Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[N:10](C(OCC)=O)[C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].O>CN(C=O)C>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:22])[CH2:20][N:31]([CH3:32])[CH3:30])=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)CCl)c2ccc(Cl)cc21
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 2-benzoyl-6-chloro-3-(chloroacetylamino)-1-(ethoxycarbonyl)indole (step 1, 890 mg, 2.12 mmol) and dimethylamine hydrochloride (520 mg, 6.36 mmol) in DMF (30 ml) was stirred for 2 h. Water (80 ml) was added and the mixture extracted with an ethyl acetate-toluene mixture (2:1 v/v, 30 ml×2). The combined organic extracts were washed consecutively with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated. The residue was treated with a solution of 1N aqueous KOH (20 ml) and EtOH (40 ml) for 1 h, volatiles removed by evaporation and the residue extracted with ethyl acetate (30 ml×2). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was recrystallized from ethyl acetate/hexane to give 350 mg (47%) of the title compound as a yellow solid. m.p.: 175-176° C. 1H-NMR (CDCl3) δ: 10.60 (1H, br s), 8.83 (1H, br s), 8.08 (1H, d, J=8.8 Hz), 7.88-7.70 (2H, m), 7.68-7.42 (3H, m), 7.29 (1H, d, J=1.8 Hz), 7.07 (1H, dd, J=1.8, 8.8 Hz), 3.04 (2H, s), 2.33 (6H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[C:8](=[CH:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[S:9][C:4]=2[CH:3]=1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[O:20]=[C:7]1[NH:6][C:5]2[CH:21]=[CH:22][C:2]([NH:1][C:28]([NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[CH:3][C:4]=2[S:9][C:8]1=[CH:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: Nc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)Nc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 7-amino-2-[(indol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (see Example 38) (0.17 g, 0.55 mmol) and tert-butyl isocyanate (0.17 g, 1.75 mmol) in dry DMF (1 ml) was stirred at room temperature for 4 days. The reaction was poured into water (25 ml) and the precipitated solid was collected by filtration. The precipitate was purified by silica gel chromatography using a gradient of (9:1) to (4:6) toluene:ethyl acetate as the mobile phase.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:15]=O)[C:12]2[CH2:17][CH2:18][CH2:19][CH2:20][C:11]=2[S:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(O)C.N>O>[C:1]1([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH:15]=[N:30][NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH2:17][CH2:18][CH2:19][CH2:20][C:11]=2[S:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1c(-c2ccccc2)nc2sc3c(n12)CCCC3)c1ccccc1
Yield: 84 %

Procedure:
0.28 g of 5,6,7,8-tetrahydro-2-phenyl-3-formylimidazo[2,1-b]benzothiazole and 0.15 g of benzohydrazide were stirred over night in 20 ml of a 0.1N hydrochloric acid-ethanol solution at room temperature and the precipitated crystal obtained by filtration. The crystals were dissolved in water and the solution was made alkaline by ammonia solution, then extracted by chloroform. The extract was washed with water and dried, then the solvent was distilled off and the residue was crystallized from ethyl acetate to obtain the desired substance in an amount of 0.35 g (yield of 84.0%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)C.O1CCCC1>[CH2:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:23](=[O:25])[CH3:24])[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18]2)[CH2:2][CH2:3]1)[CH2:27][CH3:28]
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)c1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCN1CCN(c2cc(C(C)=O)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (19 mg, 0.0555 mmol) produced in Example (82b), propionaldehyde (0.0119 mL, 0.166 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (35 mg, 0.166 mmol), followed by stirring for 1 hour at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[3-(4-propylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:21][CH:22]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=1)=[O:26])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:23][CH:22]([NH:24][C:25]([C:27]1[S:28][C:29]([C:32]([NH:34][N:35]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:33])=[CH:30][CH:31]=1)=[O:26])[CH3:21]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NC(C)C)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 40.5 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol, synthesized in accordance with WO2004/108683), 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-propylamide (40 mg, 0.18 mmol) prepared in Reference Synthetic Example 3 and p-toluenesulfonic acid (6 mg) were heated with 2-propanol (1.8 mL) for 14 hours with reflux. After cooling, the solvent was evaporated, and the resulting solid was washed with 2-propanol to give 36 mg of the desired product (yield 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:40][CH:41]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[C:5]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[N:40][CH:41]=4)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.723 g, 1.51 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (Example 190, Step 2, 0.317 g, 1.52 mmol) in THF (5 mL) was treated dropwise with LiHMDS (4.52 mL, 4.52 mmol) at 0° C. The dark red mixture was stirred at 0° C. for 30 min. Water (0.2 mL) was added to quench the reaction. The reaction mixture was partitioned between saturated aqueous ammonium chloride (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g, eluent: EtOAc in hexanes 0%-35%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.697 g, 69% yield) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 11.77 (s, 1H); 8.74 (d, J=2.34 Hz, 1H); 8.39 (br. s., 1H); 8.22 (s, 1H); 7.79-7.94 (m, 2H); 7.28 (br. s., 1H); 7.19 (t, J=9.28 Hz, 4H); 6.86 (dd, J=8.18, 3.95 Hz, 4H); 4.83 (d, J=11.55 Hz, 4H); 3.80 (d, J=4.97 Hz, 6H); 2.58 (s, 3H); 1.53 (s, 9H). m/z (ESI, +ve ion) 669.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:31]1[CH2:3][CH:2]1[CH2:1][N:4]([CH:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CC(c1ccccc1)N(CC1CO1)S(=O)(=O)c1ccc(O)cc1
Yield: 85.3 %

Procedure:
5 ml of chloroform solution containing 1 g (3.2 mmol) of N-allyl-N-α-methylbenzyl-4-hydroxybenzenesulfonamide was added to 30 ml of a chloroform solution of 828 mg (4.8 mmol) of metachloroperbenzoic acid, followed by refluxing for 2 hours. After completion of the reaction, the chloroform solution was washed with an aqueous sodium thiosulfate solution and then an aqueous sodium bicarbonate solution. After drying, the solvent was distilled off and the resulting crude product was purified by the silica gel column chromatography (hexane-ethyl acetate) to obtain 910 mg of N-(2,3-epoxypropyl)-N-α-methylbenzyl-4-hydroxybenzenesulfonamide (Compound No. 37). The melting point was found to be 82.0° to 86.0° C. The results of the elemental analysis are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:29]3[O:31][CH2:30]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)cc2)c2cccc3c2CCCC3)cc1
Reactant: ClCC1CO1
Product: COc1ccc(C(c2ccc(OCC3CO3)cc2)c2cccc3c2CCCC3)cc1
Temperature: 110 °C

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (450 mg, 0.0013 mol) anhydrous K2CO3 (2.8 gm, 1.44 mmol), epichlorohydrin (20 ml) was refluxed at 100-120° C. for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil. The oil was chromatographed over silica gel using 20% hexane:chloroform as the eluent to give the desired compound as an oil. Yield 410 mg (78.39%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:4][CH2:3]1.Cl.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([NH:32][CH2:31][CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([F:22])([F:33])[F:34])=[O:13])[CH2:6][CH2:7]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Reactant: NCCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1C(F)(F)F)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg), [2-(trifluoromethyl)phenyl]ethylamine hydrochloride (111 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (86.4 mg) and 1-hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide (3 mL) was stirred for 18 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with IN-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a preparative silica gel thin layer chromatography with a mixture of hexane and ethyl acetate (2:1). The obtained product was recrystallized from a mixture of petroleum ether and diethyl ether to give 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-{[2-(trifluoromethyl)phenyl]ethyl}benzamide (157 mg) as yellow powders.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15].Cl.N1C=CC=CC=1>O>[CH2:10]([C:8]1[S:7][C:6]2[C:14]([Cl:15])=[C:2]([Cl:1])[C:3]([OH:16])=[CH:4][C:5]=2[CH:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of 5.0 g of 6,7-dichloro-2-n-butyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride, under nitrogen, is heated with stirring in a 195° oil-bath for 5 hrs. After the reaction mixture has cooled, 1000 ml of water is added and the aqueous mixture is extracted with three 250-ml portions of ether. The organic layers are combined, washed with one 200-ml portion of 2 N hydrochloric acid, two 250-ml portions of water, dried over anhydrous magnesium sulfate and filtered. The solvent is removed to give an oil. Crystallization with pentane and cooling gives 3.3 g of 2-n-butyl-6,7-dichloro-5-hydroxybenzo[b]thiophene, mp 35°.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:18][C:17]([F:20])([F:19])[O:16][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1NCCn2c1cc1cc(OC(F)(F)F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(OC(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c12

Procedure:
The title compound, white solid (87 mg, 84%), MS (ISP) m/z=415.4 [(M+H)+], mp 243° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-(trifluoromethoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 19) (87.3 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([F:44])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]4[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:26]=4[F:25])=[CH:30][C:31]=3[F:44])[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2F)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
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: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Yield: 51.1 %

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 6.16 mmol, 1.0 eq), 2-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 6.16 mmol, 1.0 eq), Pd(PPh3)4 (0.28 g, 0.08 mmol, 0.07 eq) and Na2CO3 (1.7 g, 15.4 mmol, 2.5 eq) in dioxane/H2O (40/10 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated and purified by Pre-TLC to afford (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7 g, 51.1% yield).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.CO>O>[N:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: ClCc1ccncc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CCc1ccncc1
Yield: 37.1 %

Procedure:
A solution of potassium cyanide (25 g) in water (133 ml) and of 4-picolyl chloride hydrochloride (30 g) in reagent grade methanol (268 ml) was heated under reflux for 2 hours, concentrated under vacuum, diluted with water (500 ml) and extracted with CHCl3 (4×100 ml). Distillation of the extract afforded a single fraction of 4-pyridylacetonitrile (8.026 g), b.p. 84° C. at 0.15 mm Hg. This was dissolved in dry dimethylformamide (130 ml) and stirred with sodium hydride (3.4 g, 50% w/v dispersion in oil) for 2.5 hours. Ethyl iodide (5.7 ml, 1.93 g/ml) was added slowly with cooling and stirring. After 18 hours, excess solvent was evaporated off, the residue diluted with water (150 ml) and extracted with diethyl ether (3×300 ml). Flash chromatography (Merck Art 9385, CHCl3, 4.5×15 cm column) of the extract afforded a mixture of 2-(4-pyridyl)butyronitrile and 2-ethyl-2-(4-pyridyl)-butyronitrile (9.85 g). Acrylonitrile (4.46 ml) in t-butanol (5.5 ml) was added to a solution of the above mixture in t-butanol (18 ml) and "Triton B" (0.32 ml) with cooling and stirring. ("Triton" is a Registered Trade Mark in the UK and many other countries). After 2 hours, excess solvent was evaporated off, the residue diluted with water (150 ml) and extracted with CHCl3 (2×50 ml). Flash chromatography of the extract (CHCl3, 4.5×15 cm column) afforded a mixture of 2-ethyl-2-(4-pyridyl) butyronitrile and 4-cyano-4-(4-pyridyl)hexanonitrile (8 g). This mixture was heated under reflux with glacial acetic acid (15 ml) and conc. sulfuric acid (3 ml) during 0.5 hours, then with addition of 5N hydrochloric acid (15 ml) for a further 3 hours, cooled, diluted with water, adjusted to pH 7-7.5 with sodium hydrogen carbonate and extracted with methylene chloride. Elution from a column (4.5×30 cm) of silica gel (Merck, Kieselgel 6) with CHCl3 afforded the title compound, 2.95 g; (20% yield based on 4-pyridylacetonitrile) which crystallized from toluene, m.p. 138°-139° C. (corrected); mass spectrum, isobutane chemical ionization [MH+ ] at m/z=219: IR (KC1) cm-1 2990 (CH aromatic phenyl), 2800 (NH), 1720, 1784 (C=0 imide), 1605 (C=C, aromatic phenyl); 1H-NMR (CDCl3), δ0.87 (t,3H,CH3CH2), 1.80-2.82 (m, 6H, CH3CH2, H(4), H(5)), 7.15 (d, 2H, aromatic H(3), H(5), J=4.7 Hz), 8.55 (d, 2H, aromatic H(2), H(6), J=4.7 Hz), 9.13 (br.s., 1H, NH). Anal. C12H14N2O2, 218.25) Calcd: C,66.03; H,6.47; N,12.84, Found: C,66.00, H,6.58; N,12.87%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:10]([N:17]1[CH:21]=[CH:20]N=C1)(N1C=CN=C1)=[O:11]>>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:17][CH2:21][CH2:20][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCC1=CCCCC1
Product: O=C(NCCC1=CCCCC1)NCCC1=CCCCC1
Yield: 54 %

Procedure:
In the manner of step (a) of Example 6, 2-(1-cyclohexenyl)ethylamine (Aldrich, 94.6 g, 0.733 mole as 97%) was reacted with 1,1'-carbonyldiimidazole to give 1,3-bis[2-(1-cyclohexen-1-yl)ethyl]urea as a white powder (56.26 g, 54%), m.p. 129°-131° C.;
Reaction SMILES: CN(C)C=O.[CH3:6][CH:7]([OH:9])[CH3:8].[H-].[Na+].[Br:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21]Cl)=[CH:15][C:14]=1[O:23][CH3:24]>O>[Br:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][O:9][CH:7]([CH3:8])[CH3:6])=[CH:15][C:14]=1[O:23][CH3:24]
Reactant: CC(C)O
Reactant: COc1cc(CCl)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COC(C)C)cc(OC)c1Br
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To an N,N-dimethylformamide (15 ml) solution of 2-propanol (7.81 ml, 102 mmol) was added sodium hydride (4.08 g, 102 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the mixture was added an N,N-dimethylformamide (15 ml) solution of 2-bromo-5-(chloromethyl)-1,3-dimethoxybenzene (2.70 g, 10.2 mmol) and the mixture was stirred for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 3/1) to obtain the title compound (1.85 g, 6.40 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([PH:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:2]1([P:14](=[O:21])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=[PH](c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A 20 mL of reactor equipped with magnetic stir bar was charged with 93 mg (0.10 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 0.314 g (2.0 mmol) of bromobenzene, 0.404 g (2.0 mmol) of di-phenylphosphine oxide and 0.276 g (2.0 mmol) of K2CO3 in 5.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 8 h to afford tri-phenylphosphine oxide. 31P NMR (CDCl3, 121 MHz): δ30.3 ppm.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[ClH:1].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FCCN1CCNCC1
Reaction time: 8 h

Procedure:
Add 4N HCl in 1,4-dioxane (86.096 mmoles, 21.524 mL) to a stirred solution of 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (8.610 mmoles, 2.000 g) in dry dichloromethane (60 mL) at room temperature under nitrogen. Stir overnight under nitrogen. Concentrate under reduced pressure to afford the title compound (8.679 mmoles, 1.780 g). MS (m/z): 133 (M+1).