Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4](O)=[O:5].C1(C(Cl)(Cl)[Cl:18])C=CC=CC=1>>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([Cl:18])=[O:5]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: O=C(O)C(F)(F)C(F)(F)Br
Product: O=C(Cl)C(F)(F)C(F)(F)Br
Yield: 70.8 %

Procedure:
A mixture of 375.9 g (1.67 mol) of 3-bromotetrafluoropropionic acid, 10 g of ferric chloride, and 488.7 g (2.50 mol) of benzotrichloride was refluxed for 1.5 h, then crude product was removed, bp about 60°. Redistillation gave 287.9 g (71%) of 3-bromotetrafluoropropionyl chloride, bp 67°-68°. IR (CCl4): 5.53 (C=O). ##STR43##
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O-])=[O:14])[C:7]=2[CH:6]=[CH:5]1.N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.C(Cl)Cl.[O-2].[O-2].[Mn+4].O>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[C:7]=2[CH:6]=[CH:5]1
Reactant: O=C([O-])c1cccc2c1ccn2CC(O)c1ccccc1
Agent: [Mn+4]
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccc2c1ccn2CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
There were dissolved, in 40 ml of dimethylformamide, 5.14 g of 1-(2-hydroxy-2-phenylethyl)indole-4-carboxylate prepared in Example 320, 2.37 g of imidazole and 4.50 g of t-butyldimethylsilyl chloride and the resulting solution was stirred at room temperature for 21 hours. The solution was then poured into 100 ml of water and extracted with ethyl acetate (100 ml×2). The extract was washed in order with a 10% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, then dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 6.97 g of a pale yellow oily substance. The substance was dissolved in 20 ml of tetrahydrofuran and then dropwise added to a suspension of lithium aluminum hydride (516 mg) in tetrahydrofuran (40 ml) with ice-cooling. After stirring at room temperature for 1.5 hour, 0.52 ml of water, 0.52 ml of a 15% aqueous sodium hydroxide solution and 1.56 ml of water were, in order, added to the mixture, followed by drying over potassium carbonate, filtration and removal of the solvent through evaporation under reduced pressure to give 6.42 g of a colorless oily substance. This substance was dissolved in 70 ml of methylene chloride, followed by addition of 37.5 g of manganese dioxide, stirring at room temperature for 17 hours, filtration through a Celite layer, removal of the solvent through evaporation under reduced pressure to give 5.1 g of a pale yellow oily substance. The substance was dissolved in 40 ml of tetrahydrofuran, followed by addition of 25.8 ml of a 1.0M tetrabutylammonium fluoride solution and stirring at room temperature for 3.5 hours. water (50 ml) was added to the solution, extracted with ethyl acetate (100 ml×2), followed by washing of the extract with, in order, 5% hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated common salt solution, drying over anhydrous sodium sulfate and removal of the solvent through evaporation under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography to give 3.55 g of 1-(2-hydroxy-2-phenylethyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 75%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1.[CH2:20]([N:27]([CH2:31][Si](C)(C)C)[CH2:28]OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:27]1[CH2:31][CH:14]2[CH:13]([C:12](=[O:17])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:18])[F:19])=[CH:6][CH:7]=3)[CH2:16][CH2:15]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CCCN1c1ccc(OCC(F)(F)F)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C2CN(Cc3ccccc3)CC2CCN1c1ccc(OCC(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 30 h
Yield: 309.1 %

Procedure:
A mixture of 1-[4-(2,2,2-Trifluoro-ethoxy)-phenyl]-5,6-dihydro-1H-pyridin-2-one (0.27 g, 0.1 mmol), N-benzyl(methoxy)-N-((trimethylsilyl)methyl)methanamine (0.71 g, 0.3 mmol) and TFA (0.114 g, 0.1 mmol) in 20 mL of DCM was stirred at 45° C. for 30 h. The mixture was evaporated to dryness and the residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate=1:1) to obtain the title compound as colorless oil (0.125 g, 31%). LC-MS: 405.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12.O1CCOCC1.[NH:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Br:1][C:2]1[N:3]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([C:41]4[CH:42]=[N:38][NH:39][CH:40]=4)=[CH:10][C:9]=3[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:7][C:6]=12
Reactant: OB(O)c1cn[nH]c1
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(I)ccc32)c1Br
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(-c4cn[nH]c4)ccc32)c1Br
Yield: 44 %

Procedure:
342 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-7-iodo-2H-pyrazolo[4,3-c]isoquinoline are introduced into 13 ml of 1,4-dioxane. 74 mg of 4-pyrazoleboronic acid, 77 mg of Pd(PPh3)4 and 165 mg of sodium carbonate are added. The mixture is heated at reflux for 4 h 30 min. After cooling, the mixture is poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol mixture (95/05 by vol.), to give 136 mg of 3-bromo-5-(2,6-difluorophenyl)-7-(1H-pyrazol-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white foam), which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:4][C:3]=1[C:29]1[C:34]([C:35]#[N:36])=[CH:33][C:32]([C:37]([F:40])([F:39])[F:38])=[N:31][CH:30]=1.C(#N)C.[OH2:44].CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:29]2[CH:30]=[N:31][C:32]([C:37]([F:39])([F:38])[F:40])=[CH:33][C:34]=2[C:35]#[N:36])=[CH:4][C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[C:6]([CH:7]=1)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:44])=[O:13]
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCCO)c2ccccc21
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-[2-chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile 11-1 (65 mg, 0.11 mmol) in a mixture of DCM (0.5 mL), acetonitrile (0.5 mL) and water (0.6 mL) was added NaIO4 (71 mg, 0.33 mmol) and RuCl3 (4.5 mg, 0.022 mmol). After stirring at rt for 30 minutes, 0.5 mL of methanol was added. The mixture was stirred for 30 minutes, filtered, and purified by prep. LCMS to afford 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid 12-1. MS: 608.1 (M+H)+; tR=5.87 min (method 5).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:20][C:21]1[S:22][C:23]2[C:28]([N:29]=1)=[CH:27][CH:26]=[C:25]([O:30][C:31]1[CH:32]=[C:33]([NH:38][C:39](=[O:50])[C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=3)[CH:34]=[CH:35][C:36]=1[CH3:37])[N:24]=2>O1CCCC1.N1C=CC=CC=1.O>[CH3:37][C:36]1[CH:35]=[CH:34][C:33]([NH:38][C:39](=[O:50])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=2)=[CH:32][C:31]=1[O:30][C:25]1[N:24]=[C:23]2[S:22][C:21]([NH:20][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])=[N:29][C:28]2=[CH:27][CH:26]=1
Reactant: O=C(O)c1cocn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)c3cocn3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of 1,3-oxazole-4-carboxylic acid (126 mg, 1.12 mmol) in tetrahydrofuran (5 mL) were added oxalyl chloride (118 μL, 1.35 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue and N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(trifluoromethyl)benzamide (200 mg, 0.450 mmol) produced in Example C8(iv) were dissolved in pyridine (5 mL), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was precipitated with tetrahydrofuran to give the title compound (205 mg, 84%) as a white powder.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13])(C(C)(C)C)(C)C>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[NH4+].[Cl-]>[OH:8][CH2:9][CH2:10][CH2:11][C:12]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)CCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C(C)(C)CCCO

Procedure:
A solution of 550 mg of 12c in 4 ml of 1M tetra-n-butyl ammonium fluoride in THF was stirred at RT for 1 h. The reaction mixture was diluted with 25 ml of 5% aq. NH4Cl and the product was extracted with ethyl acetate. The organic layer was washed twice with sat. aq. NaCl, dried and concentrated. The crude material was purified by chromatography over silica gel, using a gradient of dichloromethane/ethyl acetate gradient as eluent. This provide 250 mg of 12d as a colorless oil. Rf 0.25 (CH2Cl2-ethyl acetate 8/2); MS-ESI: [M+1] 232.3, NMR (CDCl3) δ 1.32 (s, 6, 2×CH3), 1.48 (s, 9, tertC4H9), 1.55 (m, 2, CH2), 1.88 (m, 2, CH2), 2.88 (s, 3, NCH3), 3.02 (m, 2, CH2).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]1([C:17]2[C:26]([CH:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:41])[CH3:40])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:44])[CH2:20][C:21]([CH3:43])([CH3:42])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1.CO>O1CCCC1>[CH:12]1([C:17]2[C:26]([C@H:27]([OH:38])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)=[C:25]([CH:39]([CH3:40])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C@@H:19]([OH:44])[CH2:20][C:21]([CH3:42])([CH3:43])[O:22]3)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)c1cc2c(c(C3CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(C3CCCC3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
23 μl (130 μmol) of borane/N,N-diethylaniline complex are added to a solution of 0.1 mg (6.7 μmol) of (1R,2S)-1-aminoindan-2-ol in 1.0 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 15 mg (33 μmol) of 5-cyclopent-1-yl-6-{hydroxy[4-(trifluormethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 38A) in 1.0 ml of tetrahydrofuran is then added dropwise, and the mixture is stirred for 2 h. Methanol is then added, and the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the crude product by preparative HPLC (method 1) gives the diastereomerically pure target compounds.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[O:12])[C:6](=O)[O:5][C:4]([CH3:9])([CH3:8])[O:3]1.N12CCCN=C1CCCCC2>C(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][CH2:6]/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)OC/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Reaction time: 1 h

Procedure:
The solution of crude 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (˜220 ml) was cooled to 0-5° C. and treated dropwise over 10 minutes and under good stirring with a solution of 1,8-diazabicyclo (5,4,0) undec-7-ene (12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate was formed which gradually became a granular solid. After 1 h, the solid obtained was filtered and washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a light orange oil which was used as such for the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a mixture of 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one (1.0 g, 3.34 mmol) and morpholine (1.16 mL, 13.3 mmol) was added tetraisopropyl-orthotitanate (3.95 mL, 13.3 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (30.0 mL) and sodium cyanoborohydride (930 mg, 13.3 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (2.0 mL). The inorganic precipitate was filtered off and washed with ethanol. The filtrate was evaporated and purified by flash chromatography on silica gel with hexane/ethyl acetate/triethylamine 40:10:1 to give rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-morpholine (650 mg, 52%) as a yellow solid, MS: m/e=371.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: ClCCCBr
Product: ClCCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and 1-bromo-3-chloropropane using the method described in Example 41.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>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>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][N:30]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:32]=[N:31]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC1(C)OB(c2cnn(Cc3ccc4ccccc4c3)c2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(Cc4ccc5ccccc5c4)c3)ccnc21
Temperature: 120 °C
Yield: 88 %

Procedure:
4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.06 g, 0.0002 mol) and 1-(2-naphthylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.074 g, 0.00022 mol) were combined in toluene (2.0 mL, 0.019 mol) and ethanol (1.0 mL, 0.017 mol), and then potassium carbonate (0.063 g, 0.00046 mol, in 1 mL water) was added. The reaction mixture was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol) was added, sealed in a tube and heated to 120° C. in a microwave for 30 minutes. This was allowed to cool and then partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated to give 4-[1-(2-naphthylmethyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine 0.08 g, as an oily residue, LC/MS (M+H)+: 455.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:29])[C:5](=[O:28])[NH:6]2.[CH3:30]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC.O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:29])[C:5](=[O:28])[N:6]2[CH3:30]
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1c(=O)n(C)c2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
300 mg (0.768 mmol) of the compound from example 41 and 211 mg (0.768 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 109 mg (0.768 mmol) of iodomethane in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 3 h. Water was added, which formed a precipitate. The precipitate was filtered off and purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 203 mg of the title compound were obtained (65% of theory).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:51])[CH2:41][CH2:42][O:43]CC4C=CC=CC=4)=[CH:35][CH:34]=3)[CH:23]=[C:24]([O:26]COCCOC)[CH:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.C1COCC1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)(C)C.CCOCC>[OH:26][C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][OH:8])=[CH:15][CH:16]=2)[CH:21]=[C:22]([C:33]2[CH:34]=[CH:35][C:36]([O:39][C:40](=[O:51])[CH2:41][CH2:42][OH:43])=[CH:37][CH:38]=2)[CH:23]=1
Reactant: COCCOCOc1cc(-c2ccc(OC(=O)CCOCc3ccccc3)cc2)cc(-c2ccc(OC(=O)CCOCc3ccccc3)cc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C(CCO)Oc1ccc(-c2cc(O)cc(-c3ccc(OC(=O)CCO)cc3)c2)cc1
Temperature: 70 °C
Reaction time: 60 h

Procedure:
5.40 g (7.82 mmol) 3-benzyloxy-propionic acid-4″-(3-benzyloxy-propionyloxy)-5′-(2-methoxy-ethoxymethoxy)-[1,1′;3′,1″]terphenyl-4-yl ester are dissolved in 40 ml isopropanol and 10 ml THF and after addition of 1.97 g (7.82 mmol) pyridiniumtosylate are stirred for 60 h at 70° C. After cooling to RT the mixture is diluted with MTB ether, washed with sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is hydrogenated in 40 ml THF on Pd/activated charcoal until the reaction is completed. The solvent is removed in vacuo and the crude product is recrystallized from dichloromethane, to give 3-hydroxy-propionic acid-5′-hydroxy-4″-(3-hydroxy-propionyloxy)-[1,1′;3′,1″]terphenyl-4-yl ester as colourless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][O:17][C:16]([C:7]1[C:8]2[O:12][C:11]([CH3:13])([CH3:14])[O:10][C:9]=2[CH:15]=[C:4]2[O:3][C:2]([CH3:19])([CH3:1])[O:6][C:5]=12)=[O:18]
Reactant: CC1(C)Oc2cc3c(c(C(=O)O)c2O1)OC(C)(C)O3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c2c(cc3c1OC(C)(C)O3)OC(C)(C)O2
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d′]-bis(1,3)dioxole-4-carboxylic acid (10.0 g, 38.0 mmol) was dissolved in dry DMF (100 mL). Potassium carbonate (15.2 g, 110.0 mmol) was added and the reaction was heated to 55° C. for 30 min. After cooling to ambient temperature, methyl iodide (15.6 g, 110.0 mmol) was added and the solution was stirred overnight. The precipitate was filtered off and the solution was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and ether. The aqueous layer was discarded and the organic phase was dried (Na2SO4), filtered and evaporated to give 9.4 g (88%) of the pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(Br)cn1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
To a stirred solution of (5-Bromo-pyridin-2-yl)-methanol (1 g, 5.319 mmol) in CH2Cl2 (20 mL) is added drop wise thionyl chloride (0.57 mL, 7.979 mmol) at 0° C. then stirred for another 4 hours. Reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography using 7% ethyl acetate in hexane as an eluent to afford the title compound (0.8 g). 1HNMR (400 MHz, DMSO-d6) δ: 4.7 (s, 2H), 7.53 (d, 8.36 Hz, 1H), 8.09-8.11 (dd, J1=2.44 Hz, J2=8.23 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), LC-MS (m/z): [M+H]=206.0.