Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:15]=[N+:16]([O-])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[CH:21]=1)#[N:2].CC1(C)CC(C2C=CC=CN=2)C2C=C(C(O)=O)C=CC=2O1.CC(C)(OC1C=CC(C#N)=CC=1)C#C>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:10]([CH3:13])([O:11][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:21][CH:7]=1)[C:9]#[C:8][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)CC(c2ccc[n+]([O-])c2)c2cc(C#N)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1cccnc1)Oc1ccc(C#N)cc1
Reaction time: 72 h

Procedure:
The 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide used as the starting material was prepared as follows: (A) 10.25 g of 3-iodopyridine were added at room temperature to a solution of 44 mg of palladium(II) chloride, 131 mg of triphenylphosphine and 95 mg of copper(I) iodide in 200 mg of diethylamine. 9.25 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were then added and the mixture was stirred for 3 days. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (11:9) for the elution to give 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile in the form of an oil. (B) 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile were heated at reflux in 75 ml of 1,2-dichlorobenzene for 3.5 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. After recrystallization from cyclohexane there were obtained 6.7 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 98°-99° C. (C) 2.1 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 50 ml of ethyl acetate and shaken at room temperature under a hydrogen atmosphere with 50 mg of 10% palladium-on-charcoal for a total of 30 hours with several changes of catalyst. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution. 910 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were obtained in the form of an oil. (D) 610 mg of m-chloroperbenzoic acid were added to a solution of 792 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane. After stirring at room temperature for one hour the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was crystallized from t-butyl methyl ether to give 710 mg of 3-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in the form of a solid of melting point 134°-137° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@H](O)CC2)C3=O)OC1(C)C
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@H](O)CC4)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=554.1/556.0.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].OCC[C:15]#[N:16]>>[O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH2:8][C:15]#[N:16])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#CCCO
Product: CCCC(=O)CC(=O)OCCC#N
Temperature: 192.5 °C

Procedure:
A mixture of ethyl 3-oxohexanoate (33.7 mmol) and 3-hydroxypropionitrile (28.1 mmol) were placed in a round bottom flask (magnetically stirred) equipped with a short distillation path. The resulting mixture was gradually heated to 180-205° C. in an oil bath. The distillate was collected. The mixture was then cooled to room temperature and the residue was distilled under reduced pressure to give 2-cyanoethyl 3-oxohexanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[C:15]([CH2:23][C:24]([CH3:26])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>CO>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:5][C:24]([CH3:26])=[CH:23][C:15](=[O:22])[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(=O)CC(=O)c1cccnc1
Solvent: CO
Product: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1cccnc1
Yield: 78.9 %

Procedure:
To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) is added 1-nicotinoylacetone (3.68 g, 22.56 mmol), then the mixture is heated to reflux for 24 h. The solvent is evaporated under a vacuum. To the residue is added ethanol (50 ml), then the ethanol is distilled off under atmospheric pressure. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (5.51 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[C:13]([N:17]=[C:18]=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]([NH:12][C:18](=[O:19])[NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:11]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cccc(C)c1NC(N)=S
Solvent: Cc1ccccc1C
Product: Cc1cccc(C)c1NC(=S)NC(=O)NC(C)(C)C

Procedure:
To a mixture of 8.8 g. (0.05 mole) of 1-(2,6-dimethylphenyl)thiourea and 10 ml. of xylene is added 5 g. of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dimethylphenyl)-3-(t-butylcarbamyl)thiourea.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[NH:25][NH2:26])[CH:20]=[CH:21][CH:22]=1>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)Nc1cccc(C(F)(F)F)c1
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1cccc(C(F)(F)F)c1

Procedure:
ninhydrin, 4-(3-trifluoromethyl phenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:13][OH:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][O:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)COCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: c1ccc(COCC2COC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.7 %

Procedure:
To a solution of 2-benzyloxymethyl-propane-1,3-diol (4.39 g, 22.36 mmol) in tetrahydrofuran (60 ml) stirred at −5° C., was added n-butyllithium in hexane (2.5 M, 11.18 ml, 27.96 mmol) and after 20 min, a solution of p-toluenesulfonyl chloride (5.12 g, 26.85 mmol) in tetrahydrofuran (20 ml) was added. The reaction was allowed to warm to 25° C. and then stirred for 2 h. To this solution was added water slowly and then extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then dissolved in tert-butyl alcohol (90 ml) and potassium tert-butoxide (7.5 g, 66.83 mmol) was added, and the reaction was refluxed for 30 min and then stirred at 25° C. for 30 min. After such a time it was diluted with water (500 ml) and extracted with ether (2×250 ml). The extracts were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (120 g column, 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) afforded 3-benzyloxymethyl-oxetane (2.02 g, 51%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 3.19-3.32 (m, 1H, CH), 3.71 (d, J=6.9 Hz, 2H, OCH2), 4.42-4.48 (m, 2 H, 2×OCH of 2×OCH2), 4.55 (s, 2H, OCH2Ar), 4.77-4.83 (m, 2H, 2×OCH of 2×OCH2), 7.27-7.40 (m 5H, Ar).
Reaction SMILES: C1([CH:7](C2C=CC(N(C)C)=CC=2)[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[C:9]=2[C:18]([OH:20])=[O:19])C=CC=CC=1.[C:30]1(C)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:11]1([C:14]2[C:15]([C:33]3[CH:32]=[CH:31][C:30]([N:10]([CH3:17])[CH3:9])=[CH:35][CH:34]=3)=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:17])[C:9]([C:18]([OH:20])=[O:19])=[C:8]3[CH3:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1
Reactant: CN(C)c1ccc(C(c2ccccc2)c2c(C(=O)O)n(C)c3ccccc23)cc1
Product: Cc1c(C(=O)O)n(C)c2ccc(-c3ccccc3)c(-c3ccc(N(C)C)cc3)c12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
With stirring a mixture of 325.0 ml of ethanol, 47.5 g of [(phenyl)(4-dimethylaminophenyl)(4-methylphenylsulfonyl)]methane, 25.0 ml of 1-methylindol-2-carboxylic acid and 13.0 ml of concentrated hydrochloric acid was heated at reflux temperature for approximately twenty-two hours. The resultant solution was poured slowly into approximately 300.0 ml of cold water. The resulting suspension was extracted with approximately 500.0 ml of toluene. The toluene layer was separated and washed consecutively with water and saturated sodium chloride solution. The toluene layer was stirred for approximately one hour with decolorizing charcoal and filtered to remove the charcoal. The toluene was removed by evaporation leaving a dark blue-purple solid. The solid was suspended in ethanol, heated for approximately one hour and cooled to ambient temperature. The solid was collected by filtration, washed with isopropanol and dried to obtain 19.0 g of a mixture of starting methane and [(phenyl)(4-dimethylaminophenyl)(1-methyl-2-carboxyindol-3-yl]methane as determined by nuclear magnetic resonance spectroscopy. The resulting solid was suspended in approximately 300.0 ml of toluene for approximately one hour and the solid collected by filtration. The toluene-wet solid was reslurried in approximately 100.0 ml of toluene at a temperature of approximately 60° C. for approximately one hour. After cooling the slurry to approximately 40° C., the solid was collected by filtration and dried to obtain 2.47 g of [(phenyl)(4-dimethylaminophenyl)(1-methyl-2-carboxyindol-3-yl)]methane (Formula XI: R1 =R2 =R3 =R4 =R11 =B"=H; R5 =N(CH3)2 ; R9 =CH3), a cream-colored solid which melted at 214°-215° C. A significant infrared maximum appeared at 760 (C--H;s) cm-1. The nuclear magnetic resonance spectrum was concordant with the assigned structure. A toluene solution of the product spotted on an acidic clay-coated paper slowly developed a medium blue-colored image and spotted on a phenolic resin-coated paper slowly developed a dark blue-colored image.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@@H:16]3[CH3:28])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][NH2:38])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH2:36][CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C@@H:16]3[CH3:28])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cncc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccc(F)c1
Product: C[C@H]1CNCCN1Cc1cncc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 148 from above was coupled with 2-(3-fluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 407. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.4 (s, 1H) 9.0 (m, 2H) 8.5 (d, 1H) 7.4 (s, 1H), 7.2 (t, 1H), 7.1 (m, 2H), 6.9 (d, 1H), 3.71-3.65 (m, 4H) 3.57 (d, 2H), 3.47-3.44 (m, 1H), 3.39-3.31 (m, 4H), 2.9 (t, 2H), 1.6 (d, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN(C)C=O>[CH2:7]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:18]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:17]=2[F:16])[CH2:27][CH2:28]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCNCC2)c(F)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 579.2 %

Procedure:
Potassium carbonate (0.526 g, 3.80 mmol) and benzyl bromide (0.155 ml, 0.130 mmol) were added to a solution of 1-(2-fluoro-4-nitrophenyl)-[1,4]diazepane hydrochloride (compound of Reference Example 55; 0.300 g, 1.08 mmol) in anhydrous N,N-dimethylformamide (6 ml), and the mixture was stirred at 80° C. for 6 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (methanol ethyl acetate=1:1) to give the title compound (0.248 g, 69%) as a brown liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:27]([NH:29][NH2:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1.O>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:30][NH:29][C:27]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])=[O:46])=[CH:40][CH:39]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a mixture of the product of example 15 (807 mg, 1.97 mmol) and sodium carbonate (418 mg, 3.95 mmol) in tetrahydrofuran (25 ml), 4-fluorophenylacetyl chloride (374 mg, 2.17 mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature. Then water (25 ml) was added and the mixture was stirred for 1 hour. The resulting solids were collected by filtration, washed with water and PE successively and dried to give the titled product (697 mg, 64.8%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][CH2:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:30][O:31][CH3:32])[C:15]2=[N:14][C:13]=1[CH3:33])([O:9]CC)=O.O.[OH-].[Na+].O1CCC[CH2:38]1>>[CH3:33][C:13]1[N:14]=[C:15]2[C:20]([NH:21][CH2:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:30][O:31][CH3:32])=[CH:19][C:18]([CH3:38])=[CH:17][N:16]2[C:12]=1[CH2:7][OH:9]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3COC)cccn12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: COCc1cccc(C)c1CNc1cc(C)cn2c(CO)c(C)nc12
Reaction time: 4 h

Procedure:
lithium aluminum hydride (0.29 g, 7.7 mmol) was added to tetrahydrofuran (30 ml) and 3-carbethoxy-8-(2-methoxymethyl-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine (1.4 g, 3.8 mmol) dissolved in tetrahydrofuran (30 ml) was added dropwise during 80 min. at room temperature and stirred for 4 h. Water (0.29 ml) was added dropwise, followed by sodium hydroxide (15%, 0.29 ml) and finally 0.93 ml of water. After stirring 30 min. the solids were filtered off and washed thoroughly with tetrahydrofuran. The solvent was removed under reduced pressure and chromatography on silica gel (methylene chloride:methanol, 9:1) gave (0.97 g 75%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:29]1[CH:30]=[CH:31][C:32]([CH:33]=[CH:34][C:35]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:36])=[CH:38][CH:39]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C=CC(=O)Cl)cc1
Reactant: NCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)NCCS(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 4.4 g. of p-(2,2,2-trifluoro-N-hexadecylacetamido)cinnamoyl chloride as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. After stirring for 10 min., the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compounds as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 76 %

Procedure:
Using 5 g (25 mmol) of 4-methoxy-4'-hydroxybiphenyl, 50 ml of ethanol, 4.52 g (25 mmol) of 6-bromo-1-hexanol and a NaOH aqueous solution (1.05 g (26.2 mmol) of NaOH/3 ml of water), synthetic treatment was carried out in the same manner as in Example 1. The obtained crystals were recrystallized from methanol to obtain 5.71 g (yield: 76%) of 4-methoxy-4'-(6-hydroxyhexyloxy)biphenyl (13) as colorless crystals.
Reaction SMILES: [Br-].O1CCCOC1CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[CH2:40]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][C:56]3=O)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1)[CH2:41][CH3:42]>CCOCC>[CH2:40]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[CH:51][C:52]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[CH:53][CH:54]=2)=[CH:45][CH:44]=1)[CH2:41][CH3:42]
Reactant: CCCc1ccc(-c2ccc(C3CCCCC3=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (22.9 g, 50 mmols), followed by adding tetrahydrofuran (100 ml), suspending, stirring the suspension under ice cooling till the liquid temperautre reached 10° C. The resulting reaction mixture is added potassium t-butoxide (5.6 g, 50 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (100 ml) solution of (4-(4-propylphenyl)phenyl)cyclohexanone (14.0 g, 48 mmols) over 30 minutes from the dropping funnel, further stirring the reaction liquid for 5 hours after completion of the dropwise addition, adding ether (200 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-(4-propylphenyl)phenylcyclohexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[C:54]2[C:53]([NH2:55])=[N:52][CH:51]=[N:50][C:49]=2[S:48][CH:47]=1.C([O-])(O)=O.[Na+]>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(Cl)Cl.CCOCC.O1CCOCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[CH2:12][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:46]3[C:54]4[C:53]([NH2:55])=[N:52][CH:51]=[N:50][C:49]=4[S:48][CH:47]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:21]
Reactant: Nc1ncnc2scc(Br)c12
Reactant: O=C(Cc1cc(F)ccc1F)N1CCc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1ncnc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a mixture of 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (150 mg, 0.426 mmol), bis(pinacolato)diboron (114 mg, 0.447 mmol), and potassium acetate (125 mg, 1.278 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (17.39 mg, 0.021 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 C into a sealed vessel. The reaction was cooled down to room temperature. 5-bromothieno[2,3-d]pyrimidin-4-amine (103 mg, 0.447 mmol) and sat. aq. NaHCO3 (2 mL) were added, and N2 gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (17.39 mg, 0.021 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 C. The mixture was poured onto water and a precipitate was formed. The mixture was filtered, and the solid was taken up into a mixture of 20% CH3OH/CH2Cl2 mixture, and the resulting mixture was filtered, injected into a 90 g silica gel column, and purified via flash chromatography (gradient: 100% Hexanes to 100% EtOAc). The fractions containing the product were combined and concentrated to afford a solid. Trituration with Et2O afforded 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[2,3-d]pyrimidin-4-amine (120 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (t, 2H), 3.96 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 7.13-7.32 (m, 4H), 7.37 (s, 1H), 7.43 (s, 1H), 8.11 (d, J=8.08 Hz, 1H), 8.34 (s, 1H).