCl3, 400 MHz): δ7.75-7.50 (m, 2H), 7.70-7.38 (m, 3H), 7.12 (s, 1H), 4.95 (m, 1H), 3.87 (s, 3H), 2.75-0.83 (m, 15H).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:34][C:33](=[O:35])[NH:32][CH:31]=[C:30]2[C:36](Cl)=[O:37])=[CH:25][CH:24]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.Cl>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH:18][C:36]([C:30]3[C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH2:34][C:33](=[O:35])[NH:32][CH:31]=3)=[O:37])[CH:16]=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Reactant: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine (89 mg, 0.29 mmol) and (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride (74 mg, 0.29 mmol, prepared as described in Example 1) were dissolved in pyridine (2 ml) together with a crystal of DMAP and sealed in a tube. The mixture was heated to 90° C. with stirring for 18 hours. Upon cooling the mixture was diluted with dilute aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 46 mg (30.3%) of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-amide as a yellow oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([I:21])[N:6]=1.O>CS(C)=O>[I:21][C:7]1[N:6]=[C:5]([O:2][CH3:1])[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(COc2ccc(I)nc2Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(I)nc2OC)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Sodium methoxide (11 g) was added to a solution of 2-bromo-6-iodo-3-[(4-methoxybenzyl)oxy]pyridine (17 g) in dimethyl sulfoxide (90 mL), and the mixture was stirred at 90° C. for three hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→70:30) to give 6-iodo-2-methoxy-3-[(4-methoxybenzyl)oxy]pyridine as a colorless powder (10 g, 71%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([CH3:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-methyl-3-nitrobenzaldehyde (0.25 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH3CN (0.50 mmol) in methanol (1.0 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=2/1 (2 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=2/1 (6 mL), and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH3OH (5 mL×2), and eluted off using 2 N NH3 in CH3OH (5 mL). Concentration afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:40][CH2:39][C:9]2[N:10](S(C3C=CC=CC=3)(=O)=O)[C:11]3[CH:12]=[CH:13][C:14]([C:17](=[O:29])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:19]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2N(S(C3C=CC=CC=3)(=O)=O)C3C=C(C(=O)C4C=CC(Cl)=C(S(=O)(=O)N)C=4)C=CC=3C=2C1)=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1CO.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:40][CH2:39][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:17](=[O:29])[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:19]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(c3cc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)ccc3n2S(=O)(=O)c2ccccc2)C1
Agent: CCOC(=O)N1CCc2c(c3ccc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)cc3n2S(=O)(=O)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCC1CCCO1
Solvent: O
Product: CCOC(=O)N1CCc2[nH]c3ccc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)cc3c2C1
Temperature: 140 °C

Procedure:
A mixture of 5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (1 g) is dissolved in 5 mL of tetrahydrofuran-methanol-water (10:10:1) and treated with 0.344 g of potassium carbonate. The reaction mixture is heated at 140° C. for 15 min (microwave irradiation), filtered and concentrated. The residue is purified on reverse phase HPLC to give pure 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); and 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester MS (m/z): 462 (M+1); both as yellow syrups. Both isomers are separated by HPLC (Chiracel OD-H 250-4.6 mm, flow 1 ml/Min, UV 235 nM, gradient hexane-ethanol 70-30). The retention times are 6.91 min for 8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester and 10.20 min for 7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[N:31]12[CH2:39][CH2:38][CH:35]([CH2:36][CH2:37]1)[NH:34][CH2:33][CH2:32]2.O>O1CCOCC1>[N:31]12[CH2:39][CH2:38][CH:35]([CH2:36][CH2:37]1)[N:34]([C:11](=[O:13])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=1)[CH2:33][CH2:32]2
Reactant: COc1ccc(C(=O)NCC(=O)O)cc1
Reactant: C1CN2CCC(CC2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NCC(=O)N2CCN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.42 g (2 mmol) of N-(4-methoxybenzoyl)glycine dissolved in 20 ml of dioxane is placed in a 50 ml round-bottomed flask, 0.45 g (2.2 mmol) of dicyclohexylcarbodiimide is added, the mixture is stirred at room temperature for 30 minutes, 0.25 g (2 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further one hour. 20 ml of water are added, the precipitate formed is filtered off, the filtrate is extracted with chloroform, the organic phase is extracted with aqueous 0.1N hydrochloric acid solution and the aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:17][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)cc1-c1ccccc1
Yield: 99.3 %

Procedure:
A mixture of 4-methyl-2-phenylbenzoic acid (1.66 g, 7.82 mmol), prepared as in Example 227B, N-bromosuccinimide (1.40 g, 8.21 mmol) and 2,2′-azobisisobutyronitrile (25 mg) in carbon tetrachloride (30 mL) was stirred at reflux for 1 hour. The reaction mixture was poured into ethyl acetate and extracted with water (3×) and brine, dried, filtered, and concentrated in vacuo to give 4-bromomethyl-2-phenylbenzoic acid (2.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc2ccc(Br)cn12
Reaction time: 3 h

Procedure:
Stirring solution of 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde [see Bioorg. Med. Chem. Let. 15(17), 5837-5844; 2007; Int'l Pat. App. Pub. no, 2011/055320] (1.5 g, 6.6 mmol) in MeOH (20 mL) was cooled to 0° C. and NaBH4 (0.50 g, 13.2 mmol) was added in portions for a period of 20 min. Cooling was removed after 1 h and allowed to stir for 3 h. The reaction mixture was quenched with water and concentrated by rotary evaporator to dryness. Subsequently, the solid concentrate was diluted with water and collected on the Buchner funnel by suction filtration. The solid was suction dried to obtain (6-bromoimidazo[1,2-a]pyridin-3-yl)methanol as a pale yellow crystalline solid (0.83 g). 1H NMR (300 MHz, DMSO-d6) δ 8.63 (dd, J=2.0, 0.9 Hz, 1H), 7.55 (dd, J=9.5, 0.9 Hz, 1H), 7.52 (s, 1H), 7.36 (dd, J=9.5, 2.0 Hz, 1H), 5.27 (t, J=5.4 Hz, 1H), 4.79 (d, J=5.3 Hz, 2H). See J. Med. Chem., 54(7), 2455-66 (2011).
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[C:12]2[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29].[F-].[K+].O>C1(C)C=CC=CC=1.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>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[C:7]([S:8]([N:11]([C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[C:12]3[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=1)#[N:29]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(C#N)cc1
Temperature: 50 °C
Yield: 82.5 %

Procedure:
A stirred mixture of 1,1′-bis(diphenylphosphino)ferrocene (0.532 g) and palladium (II) acetate (0.162 g) in deoxygenated toluene (95 ml) was heated at 50° C. under argon for 30 minutes then cooled to ambient temperature. 2-Chloro-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (10 g), 4-cyanophenylboronic acid (8.47 g), potassium fluoride (8.37 g) and water (95 ml) were added and the resultant mixture was stirred and heated under reflux for 8 hours then cooled. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml) then filtered through diatomaceous earth. The aqueous layer was separated and extracted further with ethyl acetate (2×100 ml). The organic extracts were combined, washed with aqueous sodium carbonate (100 ml of a 2M solution) and water (100 ml) then treated with charcoal and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallised from ether/isohexane to give 2-(4-cyanophenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (9.58 g) as a solid, 1H NMR (DMSO-d6): 0.6 (d, 6H), 1.6 (m, 1H), 2.6 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 7.7 (d, 2H), 7.9 (m, 3H), 8.2 (s, 1H), 8.9 (d, 1H),9.0 (d, 1H); mass spectrum (+ve ESP): 482 (M+H)+.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.Cl[C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>CO>[F:4][C:5]([F:13])([F:14])[C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a flask containing a solution of 45.4 grams (0.21 mole) 25% sodium methoxide in 100 milliliters of methanol were added 81.5 grams (0.5 mole) 3-trifluoromethylphenol and 15.8 grams (0.1 mole) 2-chloronicotinic acid. The reaction mass was heated and the methanol distilled off. The pot temperature was raised to 180° C. and held at that level for one hour. The mixture was then cooled to 100° C. and poured into 500 milliliters ice water. The aqueous mixture was extracted with 3 portions of 200 milliliters each, of diethyl ether, then acidified with glacial acetic acid. A solid precipitated, which was filtered, washed with water and dried, to give 25.8 grams (91.2% of theoretical yield) of 2-(3-trifluoromethylphenoxy)nicotinic acid, m.p. 149°-151° C.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:15][CH3:16])[C:4]=1[N+:17]([O-:19])=[O:18])=O.[Br-].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:22]1.C(=O)([O-])[O-].[K+].[K+].O>CO.C(O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](/[CH:30]=[CH:1]/[C:3]2[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([O:15][CH3:16])[C:4]=2[N+:17]([O-:19])=[O:18])=[N:22]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)COc1ccc(C=O)c([N+](=O)[O-])c1OC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Methyl (4-formyl-2-methoxy-3-nitrophenoxy)acetate (2.3 g, 8.5 mmol) obtained in Step 1, (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (4.4 g, 9.4 mmol) and potassium carbonate (2.4 g, 17 mmol) were dissolved in methanol (15 mL) and the solution was stirred at room temperature for 2.0 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was reslurried with ethanol to obtain methyl (E)-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}acetate (2.8 g, 87%).
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][OH:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[O:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCOc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCOc2cc(C=O)ccc21
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-(4-azido-3,4-dihydro-2H-chromen-7-yl)methanol (3.293 g, 16.05 mmol) in 50 mL DCM was added manganese dioxide (160.3 mmol, 10.0 eq). The reaction mixture was allowed to stir overnight. A second portion of manganese dioxide (57.84 mmol, 3.5 eq) was added and stirred an additional 4 h. The reaction mixture was filtered and concentrated to yield the aldehyde.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)(=[O:12])[CH3:11]>C1(C)C(C)=CC=CC=1>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CC(=O)OCc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 77 %

Procedure:
10.35 g. (0.11 mole) of phenol, 6.15 g. (0.11 mole) of potassium hydroxide and 35 cm3. of xylene are weighed together. The water is azeotropically distilled with stirring and boiling. 5 cm3. of pyridine and 0.5 g. of copper(I) chloride are added then 22.91 g. (0.1 mole) of 3-bromobenzyl acetate are dropped into the reaction mixture during 15 minutes with stirring and boiling. The reaction mixture is boiled with stirring for an additional three hours. After cooling the reaction mixture is filtered off and the filtrate washed with a mixture of 25 cm3. of 15% sodium chloride solution and 2 cm3. of 40% sodium hydroxide solution. The organic phase is evaporated in vacuo. The residue is distilled in vacuo and so 18.65 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 142°-145° C./53.2 Pa, nD20 : 1.5621, yield 77%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)C>[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
(28 mmol, 1 eq.) of bromobenzene and 9 g (42 mmol, 1.5 eq.) of K3PO4 are added to a solution of 5.13 g (42 mmol, 1.5 eq.) of phenylboronic acid in 60 ml of isopropanol. The mixture is stirred at room temperature for 45 minutes, and 0.02 g (14.03 μmol, 0.05 mol %) of [{Pd[P(C2F5)2O]2H}2(μ-Cl)2], prepared in accordance with Example 13, is subsequently added, and the reaction mixture is stirred at room temperature for 3 hours. After addition of 100 ml of water, the reaction mixture is extracted with 200 ml of hexane. The organic phase is washed with saturated sodium chloride solution and dried using MgSO4. After filtration and removal of the solvent (in vacuo), 3.16 g of biphenyl are isolated as a white solid. The yield is 73%, based on the amount of bromobenzene employed.