Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:34])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:27]=[N:28][C:29](F)=[CH:30][C:31]=4[CH3:32])=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([C:12]2[CH:13]=[C:14]([CH3:34])[C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4[C:31]([CH3:32])=[CH:30][C:29]([N:3]5[CH2:7][CH2:6][CH2:5][C:4]5=[O:8])=[N:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)=[N:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Temperature: 25 °C

Procedure:
Under a nitrogen stream, sodium hydride (47 mg) was suspended in N,N-dimethylformamide (10 mL), pyrrolidin-2-one (74 μL) was added, and the mixture was stirred at room temperature. Then, a solution of [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (210 mg) described in Preparation Example 140 in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at 95° C. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give 1-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}pyrrolidin-2-one. The obtained 1-{5-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-4-methylpyridin-2-yl}pyrrolidin-2-one was dissolved in dichloromethane, 1N hydrogen chloride/diethyl ether (5 mL) was added, and the precipitate was collected by filtration to give the title compound (12 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:32])[C:12]=1[C:13](=[O:31])[NH:14][C:15]1[C:20]([Br:21])=[CH:19][N:18]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:17]2[CH:16]=1)=[O:7])C.O.Cl>C1COCC1.CO>[Br:21][C:20]1[C:15]([NH:14][C:13]([C:12]2[N:11]([CH3:32])[N:10]=[CH:9][C:8]=2[C:6]([OH:7])=[O:5])=[O:31])=[CH:16][C:17]2[N:18]([CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:19]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaOH (3N, 0.65 ml) was added to a solution of 5-(6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (460 mg, 0.98 mmol) in a mixture of THF (5 ml) and methanol (5 ml), and the reaction mixture was stirred at r.t. overnight. An additional amount of NaOH (3N, 0.65 ml) and water (2 ml) were added and the mixture was heated to reflux (1 h). After cooling to r.t., HCl (conc., ˜0.7 ml) was added to the cooled mixture, and the brown suspension was stirred at r.t. (15 min). The suspension was then filtered, and the precipitated title compound (150 mg, 35%) was washed with a small amount of water, dried under vacuum, and used in the next step without further purification. MS (m/e)=440.3 [M+H+].
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:31][C@@H:32]1[C@@H:36]([OH:37])[CH2:35][CH2:34][O:33]1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:31][C@@H:32]6[C@@H:36]([OH:37])[CH2:35][CH2:34][O:33]6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Reactant: OC[C@H]1OCC[C@@H]1O
Product: O=c1c2ccc(OC[C@H]3OCC[C@@H]3O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with (2R,3S)-2-Hydroxymethyl-tetrahydro-furan-3-ol by method Y. The product with the molecular weight of 493.58 (C28H32FN3O4) was obtained in this way; MS (ESI): 494 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>ClCCl>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][C:19](=[O:22])[CH2:20][CH3:21])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: NC1CCc2nc(Br)sc2C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCc2nc(Br)sc2C1
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A solution of 2-Bromo-4,5,6,7-tetrahydro-benzothiazol-6-ylamine (0.36 grams, 1.5 mmol, obtained in above step) and triethylamine (0.43 mL, mmol) in dichloromethane (15 mL) was cooled to 0° C. Propionylchloride (0.17 mL, 1.8 mmol) in dichloromethane (2 mL) were added and stirred the reaction mass for 30 minutes. After completion of reaction, the mass was poured onto ice cold water and the product was extracted with ethyl acetate (3×15 mL). The combined organics were washed with water followed by brine, dried over anhydrous sodium sulphate and the organic volatiles were evaporated under vacuum. The residue was purified by flash chromatography (methanol/chloroform, 2/98) to obtain the title compound (0.4 grams).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:22][O:23]CC=C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].FC(F)(F)C(O)=O>C(O)C.[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>[CH2:1]([O:19][CH2:20][CH:21]([CH2:22][OH:23])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCOCC(COCCCCCCCC/C=C\C/C=C\CCCCC)OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\C/C=C\CCCCC
Yield: 65.4 %

Procedure:
1,2-Dilinoleyloxy-3-allyloxypropane (25) (18 g, 28.6 mmol) was dissolved in ethanol (150 mL) in a 500 mL round bottom flask with a stir bar. Trifluoroacetic acid (15 mL) and tetrakis (triphenylphosphine) palladium(0) (5.0 g, 4.3 mmol) were added and the flask flushed with nitrogen. A water condenser was fitted and the flask wrapped tin foil to reduce exposure to light. The reaction was refluxed under nitrogen overnight. The solution was concentrated to an orange oil, then redissolved in DCM (250 mL), and washed with water (2×200 mL) and saturated brine (1×200 mL). The aqueous phases were combined and extracted with DCM (2×100 mL). Organic phases were combined, dried over MgSO4 and concentrated. The crude product was purified by column chromatography to yield 1,2-dilinoleylglycerol as a colorless oil (11.0 g, 18.7 mmol, 65.3%).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]2[CH3:23])=[N:8][CH:9]=1)#[N:3]>>[ClH:1].[CH3:23][CH:11]1[CH2:12][NH:13][CH2:14][CH2:15][N:10]1[C:7]1[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][N:8]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C#N)cn1
Agent: Cl
Product: CC1CNCCN1c1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6N HCl (1 mL) was added to the compound tert-butyl 4-(5-cyanopyridin-2-yl)-3-methylpiperazine-1-carboxylate (120 mg, 0.39 mmol) and the reaction mixture was stirred at 90° C. for 30 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and triturated with ether to afford 6-(2-methylpiperazin-1-yl)nicotinonitrile hydrochloride (90 mg, crude). 1H NMR (400 MHz, D2O) δ 8.39 (d, J=2.0 Hz, 1H), 7.85 (dd, J=9.3 Hz, J=2.3 Hz, 1H), 6.95 (d, J=9.5 Hz, 1H), 4.74 (m, 2H), 4.32-4.27 (m, 1H), 3.48-3.41 (m, 1H), 3.35-3.28 (m, 2H), 3.17-3.10 (m, 1H), 1.27 (d, J=7.0 Hz, 3H)
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH:19]=O>>[C:1]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:19]([C:18]3[C:17]([O:16][CH3:15])=[CH:24][CH:23]=[CH:22][C:21]=3[O:25][CH3:26])[CH2:22][CH2:21][CH2:18][C:17]2=[O:16])=[CH:5][CH:6]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available [1,1′-biphenyl]-4-ylmethanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 401.85 g/mol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12](=O)[NH:13][C@H:14]1[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16][CH2:15]1)(C)(C)C.O.[OH-].[Na+]>C1COCC1>[CH3:12][NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C

Procedure:
A 2M solution of lithium aluminium hydride in THF (4.6 ml) was added dropwise to a solution of cis-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester (1 g, 4.6 mmol) in THF (5 ml) stirring at ambient temperature. After stirring for 30 minutes the mixture was heated at reflux for 16 hours. After allowing to cool, water (0.35 ml) followed by 2N sodium hydroxide (0.35 ml) and water (0.35 ml) were carefully added. The white precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The remaining aqueous was diluted with water and neutralised by dropwise addition of 4N hydrochloric acid. The aqueous was slowly passed through an ion exchange column (SCX, 10 g) and after washing with methanol the product was eluted with 2M ammonia in Methanol solution. Fractions combined and concentrated under reduced pressure to afford cis-4-methylaminocyclohexanol (455 mg, 76%).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][C@H:4]1[CH2:9][C@H:8]([O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]([C:19]#[CH:20])(O)[CH:5]1[CH3:21].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:26][Si:2]([CH3:1])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][C@H:4]1[CH2:9][C@H:8]([O:10][Si:11]([CH3:16])([CH3:17])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:7][C:6]([C:19]#[CH:20])=[C:5]1[CH3:21]
Reactant: C#CC1(O)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1C
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C#CC1=C(C)[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
90 mg (0.23 mmol) of 10 in 8 ml of pyridine is introduced, and 50 μl of thionyl chloride is added under argon. It is stirred for 10 minutes at room temperature, poured onto ice water and extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, the solvent is removed and the crude product is purified by chromatography on silica gel (mobile solvent: EE:H=1:19; Rf =0.9), whereby 71 mg (0.20 mmol) of title compound 11 is obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][N:27]([CH3:47])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:47][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)=[CH:34][N:33]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN(C)CCCOc1ccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with dimethyl-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yloxy]-propyl}-amine to give 121. MS(ESI+) 531.2. 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=2.2, 1H), 8.38 (d, J=8.3, 1H), 8.30 (s, 1H), 8.09 (dd, J=8.7, 2.5, 1H), 7.54 (dd, J=8.3, 1.8, 1H), 7.41 (d, J=1.7, 1H), 6.89 (d, J=8.6, 1H), 5.87 (q, J=8.7, 2H), 4.43 (t, J=4.9, 2H), 4.33 (t, J=6.6, 2H), 3.49 (t, J=4.9, 2H), 2.37 (t, J=7.1, 2H), 2.16 (s, 6H), 1.87 (p, J=6.8, 2H)
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([CH2:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[C:15](O)=[O:16])[CH2:10][CH2:9]1)[CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[F:25][C:23]1[CH:24]=[C:19]2[C:20](=[C:21]([F:27])[C:22]=1[F:26])[C:15](=[O:16])[CH:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]1)[CH2:18]2
Reactant: CCC[C@H]1CC[C@H](C(Cc2cc(F)c(F)c(F)c2)C(=O)O)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](C2Cc3cc(F)c(F)c(F)c3C2=O)CC1
Reaction time: 2 h

Procedure:
Dichloromethane (25 ml) and thionyl chloride (20 ml) were added to 2-(trans-4-propylcyclohexyl)-3-(3,4,5-trifluorophenyl)propionic acid crude product (12.3 g), and refluxed while heating for 4 hours. The dichloromethane was distilled off at normal pressure and the thionyl chloride was distilled off under reduced pressure followed by the addition of dichloromethane (50 ml) to the residue to prepare a dichloromethane solution of 2-(trans-4-propylcyclohexyl)-3-(3,4,5-trifluorophenyl)propionic acid chloride. This was then dropped in to a dichloromethane suspension (20 ml) of aluminum chloride (8 g) at room temperature over the course of 30 minutes. Moreover, after stirring for 2 hours, the reaction solution was poured into 10% hydrochloric acid while cooling with ice. The organic layer was concentrated after drying with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 5,6,7-trifluoro-2-(trans-4-propylcyclohexyl)-1-indanone crude product (8.8 g, purity: 73%). This was then recrystallized from ethanol to obtain 5,6,7-trifluoro-2-(trans-4-propylcyclohexyl)-1-indanone (5 g, purity: 99%). This compound had a molecular weight of 310 as determined by mass analysis.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1S(C)(=O)=O.O>CN(C=O)C>[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:4]3[CH:3]=[CH:2][N:1]=[C:5]23)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2cccnc21
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (175 mg) obtained in Example 9, step C) in DMF (2 ml) was added sodium hydride (60% in oil, 32 mg) at room temperature by small portions. After stirring for 10 min, a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (169 mg) in DMF (1.5 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (THF) and recrystallized from methanol/water to give the title compound (179 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])[OH:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH3:28]>C(#N)C>[CH2:27]([N:14]1[CH2:13][CH2:12][CH:11]([C:7]2[C:6]([F:17])=[C:5]([CH:3]([OH:4])[C:2]([F:1])([F:18])[F:19])[CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:15]1)[CH3:28]
Reactant: OC(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(C(O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodoethane (0.01 g). MS m/z (rel. intensity, 70 eV) 305 (M+, 17), 304 (13), 291 (15), 290 (bp), 149 (5).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[C@H:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@@H]3O[C@@H]3CO2)cc1
Product: COc1ccc(CN[C@@H]2C[C@@H](C(c3ccccc3)c3ccccc3)OC[C@@H]2O)cc1

Procedure:
(1R, 4S, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28b (0.021 g, 0.079 mmol) was reacted with p-methoxybenzylamine (0.22 g, 1.58 mmol) (Procedure E) to yield (3R, 4R, 6S)-6-benzhydryl-4-(4-methoxy-benzylamino)-tetrahydropyran-3-ol, (−)-29 g 0.02 g (63%, [α]D=(−)63.75, c=1, MeOH).
Reaction SMILES: Cl[Pd:2]Cl.[Li+].[Cl-].CC([O-])=O.[Na+].[S:11]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[NH:14]1)(=[O:13])=[O:12]>CO.O>[Pd:2].[S:11]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[NH:14]1)(=[O:12])=[O:13]
Reactant: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: [Pd]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Two-necked 25 ml RB flask was charged with PdCl2 (0.177 g, 1 mmol), LiCl (0.100 g, 2.4 m mol) and MeOH (2 ml). The resulting reaction mixture was stirred under argon atmosphere at 25° C. for 2.5 h. Then to the same reaction was added NaOAc (0.123 g, 1.5 mmol), and a solution of saccharin (formula 7) (0.183 g, 1 mmol) in MeOH (2 ml). The resulting reaction mixture was stirred at 25° C. for 72 h. Then distilled water (6 ml) was added to it and the solid was filtered on sintered funnel, washed with water and dried under reduced pressure (5 mm) for 3 h to afford palladium complex (formula 8) where in R═H and R1=Me as brown colored solid. Yield: 75%, mp: 240° C. (decomp.)
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:26])=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([Cl:26])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOC(=O)OCc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOC(=O)OCc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(Allyloxycarbonyl)oxymethyl]benzoic acid (850 mg, 3.60 mmol) obtained from Example 17-(2) was dissolved in dichloromethane (5 ml), and N,N-dimethylformamide (0.05 ml) and oxalyl chloride (570 mg) were added thereto. The mixture was stirred at room temperature for 1 hour, then toluene was added thereto, and the solution was concentrated under reduced pressure to give crude 2-[(allyloxycarbonyl)oxymethyl]benzoyl chloride.
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.[CH2:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][NH:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].[ClH:37].CO>CN(C)C(=O)C.CO.O>[ClH:37].[CH3:19][C:3]1([CH2:2][CH:24]2[CH2:25][CH2:30][C:29]3[CH:28]=[CH:27][CH:26]=[CH:20][C:21]=3[NH:22][CH2:23]2)[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Reactant: c1ccc2c(c1)CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CO
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CC1CCc3ccccc3NC1)C2
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 45 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (520 mg, 1.40 mmol), 2,3,4,5-tetrahydro-1H-3-benzazepine (309 mg, 2.10 mmol) and potassium carbonate (387 mg, 2.80 mmol) in N,N-dimethylacetamide (3 ml) was stirred for 3.5 hours at 180° C. under nitrogen atmosphere. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain an oil. The oil was dissolved in methanol and combined with 10% hydrogen chloride-methanol solution (1.5 ml), and concentrated under reduced pressure. The residue was crystallized from methanol-diisopropyl ether to obtain 269 mg of the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Reactant: NCCc1ccccc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]([NH2:31])=[NH:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH2:31][C:29](=[NH:30])[NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: N=C(N)NS(=O)(=O)c1ccc(N)cc1
Product: N=C(N)NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(amino-imino-methyl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.85 (d, 1H), 7.8 (d, 2H), 7.5 (d, 2H), 7.4 (d, 1H), 7.3 (d, 1H), 6.5 (d, 1H), 5.7 (s, 1H); C17H14N6O3S2: APCI-MS m/z 415 (M+H)+.