Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:43][C:24]4=[N:25][CH:26]=[C:27]([Br:42])[C:28]([N:29]5[CH2:34][CH2:33][N:32]([CH2:35][C:36]6[N:37]=[C:38]([CH3:41])[S:39][CH:40]=6)[CH2:31][CH2:30]5)=[C:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:42][C:27]1[C:28]([N:29]2[CH2:30][CH2:31][N:32]([CH2:35][C:36]3[N:37]=[C:38]([CH3:41])[S:39][CH:40]=3)[CH2:33][CH2:34]2)=[C:23]2[N:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:16][CH:17]=3)[NH:43][C:24]2=[N:25][CH:26]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCNCC6)cc5)nc34)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
tert-Butyl-4-(4-(6-bromo-7-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (0.022 g, 0.033 mmol) was suspended in DCM (2.0 mL) and the mixture cooled in an ice bath. TFA (0.5 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (5 g), washed with methanol and then eluted with ammonia (0.2M) in methanol. The filtrate was collected and the solvent removed in vacuo to give the title compound as a off-white solid (0.017 g, 91%); 1H-NMR (500 Mz, DMSO-d6): δ 2.26-2.36 (m, 4H), 2.61-2.75 (m, 11H), 3.50 (s, 2H, NCH2), 3.61-3.70 (m, 6H), 7.32 (s, 1H, thiazole 5-H), 7.45 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.13 (d, J=8.05 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.19 min—567/569 [(M+H)+, Br isotopic pattern]; ESI-HRMS: Found: 567.1634, calculated for C26H32N8SBr (M+H)+: 567.1654.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1>COCCOC.C(=O)([O-])O.[Na+]>[N+:9]([C:7]1[CH:8]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Nc1c([N+](=O)[O-])cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A stirred solution of 4-Bromo-2,6-dinitroaniline (3 g, 11.45 mmol) in 1,2-dimethoxyethane (83 ml) was purged with nitrogen for 15 min and treated with aqueous sodium hydrogen carbonate solution (1M, 22.8 ml) followed by pyridine 3-boronic acid (2.1 g, 17.17 mmol) and 1,1-bis-(diphenylphosphino)ferrocene palladium (II) chloride complex (0.94 g, 1.15 mmol). The resultant mixture was boiled under reflux in a nitrogen atmosphere for 18 h. After cooling to ambient temperature, the dark mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×250 ml). This was dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 30% to 100% ethyl acetate in 40-60 petroleum ether. The 2,6-Dinitro-4-pyridin-3-yl-aniline was obtained as a yellow solid (1.46 g, 49%).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.N1C=CC=CC=1.C(N)CN>CN(C=O)C>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[C:5]([C:1]#[N:2])[CH:13]=[CH:12][C:8]1=2
Reactant: N#C[Cu]
Reactant: Brc1ccc2sccc2c1
Solvent: NCCN
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2sccc2c1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
A mixture of CuCN (86 g, 960 mmol), 5-bromobenzo[b]thiophene (157 g, 723 mmol), pyridine (80 mL) and DMF (1400 mL) was heated at reflux for 14 h. After cooled to 80° C., the reaction mixture was poured into a cold aqueous solution of ethylenediamine (400 mL in 2 L water) cooled by an icebath. The product was extracted with ether (2×1.5 L). The ether layer was washed with brine (1 L), dried (Na2SO4), and concentrated. The residue was recrystallized from CHCl3/Hexanes (50 mL/2000 mL) to give benzo[b]thiophene-5-carbonitrile (106 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.61 (d, J=5.4 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.41 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:5][C:4]([CH3:17])=[N:3]1.O=P(Cl)(Cl)[Cl:20]>>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:9]([C:10]([Cl:20])=[C:5]2[C:4]([CH3:17])=[N:3]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Temperature: 0 °C

Procedure:
A mixture of N-(1,3-dimethyl-pyrazol-5-yl)anthranilic acid (7 g, 0.03 mol) and POCl3 (40 ml) was heated on a steam bath for 3 hours. The reaction mixture was then poured into ice-water (600 ml) and then basified with NH4H. The mixture was extracted with ether (3×200 ml) and the combined ether layers were dried over MgSO4 and evaporated to afford 7.0 g of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, m.p. 127°-129° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl:21][C:22]1[S:26][C:25]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH2:27][C:25]3[S:26][C:22]([Cl:21])=[CH:23][CH:24]=3)[C:29]2=[O:38])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(Cc2ccc(Cl)s2)c2ccccc21
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a pale yellow solution of 4-(benzyloxy)phenol (9.01 g, 45.0 mmol) in anhydrous tetrahydrofuran (100.0 mL) was added isopropylmagnesium chloride (26.3 mL, 52.5 mmol, 2.0 M solution in tetrahydrofuran) at 0° C. The reaction solution was stirred for 0.5 h followed by the addition of 1-((5-chlorothiophen-2-yl)methyl)indoline-2,3-dione (8.31 g, 30.0 mmol) in portions. The reaction mixture was stirred for 16 h at ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution (50.0 mL) and concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride solution (2×25.0 mL), brine (2×25 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate to afford 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (4.90 g, 28%) as a colourless solid: mp 174-175° C.; 1H NMR (300 MHz, CDCl3) δ8.45 (br, 1H), 7.40-7.27 (m, 7H), 7.14 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=2.9 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.79 (d, J=3.7 Hz, 1H), 6.70 (d, J=3.7 Hz, 1H), 6.43 (d, J=2.9 Hz, 1H), 4.86 (ABq, 2H), 4.84 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 178.3, 152.6, 149.790, 141.7, 136.8, 135.8, 130.4, 130.1, 129.1, 128.6, 127.9, 127.6, 126.3, 126.2, 126.0, 125.9, 124.3, 120.2, 116.3, 114.4, 109.6, 79.1, 70.6, 39.2; MS (ES+) m/z 478.2 (M−1), 476.2 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[N:12]=[N:13][C:14]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[ClH:24].[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[N:13]=[N:12][C:11]([C:8]3([NH2:7])[CH2:10][CH2:9]3)=[CH:16][CH:15]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nn2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C3(N)CC3)nn2)cn1
Reaction time: 2 h

Procedure:
{1-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropyl}-carbamic acid tert-butyl ester (51 mg, 0.16 mmol) was dissolved in CH2Cl2 (1 mL) and 4M HCl in dioxane (2 mL, 4 mmol) was added. After 2 h, the solvents removed under a stream of N2 to give the title compound as an orange solid, m/z=216.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].CN(C)C=O>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH2:5][CH2:6][O:7][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-4-hydroxy-butyric acid methyl ester (535 mg, 2.0 mmol) in tetrahydrofuran (5 mL). To this mixture was then added imidazole (330 mg, 4.8 mmol) and t-butyl dimethyl silyl chloride (360 mg, 2.4 mmol) and within a minute solids started to appear and N,N-dimethylformamide (1 mL) was added to solubilize the material. The mixture was stirred for 16 h at 25° C. and then diluted with water (50 mL) and the aqueous layer extracted with diethyl ether (2×50 mL) dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 16% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-(t-butyl-dimethyl-silanyloxy)-butyric acid methyl ester (478 mg, 63%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20].C([Li])CCC.CCCCCC.CN(C)[CH:34]=[O:35]>O1CCCC1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:34]=[O:35])=[C:3]([CH2:18][CH2:19][CH3:20])[CH:4]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CN(C)C=O
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 485.1 %

Procedure:
To a nitrogen purged 3-necked flask was added 2-(4-bromo-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.74 mmol, 1 g) in anhydrous tetrahydrofuran (15 mL). The solution was cooled to −78° C. before the addition of n-butyl lithium in hexane (2.5M, 8.22 mmol, 3.29 mL). The mixture was stirred at −78° C. for 15 minutes before the drop wise addition of N,N-dimethylformamide (3.01 mmol, 0.220 g). The mixture was stirred at −78° C. for 10 minutes and was then allowed to warm to room temperature and stir for 30 minutes. The mixture was quenched with water (10 mL) and diluted with ethyl acetate (100 mL). The organic phase was separated, washed with water (2×50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate/90% heptane) to afford the title compound (4177 mg).
Reaction SMILES: [CH:1]12[CH2:29][CH2:28][CH:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:44]([C:47]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3CC4CCC3CO4)N=2)=CC=1)=[C:45]=[O:46]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:1]12[CH2:29][CH2:28][CH:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:14]=[CH:15][C:16]([NH:17][C:45]([NH:44][CH3:47])=[O:46])=[CH:18][CH:19]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of 4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (50 mg, 0.12 mmol) in dichloromethane (2.5 mL) was treated triethylamine (160 μL), followed by triphosgene (27 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.2 mL)—was added to the 5-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 462.3 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl.C(OC(NC1SC(C(N2CCN(C3C=C4C(=CC=3)NC(=O)CC4)CC2)=O)=C(C)N=1)=O)(C)(C)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([N:19]1[CH2:20][CH2:21][N:16]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH2:17][CH2:18]1)=[N:3][CH:4]=[CH:5]2
Reactant: COc1cc2ccnc(Cl)c2cc1OC
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)N1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Solvent: ClC(Cl)Cl
Product: COc1cc2ccnc(N3CCN(c4ccc5c(c4)CCC(=O)N5)CC3)c2cc1OC
Yield: 37.3 %

Procedure:
1-Chloro-6,7-dimethoxyisoquinoline (0.63 g) and 6-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinone (1.30 g) were mixed at 200° C. for 1.5 hours under stirring. The mixture was dissolved in a mixture of chloroform and methanol (10:1 V/V) and subjected to a column chromatography on silica gel (eluent:methanol in chloroform, 0-2% V/V). The fractions containing the object compound were combined and concentrated and the residue was triturated with diisopropyl ether to give 6-[4-(6,7-dimethoxyisoquinolin-1-yl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone (0.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1I.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][N:13]=1.C(N(CC)CC)C.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([NH2:11])=[N:13][CH:14]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: CCc1nccc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.0 g (3.7 mmol) 4-chloro-3-iodo-2-ethyl-pyridine and 485 mg (4.1 mmol) 2-amino-5-ethynyl-pyridine using 36 mg (0.40 mmol) CuI, 131 mg (0.40 mmol) PdCl2(PPh3)2 and 5.2 mL (39.5 mmol) triethylamine in 25 mL dry DMF. After completion of the reaction the reaction mixture is added dropwise into water. The precipitate is filtered off and taken up with iPrOH. The product remains is solution while the side-product (alkyne dimer from Glaser-homo-coupling) forms a precipitate and is filtered off. The mother liquid is concentrated under vacuum. Yield: 718 mg (75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1.C1(C)C(O)=CC=CC=1.BrC1C=CC(C=O)=CC=1>>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccccc1Oc1ccc(CO)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: Cc1ccccc1O
Agent: O=Cc1ccc(Br)cc1
Product: COC(=O)CCc1ccc(OCc2ccc(Oc3ccccc3C)cc2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and [4-(2-methylphenoxy)phenyl]methanol (synthesized in the same manner as in Reference Example 201 from o-cresol and 4-bromobenzaldehyde (mixture with side product)) (preparative HPLC (gradient cycle A) was used for purification). colorless crystals (yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C=O
Yield: 98.2 %

Procedure:
4.3 g of 5-chlorosalicylaldehyde, together with 7.8 g of methyl iodide and 5.7 g of potassium carbonate, in 100 ml of acetone are heated to reflux (1 hour). After filtration, the filtrate is concentrated. 4.6 g of the title compound are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23].[CH:24]1([C:27]2[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]=[C:10]([C:20]([NH:33][CH2:32][C:30]3[N:31]=[C:27]([CH:24]4[CH2:26][CH2:25]4)[S:28][CH:29]=3)=[O:21])[CH:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(C(=O)O)ncc2OCC(F)(F)F)ccc1Cl
Reactant: NCc1csc(C2CC2)n1
Product: Cc1cc(-c2cc(C(=O)NCc3csc(C4CC4)n3)ncc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 4-(4-chloro-3-methylphenyl)-5-(2,2,2-trifluoroethoxy)picolinic acid (example BN) and 2-cyclopropyl-4-thiazolemethanamine (CAN 1083299-53-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 482.0911 (M+H)+.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:37][N:36]=2)=[C:31]([F:51])[CH:30]=1)S(C(F)(F)F)(=O)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].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.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.C1(C)C=CC=CC=1.O>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[N:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:37][N:36]=4)=[C:31]([F:51])[CH:30]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc1
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCc1cnc(-c2ccc(-c3ccc4c(c3)CC(CCCCCCCC)C4)cc2F)nc1
Yield: 73.8 %

Procedure:
0.40 g (1.46 mM of 2-octylindan-5-boronic acid, 0.60 g (1.30 mM) of 3-fluoro-4-(5-decylpyrimidine-2-yl)phenyl triflate, 1.2 ml of ethanol, 2 ml of toluene, 2 ml of 2M-sodium carbonate aqueous solution and 0.07 g of tetrakis (triphenylphosphine) palladium (O) were mixed and heat-refluxed for 200 minutes under stirring. After the reaction, the reaction mixture, water and toluene were added to followed by filtration under reduced pressure. The toluene layer was washed with a common salt aqueous solution followed by drying with anhydrous sodium sulfate. Then, the sodium sulfate was removed from the mixture and the resultant mixture was evaporated to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and treated with activated carbon, followed by recrystallization from acetone to obtain 0.52 g of 2-octyl-5-[3-fluoro-4-(5-decylpyrimidine-2-yl)phenyl]indan (Yield: 73.8%). ##STR316##
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[S:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:21]([OH:22])[C:20]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[S:18][C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: CN1CCC(Cl)CC1
Reactant: O=Cc1cc(Cl)ccc1Sc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C(O)c2cc(Cl)ccc2Sc2cc(F)ccc2F)CC1
Yield: 100 %

Procedure:
A solution of a Grignard reagent is prepared by reaction of 11.35 g of 4-chloro-1-methylpiperidine with 2.3 g of magnesium in 70 ml of tetrahydrofuran and is then treated for 10 minutes with a solution of 16.1 g 2-(2,5-difluorophenylthio)-5-chlorobenzaldehyde in 40 ml of tetrahydrofuran, added dropwise. The mixture is refluxed for 4 hours and, after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is washed with water, dried with potassium carbonate and evaporated. There are obtained 21.7 g (100%) crude oily α-(-methyl-4-piperidyl)-2-(2,5-difluorophenylthio)-5-chlorobenzyl alcohol which is used in this state for the final step.
Reaction SMILES: C([S:4][C@@H:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)C.[OH-].[Na+]>>[SH:4][C@@H:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1
Reactant: CC(=O)S[C@H]1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Product: S[C@H]1CN2CCC1CC2
Yield: 45.8 %

Procedure:
(3R)-3-Mercaptoquinuclidine may be obtained in a manner similar to that described in Example 2, but starting with (3R)-3-(acetylthio)quinuclidine (32.5 g) and 10N aqueous sodium hydroxide solution (35 cc); (3R)-3-mercaptoquinuclidine (11.5 g) is obtained in the form of white crystals which melt at 45° C. and distil at 90° C. under 830 Pa (αD20 =+121°, C=1.1, methanol).
Reaction SMILES: [CH:1]([N:4](C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][CH3:27])C(OC(C)(C)C)=O)([CH3:3])[CH3:2].[ClH:49]>C(OCC)C>[ClH:49].[ClH:49].[ClH:49].[ClH:49].[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:25][CH2:26][CH3:27])([CH3:3])[CH3:2]
Reactant: CCCN(CCCN(C/C=C/CN(CCCN(C(=O)OC(C)(C)C)C(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCNCCCNC/C=C/CNCCCNC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.24 g (0.35 mmol) of (E)-1-isopropyl-14-propyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 4 ml of 3N methanolic hydrochloric acid is stirred for 4 h at room temperature. Then the reaction mixture is diluted with 6 ml of diethyl ether and is worked up analogously to Example 1. The resulting title compound melts at >260° C. 1H-NMR (D2O): δ0.97(t,3H); 1.32(d,6H); 1.63-1.76(m,2H); 2.04-2.17(m,4H); 3.02(t,2H); 3.12-3.19(m,8H); 3.37-3.49(m,1H); 3.78(d,4H); 6.05-6.07(m,2H).