Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH:15]=[C:14]2[C:33](OCC)=[O:34])=[CH:10][CH:9]=1>C(OCC)C>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[CH:15]=[C:14]2[CH2:33][OH:34])=[CH:38][CH:39]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(Cn2c(CO)cc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
Lithium aluminum hydride (0.244 g, 6.1 mmol) was added portionwise to a stirring solution of ethyl 1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indole-2-carboxylate (2.0 g, 4.4 mmol) in ethyl ether (17 mL) at 0° C. under a nitrogen atmosphere over a period of 5 minutes. The mixture was then warmed up to room temperature. After the reaction mixture was stirred at room temperature for 5 hour, the reaction was carefully quenched with water then filtered. The filtrate was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound as a white solid (1.56 g, 86%). Mass spectrum (ESI, [M+H]+) m/z 412. 1HNMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.76 (d, 2H, J=6.71 Hz), 7.45-7.35 (m, 4H), 7.08 (d, 2H, J=7.74 Hz), 6.96 (d, 2H, J=8.09 Hz), 6.50 (s, 1H), 5.44 (s, 2H), 5.35 (t, 1H), 4.60 (d, 2H), and 2.23 ppm (t, 3H).
Reaction SMILES: C(O[C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[O:12][C:13]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:14]=3[C:15]=2[C:16](=[O:29])[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:8]=[N:7]1)C.[NH3:37]>>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:14]2[C:15]([C:16](=[O:29])[C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH2:5][C:4]([NH2:37])=[O:36])[CH:10]=3)[O:12][C:13]=2[CH:33]=1
Reactant: N
Reactant: CCOC(=O)Cn1cc(-c2oc3cc(OC)ccc3c2C(=O)c2cc(OC)c(OC)c(OC)c2)cn1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cnn(CC(N)=O)c3)oc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
{4-[6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2-yl]-pyrazol-1-yl}-acetic acid ethyl ester (30 mg, 0.061 mmol) was treated with 28% aqueous ammonia solution and the resulting reaction mixture was stirred at 80° C. for 3 h. After cooling to room temperature the solution was concentrated under vacuum and the residue subjected to flash column chromatography (silica gel, sequential elution—1:1 hexane:ethyl acetate, ethyl acetate). The resulting product was further purified by trituration with 1:1 hexane:diethyl ether to give the title compound as a yellow solid (4 mg, 14%). 1H-NMR (CDCl3) δ 8.29 (s, 1H), 8.14 (s, 1H), 7.13 (s, 2H), 7.12 (d, J=8.7 Hz, 1H), 7.05 (d, J=2.1 Hz, 1H), 6.81 (dd, J=8.7, 2.1 Hz, 1H), 6.14 (br s, N—H), 5.46 (br s, N—H), 4.83 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.78 (s, 6H).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:17])=[CH:20][CH:21]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(Cn2cnc3cnccc32)cc1
Reactant: C1COCCN1
Product: O=C(c1ccc(Cn2cnc3cnccc32)cc1)N1CCOCC1
Temperature: 150 °C

Procedure:
A suspension of ethyl 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)benzoate (0.50 g, 0.0018 mol) in morpholine (10 ml) was maintained at 150° C. in a bomb calorimeter for 3 days. The morpholine was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 10% ethanol in chloroform) and recrystallized from diethyl ether-ethyl acetate to yield [4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl)phenyl](4-morpholinyl)methanone as a colorless crystalline solid, having a melting point of 188°-190° C. and the following physical characteristics:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=2[F:1])[C:6]#[N:7])=[CH:20][CH:19]=1
Reactant: O=C(CBr)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: N#Cc1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(F)c(OCC(=O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Yield: 102 %

Procedure:
4-Fluoro-3-hydroxy-benzonitrile (15 g), 2-bromo-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (45 g), and potassium carbonate 45 g) were suspended together in 630 mL acetone with stirring. The mixture continued to stir for 18 hours, then was concentrated to dryness. The solid residue was taken up in 500 mL diethyl ether and stirred 1.5 h, then 1 L water was added and stirred vigorously an additional 3 hours. The solid product was collected by filtration and washed with 200 mL diethyl ether three times. It was then dissolved in THF, filtered to remove any remaining inorganic salt, and evaporated again to dryness. After drying under vacuum 18 h, 48 g of desired product was obtained (quantitative). 1H NMR (400 MHz, DMSO-d6): 7.97 (d, 2H), 7.66 (d, 1H), 7.45 (m, 2H), 7.46 (m, 3H), 7.16 (d, 2H), 5.72 (s, 2H), 5.25 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:49].[K+]>O1CCOCC1.O.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]>[Br:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:49]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(O)c(Br)c1Nc1ccccc1
Temperature: 90 °C
Yield: 59.2 %

Procedure:
To a solution of (2-bromo-3-fluoro-6-nitrophenyl)phenylamine (1.5 g, 4.8 mmol) in dioxane (20 mL) and water (10 mL) was added tris(dibenzylideneacetone)dipalladium (0) (88 mg, 0.96 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (164 mg, 0.39 mmol) and potassium hydroxide (812 mg, 14.4 mmol). The reaction mixture was degassed by bubbling argon through the mixture whilst undergoing sonication. The reaction mixture was heated at 90° C. for 3 h before being diluted with water and acidified to ˜pH 3 by addition of HCl (1N). The mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as a yellow solid (879 mg, 59%). 1H NMR 400 MHz 6 (CDCl3): 8.85 (1H, br s), 8.18 (1H, d, J=12.6 Hz), 7.31-7.24 (2H, m), 7.10-7.03 (1H, m), 6.92-6.86 (2H, m), 6.80 (1H, d, J=12.6 Hz).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:8]1[C:9](=[O:17])[CH2:10][CH:11]([CH:15]=[O:16])[CH2:12][C:13]=1[OH:14])(=[O:7])[CH2:4][CH2:5][CH3:6]>O1CCCC1.O>[C:3]([C:8]1[C:13](=[O:14])[CH2:12][CH:11]([CH2:15][OH:16])[CH2:10][C:9]=1[OH:17])(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC(=O)C1=C(O)CC(C=O)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)C1=C(O)CC(CO)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
0.1 g of sodium borohydride was added to 2.0 g of 2-butyryl-5-formyl-3-hydroxycyclohex-2-en-1-one in 30 ml of aqueous tetrahydrofuran; the mixture was stirred for 2 hours at 25° C. The mixture was then diluted with water, extracted several times with diethyl ether, dried and concentrated. There was obtained 1.5 g of 2-butyryl-3-hydroxy-5-hydroxymethylcyclohex-2-en-1-one (compound no. 3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH2:25]>C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][C:17]([NH:25][CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: CNc1ccc([C@@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1[N+](=O)[O-]

Procedure:
96 g (0.278 mol) of (R)-2-tert.butyloxycarbonylamino-2-(4-chloro-3-nitro-phenyl)-propionic acid and 440 ml of methylamine solution (40% solution in water) are heated to 90° C. in a pressurised vessel for seven hours. After cooling, the reaction solution is adjusted to pH 3.5 by the addition of glacial acetic acid, whilst cooling with ice, and extracted with ethyl acetate. After the solvent has been evaporated off, the residue remaining is washed with ether and dried.
Reaction SMILES: [C:1](SSC(C)(C)C)(C)(C)C.II.[S:13]([CH:37]([CH2:55]N=[N+]=[N-])[CH2:38][C@H](NC(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[S:14][CH:15]([CH2:33][N:34]=[N+:35]=[N-:36])[CH2:16][C@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18](=[O:19])[C@@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:16][CH:15]([S:14][S:13][C:37]([CH3:1])([CH3:55])[CH3:38])[CH2:33][N:34]=[N+:35]=[N-:36])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(CN=[N+]=[N-])C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)SSC(C)(C)C
Agent: II
Product: CC(C)(C)OC(=O)N[C@@H](CC(CN=[N+]=[N-])SSC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
Di-tert-butyl disulfide (5.67 ml, 29.4 mmol) and iodine (57 mg, 0.226 mmol) were added to (2S,2'S)-di-tert-butyl 4,4′-disulfanediylbis(5-azido-2-((tert-butoxycarbonyl)amino)pentanoate) (Compound 38) (312 mg, 0.452 mmol), and the mixture was stirred at 60° C. for 18 hours. The reaction solution was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-5-azido-2-tert-butoxycarbonylamino-4-tert-butyldisulfanyl-pentanoic acid tert-butyl ester (Compound 39) (161 mg, 81%).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.C([O:34][C:35](=[O:57])[C:36]([CH3:56])([O:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][C:36]([CH3:56])([O:45][C:46]4[CH:51]=[CH:50][C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:48][CH:47]=4)[C:35]([OH:57])=[O:34])=[CH:43][CH:42]=3)[N:11]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 22 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 1, Part I)was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 93:7 CH2Cl2:methanol to produce a white solid (22%). MS [EI+] 590 (M+H)+, [EI−] 588 (M−H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[CH3:9].[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:16][C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:10][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14]
Reactant: [Br-]
Reactant: COc1cc(NC(=O)C(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a solution of N-(3-methoxy-4-methyl-phenyl)-isobutyramide (5.0 g, 24.1 mmol) in dichloromethane (200 mL) was added tetrabutylammonium tribromide (12.2 g, 25.3 mmol) at 0° C. The mixture was then stirred at room temperature for 20 hours. The solution was washed with water, brine, aqueous sodium bicarbonate solution, brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 6.83 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.29 (d, J=7.03 Hz, 6 H), 2.15 (s, 3 H), 2.59 (m, 1 H), 3.84 (s, 1 H), 7.24 (s, 1 H), 7.65 (bs, 1 H), 8.08 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:18]=[C:19]([C:23]([I:26])=[CH:24][N:25]=2)[C:20](O)=[O:21])=[C:14]([CH2:29][CH2:30][CH3:31])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].B.O1CCCC1.[OH-].[Na+].Cl>O1CCCC1.O>[F:33][C:2]([F:1])([F:32])[C:3]([C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH2:20][OH:21])[C:23]([I:26])=[CH:24][N:25]=2)=[C:14]([CH2:29][CH2:30][CH3:31])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)O)c(I)cn1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(CO)c(I)cn1
Yield: 91.1 %

Procedure:
To a solution of 2-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propy phenoxy)-5-iodoisonicotinic acid (441 mg, 0.741 mmol) in tetrahydrofuran (3.7 mL), a solution of borane-tetrahydrofuran (2.97 mL, 1 M in THF solution) was added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, water, 1N aqueous solution of sodium hydroxide and 5% aqueous solution of hydrochloric acid were added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried using sodium sulfate. The organic layer was concentrated in vacuo, and the obtained residue was purified using column chromatography (hexane/ethyl acetate). (2-(4-(1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-5-iodopyridin-4-yl)methanol (391 mg, yield 91%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(N3CCOCC3)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2N2CCOCC2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[S:6]([N+:10]12[CH2:17][CH2:16][N:13]([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)([OH:9])(=[O:8])=[O:7].B(F)(F)[F:19].FF>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:1][B-:2]([F:5])([F:4])[F:3].[F:19][N+:13]12[CH2:14][CH2:15][N+:10]([S:6]([OH:9])(=[O:7])=[O:8])([CH2:11][CH2:12]1)[CH2:17][CH2:16]2
Reactant: O=S(=O)(O)[N+]12CCN(CC1)CC2
Reactant: FB(F)F
Agent: FF
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: O=S(=O)(O)[N+]12CC[N+](F)(CC1)CC2

Procedure:
A solution of 1-sulfo-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (28 g, 10 mmole) and boron trifluoride gas (6.7 g, 10 mmole) in acetonitrile (125 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 12 mmole). The reaction was evaporated, the remaining solid washed with DME and dried to afford 1-fluoro-4-sulfo-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[N:34]1[CH:38]=[N:37][C:36]([C:39](=[O:41])[CH3:40])=[N:35]1>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:39]([C:36]4[N:37]=[CH:38][N:34]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33][O:28]5)[N:35]=4)([OH:41])[CH3:40])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1
Reactant: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1ncn(C2CCCCO2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncn(C4CCCCO4)n3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (90 mg, 0.36 mmol) in dry THF (1.5 mL) at −78° C. under an atmosphere of nitrogen was added 2M LDA in THF (0.45 mL, 0.903 mmol). After 5 minutes, 1-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]ethanone (211.45 mg in 1.5 mL dry THF, 1.08 mmol) was added. After 20 minutes the mixture was allowed to warm up to RT, then stirred for a further 30 minutes. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 2-11% methanol gradient in DCM) to give the title intermediate as a pale yellow oil: 1H NMR (500 MHz, DMSO) delta 1.76-1.56 (3H, m), 1.90 (3H, s), 2.18-1.94 (3H, m), 2.58 (3H, s), 3.74-3.60 (1H, m), 4.03-3.87 (1H, m), 5.60-5.43 (1H, m), 6.27 (1H, s), 6.96 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.34 (1H, d, J=8.1 Hz), 7.84 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=5.5 Hz), 8.68 (1H, s), 8.84 (1H, s); LC-MS: m/z=+445.05 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1.[C:16]1([CH2:22][CH2:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:22][CH2:23][CH2:24][NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]23[O:15][CH2:14][CH2:13][O:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc2c(c1)C1(OCCO1)C(=O)N2
Reactant: O=CCCc1ccccc1
Product: O=C1Nc2ccc(NCCCc3ccccc3)cc2C12OCCO2

Procedure:
By reaction of 5-amino-3,3-ethylenedioxy-2-oxindole with 3-phenylpropanal using the procedure of Example 1, the title compound was prepared.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10](O)[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1)([OH:3])=[O:2].C(O)=[O:18].C([O-])=O.[Na+].C1(C=CC(O)=CC=1)O>O1CCOCC1.O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:11]([OH:15])[CH:12]=[CH:13][C:14]1=[O:18])([OH:3])=[O:2]
Reactant: O=CO
Reactant: O=C(O)CCCCCCC(O)c1ccco1
Agent: O=C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCC1C(=O)C=CC1O

Procedure:
A stirred mixture of 65.0g (0.287 mol) of α-(6-carboxyhexyl)furfuryl alcohol (Example 6), 113 ml of 97% formic acid, 4.95g of sodium formate, 100 mg of hydroquinone, and 1430 ml of 3:2 dioxane-water is heated at reflux temperature for 19 hr. The solution is concentrated to volume of about 750 ml, diluted with water, saturated with salt, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated with toluene chaser to give an amber solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([CH2:40]O)[CH:34]=[CH:33]2.O>C(Cl)Cl>[Br:20][CH2:40][C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:24]3[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[CH:31]=2)[CH:36]=1
Reactant: BrBr
Reactant: OCc1ccc2cc(-c3c(Cl)cccc3Cl)ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1cccc(Cl)c1-c1ccc2cc(CBr)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of PPh3 (0.251 g) in CH2Cl2 (1 ml) is added drop by drop, at 0° C., a solution of bromine (0.049 ml) in CH2Cl2 (1 ml). After 30 min, [6-(2,6-dichlorophenyl)-2-naphthyl]methanol 287 (0.242 g) is added. The mixture is stirred, under argon, at RT for 6 h. Water (2 ml) is added. The aqueous phase is extracted with CH2Cl2 (3×5 ml). The organic phases are dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 40/60 as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19](Br)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncccc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncccc2-c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
To a stirred solution of 3-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (101) (163 mg, 0.48 mmol) in dioxane (10 mL) was added phenylboronic acid (78) (87 mg, 0.71 mmol), Na2CO3 (152 mg, 1.4 mmol) and H2O (2 mL). The reaction mixture was degassed with N2 and then PdCl2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was left to reach RT and filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (20 mL×3). The combined filtrates were evaporated in vacuo and the residue was purified by column chromatography ((EtOAc:Petrol ether=4:1) to give the desired compound (102) (138 mg, 0.41 mmol, 85% yield).