Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(O)C2CC(C)(C)OC=2C=1[F:45])=O.N1(C(C2C=CC(Br)=CC=2)=O)CCC1>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:26][CH2:27][CH2:28]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[C:6]=1[F:45])=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1F)OC(C)(C)C2
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: O=C(c1ccc(Br)cc1)N1CCC1
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1F)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 7-fluoro-4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (190a) and azetidin-1-yl-(4-bromo-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.61-7.65 (m, 2 H) 7.05 (d, J=4.55 Hz, 1 H) 6.94 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 4.27-4.37 (m, 2 H) 4.23 (s, 2 H) 3.90 (s, 3 H) 2.91 (s, 2 H) 2.32-2.40 (m, 2 H) 1.52 (s, 6 H); LCMS for C22H22FNO5 m/z 400.20 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])CCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:5]1[S:4][C:3]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[C:2]([CH3:1])[CH:6]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccsc1C1OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(C2OCCO2)s1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-methylthien-2-yl)-1,3-dioxolane (intermediate 75, 1.5 g) in tetrahydrofuran (50 ml), stirred at −60° C. under a nitrogen atmosphere, was treated drop-wise with 1.6M n-butyl lithium in hexanes (6.1 ml). The reaction mixture was stirred at this temperature for 1 hour and tributyltin chloride (2.6 ml) was added; stirring was continued at −60° C. for 1 hour and then the reaction allowed to warm to ambient temperature. After 18 hours the reaction mixture was diluted with diethylether and this mixture was extracted with water and the ether layer dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (50:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2=[N:7][N:8]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][NH:19][C:29](=[O:33])[C:30]([CH3:32])=[CH2:31])[CH:13]=[C:12]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:11]=3[OH:24])[N:9]=[C:5]2[CH:4]=1
Reactant: CC(C)(C)c1cc(CCCN)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCCc1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
The title compound is prepared by the reaction of the compound of Example 58 with methacryloyl chloride in the presence of triethylamine in toluene.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].O>N1C=CC=CC=1>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(CCO)c1ccc(OCc2ccccc2)cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)OCCC(C)c1ccc(OCc2ccccc2)cc1
Yield: 95 %

Procedure:
2.56 (10 millimols) of (+)-3-methyl-3-(4benzyloxyphenyl)propanol (XI-1) obtained in Preparation Example (starting material compound (V)) 1, was dissolved in 20 ml of pyridine and 1.38 g (13 millimols) of butyrylchloride was added at 30°-40° C. and reacted for 2 hours. The reaction mixture was poured into 200 ml of water and extracted with 200 ml of toluene and separated and then washed with, in the order, 1N aqueous solution of hydrochloric acid, water, 5% aqueous solution of sodium bicarbonate and water, and thereafter dried on anhydrous magnesium sulfate. After the solvent was distilled out under the reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: toluene-ethyl acetate) to provide 3.1 g (yield: 95%) of (+)-4-benzyloxy-l-(1-methyl-3-butyryloxypropyl) benzene (VIII-9).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[Se](=O)=[O:38]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:38])[C:5]2[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
4-(6-Chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (Example 106, Step 1; 450.9 mg, 0.911 mmol) was dissolved in dioxane (10 mL) and selenium dioxide (303 mg, 2.73 mmol) was added. The reaction mixture was stirred at reflux over the weekend. The reaction was filtered over celite, rinsed with ethyl acetate, and concentrated in vacuo. The residue was diluted with DCM and filtered over celite. The filtrate was concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (5-40% EtOAc/Hexanes) gave 6-chloro-3-morpholino-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde. MS ESI calc'd. For C30H26ClN4O2 [M+H]+ 509. found 509.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([CH2:2][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 50.8 %

Procedure:
10 g (36 mmol) of 2-bromomethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 6 g (36 mmol) of ethyl 4-hydroxybenzoate and 7.2 g (52 mmol) of anhydrous potassium carbonate in 60 ml of dimethylformamide were refluxed for 5.25 h. The mixture was then poured into water and extracted several times with ether, and the organic phase was washed with water, dried over Na2 SO4 and concentrated. Recrystallization from methanol resulted in 6.7 g of the title compound of melting point 109°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:15]=1.C[O-].[Na+].[C:21](=O)([O:24]C)[O:22]C>>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[C:13](=[O:14])[CH:12]([C:21]([OH:24])=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:15]=1
Reactant: COC(=O)OC
Reactant: COc1cc2c(cc1OC)C(=O)CCCCC2
Agent: C[O-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(=O)C(C(=O)O)CCCC2
Temperature: 0 °C

Procedure:
A mixture of 2,3-dimethoxy-5,6,7,8,9,10-hexahydrobenzocycloocten-5-one [R. Legros and P. Cangiant, Compt. Rend., 250, 147 (1960)] (0.8 g), sodium methoxide (0.34 g) and dimethyl carbonate (3.6 ml) is heated for two hours under reflux in a stream of nitrogen. The reaction mixture is cooled, and then poured into ice-water containing 1N HCl (20 ml), and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and then concentrated under reduced pressure to afford methyl ester of 2,3-dimethoxy-5-oxo-5,6,7,8,9,10-hexahydrobenzocyclooctene-6-carboxylic acid as a pale yellow oily product (0.85 g). This product is dissolved in methanol (25 ml) and methylene chloride (15 ml). To the solution is added sodium borohydride (0.4 g) in limited amounts with stirring. The mixture is stirred for 1.5 hours. After addition of water (50 ml), the reaction mixture is shaken thoroughly. The organic layer is separated, and the aqueous layer is extracted with methylene chloride. The organic layers are combined and concentrated under reduced pressure. The residue is dissolved in a mixture of methanol (3 ml) and acetone (10 ml). To the solution is added a 1N aqueous solution of sodium hydroxide (10 ml), and the mixture is stirred at 60° C. for 10 minutes. The reaction mixture is cooled and then made acid with hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure. To the residue is added dioxane (8 ml) and concentrated hydrochloric acid (3 ml), and the mixture is stirred at 90° C. for 30 minutes. After cooling, water (50 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and then concentrated under reduced pressure. Precipitating crystals are collected by filtration to give 2,3-dimethoxy-5,6,7,8-tetrahydrobenzocyclooctene-9-carboxylic acid (0.6 g). This product is recrystallized from ethyl acetate to give colorless needles, m.p. 200°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)cc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c(Br)c1

Procedure:
To a 500 ml 3-necked pyrex round bottomed flask equipped with a magnetic stirring bar, reflux condenser and argon inlet was added 2-bromo-4-chlorotoluene (10.00 g, 48.67 mmol), N-bromosuccinimide (18.66 g, 48.67 mmol) and dry, degassed carbon tetrachloride (200 ml). The stirred mixture was heated at reflux while being irradiated at a distance 10 cm by a 150 watt Hanovia low pressure mercury Lamp for 4 hours. The cooled reaction mixture was diluted with carbon tetrachloride and washed with water (2×200 ml) and brine (400 ml). Drying (MgSO4), filtration, and removal of the solvent in vacuo left compound (2a) as a colorless oil. HPLC analysis indicates the material to be approximately 80% of the monobromo and 20% of the dibromo material. 'H NMR (CDCl3) δ4.55 (s, 2H), 7.00-7.65 (m, 3H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(Cl)Cl>[N+:32]([C:35]1[CH:36]=[CH:37][C:38]([S:41]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:43])=[O:42])=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 0 °C
Yield: 56.5 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (250 mg, 0.62 mmol, Example 91, Step 1), CH2Cl2 (5 mL) and triethylamine (0.26 mL, 1.87 mmol). 4-Nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C. the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (180 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:5](=O)[CH3:6].[CH2:23]([NH2:29])[C@H:24]1[O:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])[N:29]([CH2:23][C@@H:24]2[CH2:25][CH2:26][CH2:27][O:28]2)[C:5]=1[CH3:6])=[O:22]
Reactant: NC[C@@H]1CCCO1
Reactant: COC(=O)C(CC(=O)c1ccccc1OC(F)(F)F)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2OC(F)(F)F)n(C[C@@H]2CCCO2)c1C
Temperature: 25 °C

Procedure:
To a solution of 250 mg of 3-oxo-2-[2-oxo-2-(2-trifluoromethoxy-phenyl)-ethyl]-butyric acid methyl ester in methanol was added 84 μl of (S)-tetrahydrofurfurylamine and 5 mg of p-toluene sulfonic acid. The reaction mixture was then heated at reflux for 24 hours. After such time the reaction mixture was allowed to cool to room temperature before being concentrated in vacuo and purified by column chromatography to give 171 mg of the title compound; MS (EI) 383.1 (M)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29]([CH:31]4[CH2:32][CH2:33]4)=[O:30])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Product: CC(C)c1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-isopropylphenyl)-1-butanone and N-[3-(4-piperidinyl) phenyl]cyclopropanecarboxamide: ESMS m/e: 433.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][P:18](=[O:27])([O:23][CH:24]([CH3:26])[CH3:25])[O:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH:24]([O:23][P:18]([CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:27])[O:19][CH:20]([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(COc1ccc(C=O)cc1)OC(C)C
Reaction time: 17 h
Yield: 26.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (152 mg, 1.25 mmol) in DMF (20 mL) was added potassium carbonate (223 mg, 1.62 mmol), followed by diisopropyl bromomethylphosphonate (484 mg, 1.87 mmol). The mixture was heating in DMF at 90° C. under stirring for 17 hours. After evaporation of DMF under reduced pressure, 100 mL of water were added and the mixture was extracted with ethyl acetate (3*200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate (5:5)) to give 98.2 mg of an oil (26% yield). 1H NMR (250 MHz, CDCl3): δ 1.33 (t, J=6.0 Hz, 12H), 4.25 (d, J=10.2 Hz, 2H), 4.82 (q, J=6.0 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 9.87 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 25.4 (dd, J=12.7; 3.4 Hz), 64.0 (d, J=171.0 Hz) 73.3 (d, J=6.2 Hz), 116.3, 132.2, 133.3, 164.8 (d, J=13.4 Hz), 192.0. 31P NMR (202 MHz, CDCl3): δ 16.0
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]=2[OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23]O>>[C:6]1([CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([O:18][CH3:23])=[O:17])[C:14]=2[OH:22])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Cc2ccccc2)c1O
Yield: 46 %

Procedure:
To a solution of the acid (0.47 g, 2.1 mmol) in dry methanol (40 ml) was added conc. Sulfuric acid (0.47 g) and the solution heated to reflux for 96 h. Upon cooling the methanol was removed and the residue taken up in water (50 ml), and extracted with dichloromethane (3×30 ml). The combined extracts were dried (Na2SO4), and the solvent removed. The residue was eluted through a silica column using 5% ethyl acetate in petroleum spirit to yield a colorless oil (0.23 g, 46%). 1H-NMR (CDCl3, 300 MHz): δ 3.94 (s, 3H), 4.03 (s, 2H), 6.81 (t, 1H, J=8 Hz), 7.20-7.32 (m, 6H), 7.73 (dd 1H, J=8 Hz, 1.5 Hz), 11.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@H:20]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=4)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:35][O:23][C:22](=[O:24])[CH2:21][C@H:20]([NH:19][C:17]([C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:18])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=1
Reactant: CS(=O)(=O)c1cc([C@H](CC(=O)O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propionic acid in methanol (1 mL) and benzene (4 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (126 μL, 0.252 mmol). After 10 minutes, the mixture became homogeneous and the resulting reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was purified by silica gel chromatography using a gradient of 0-8% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:29].[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)#[CH:32].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:22]2[CH:27]=[CH:26][C:25]([C:32]#[C:31][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:24][CH:23]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(I)cc2)cc1C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(C#Cc3ccccn3)cc2)cc1C

Procedure:
A solution of (Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (283 mg, 0.55 mmol), 2-Ethynyl-pyridine (0.167 ml. 1.65 mmol), bis(triphenylphosphine) palladium(II) chloride (0.015 g, 0.022 mmol), copper(I) iodide (0.31 mg, 0.002 mmol) in dry triethylamine (4 ml) were heated to 120° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding {2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-acetic acid methyl ester as a yellow solid.
Reaction SMILES: [H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>O1CCOCC1.[Cu]Br>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[CH:28][CH:27]=1
Reactant: Brc1ccc(I)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of 60 wt %-sodium hydride (2.47 g, 61.7 mmol) in 1,4-dioxane (103 ml) and hexamethylphosphoramide (7.70 ml) was added diethyl malonate (9.88 g, 61.7 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for one hour and copper(I) bromide (10.6 g, 74.0 mmol) and 1-bromo-4-iodobenzene (19.2 g, 67.9 mmol) was added. The mixture was refluxed for 5 hours and cooled to room temperature. The solid materials were filtered off through a pad of Celite. After concentration, the residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=24/1) to afford diethyl 2-(4-bromophenyl)malonate as colorless oil (8.82 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:13]3[N:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:21][O-:22].[Na+].ClCCl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:13]3[N:18]=[C:17]([C:19](=[NH:20])[O:22][CH3:21])[CH:16]=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1cccc(-c2cnc(-c3cncc(F)c3)s2)n1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=N)c1cccc(-c2cnc(-c3cncc(F)c3)s2)n1

Procedure:
6-[2-(5-Fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carbonitrile (0.33 g, 1.17 mmol) and sodium methoxide (0.13 g, 0.23 mmol) were stirred in methanol (10 ml) and dichloromethane (10 ml) at room temperature for 3 d. The precipitated solid was filtered off and the solvent of the filtrate was removed under reduced pressure. The residue was dissolved in dichloromethane and filtered through Celite. The solvent of the filtrate was removed under reduced pressure. This gave 0.32 g (83% of theory) of methyl 6-[2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-yl]pyridine-2-carboximidoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:32]=1.O>CCOCC>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)([OH:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:32]=1
Reactant: COc1ccc2c(c1)CCCCC2=O
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)CCCCC2(O)c1cc(OC)c(OC)c(OC)c1
Temperature: -30 °C
Yield: 49.6 %

Procedure:
200 mL of anhydrous ether was, added to 3,4,5-trimethoxybromobenzene (1.23 g, 4.97 mmol) in a 500 mL round bottom flask under nitrogen. The temperature of the reaction mixture was brought to −78° C. n-Butyllithium (4.5 mL, 11.25 mmol) was added dropwise. The reaction mixture was then stirred until the temperature was raised gradually to −30° C. 30 (0.86 g, 4.5 mmol) dissolved in 25 mL of dry ether was added dropwise and the reaction mixture was allowed to stir until the temperature warmed up to room temperature. 25 mL of water was added and the product was extracted with ether (3×50), combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Purification by column chromatography (silica gel, 20:80 EtOAc:Hexanes) yielded 800 mg (49%) of 32 as pale yellow oil Rf: 0.16 (30:70, EtOAc:Hexanes).