Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH2:30]1[CH2:35][CH2:34][N:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1>>[ClH:20].[ClH:20].[N:33]1([CH:36]2[CH2:41][CH2:40][N:39]([CH2:19][CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[O:10][C:9]([C:21]3[N:26]=[CH:25][N:24]5[CH:27]=[CH:28][CH:29]=[C:23]5[CH:22]=3)=[CH:8][C:7]4=[N:6][OH:5])[CH2:38][CH2:37]2)[CH2:34][CH2:35][CH2:30][CH2:31][CH2:32]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCC(N4CCCCC4)CC3)cc12

Procedure:
6-(2-[1,4′]bipiperidinyl-1′-yl-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, dihydrochloride was prepared in 34% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and N-(4-piperidino)piperidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:21]2[CH:26]=[N:25][CH:24]=[C:23](Cl)[N:22]=2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[CH2:30].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[C:21]2[N:22]=[C:23](/[CH:30]=[CH:29]/[C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH:24]=[N:25][CH:26]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N(c1cncc(Cl)n1)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C=C/c1cncc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccccc3)C2)n1
Temperature: 150 °C
Reaction time: 72 h

Procedure:
To a stirred solution of tert-butyl [(3R)-1-benzyl-3-pyrrolidinyl](6-chloro-2-pyrazinyl)carbamate (910 mg) in DMF (15 mL) was added ethyl acrylate (1.27 mL), palladium(II) acetate (26 mg), tris(2-methylphenyl)phosphine (107 mg), and N,N-diisopropylethylamine (1.22 mL). The mixture was stirred in the sealed tube at 150° C. for 3 days. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (96:4 v/v) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl](tert-butoxycarbonyl)amino}-2-pyrazinyl)acrylate (755 mg) as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:12][CH2:11][CH2:10][Br:9]
Reactant: BrCCCBr
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccccc1OCCCBr
Reaction time: 24 h
Yield: 44.1 %

Procedure:
To a solution of 2-methylphenol (0.0954 g, 0.924 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (1.00 mL, 9.85 mmol) followed by Cs2CO3 (0.469 g, 1.44 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0934 g, 44.1%). EI-MS Rt (2.45 min).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][CH:7]([CH3:14])[CH2:6]1)=[O:3].C[O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[C:26]([CH3:32])[CH:25]=1>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C@H:21]2[CH2:22][C:17](=[O:16])[CH:18]=[CH:19][N:20]2[C:2]([O:4][C@@H:5]2[CH2:6][C@H:7]([CH3:14])[CH2:8][CH2:9][C@H:10]2[CH:11]([CH3:13])[CH3:12])=[O:3])=[C:26]([CH3:32])[CH:25]=1
Reactant: Cc1cc(F)ccc1[Mg]Br
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: COc1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (−)-menthyl chloroformate (3.53 mL) in dry THF (15 mL) was added to a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL) previously cooled to −78° C. under a nitrogen atmosphere. After 15 minutes, the solution containing the 4-fluoro-2-methyl-phenyl magnesium bromide was added drop-wise, and the mixture was stirred at −78° C. for 1 hour. The reaction was quenched by the addition of 1M hydrochloric acid solution (20 mL), warmed to r.t. and stirred at 23° C. for 30 minutes. After extraction with AcOEt (2×150 mL), the combined organic extracts were washed with brine (50 mL), dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/THF/toluene 8:1:1) to give:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:21].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:18][C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])[CH3:19]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)s2)CC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)s2)CC1
Temperature: 65 °C
Yield: 70.8 %

Procedure:
A solution of tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate (2.5 1 g, 8.50 mmol) in ethanol (85 ml) was added in one portion to a solution of silver (I) nitrate (10.0 g, 58.8 mmol) and sodium hydroxide (4.83 g, 120.6 mmol) in water (85 ml). This mixture was stirred and heated at 65° C. for 22 h. The mixture was cooled by the addition of ice and then filtered to remove silver salts. The filtrate was carefully evaporated to remove the ethanol and the resulting aqueous solution was filtered again through a glass-fibre pad to remove tarry material. The filtrate was then diluted with water to a total volume of 400 ml and then acidified to pH 5 with acetic acid. The precipitate was filtered off, washed with water and then dried in a vacuum oven at 45° C. overnight to give 5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylic acid (1.88 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([N:32]([CH3:34])[CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O:38]CC)=[O:37].[OH-].[Na+].C(O)C>O1CCCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([N:32]([CH3:34])[CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4N(C)C)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1nc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-(dimethylamino)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (77 mg, 0.14 mmol) was diluted with terahydrofuran (1 mL) followed by the addition of aq. NaOH (341 μL, 0.68 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The pH of the aqueous layer was adjusted to 6 with 1N aqueous NaOH and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(2-(6-cyclopropyl-2-(dimethylamino)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (70 mg, 0.13 mmol, 96% yield).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12](I)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH2:17].C(N(CCCC)CCCC)CCC>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:1][C:2]1[CH:14]=[CH:13][C:12]([CH:17]=[CH:16][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:11][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1
Reactant: CC(C)COC(=O)c1cc(I)ccc1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1

Procedure:
Isobutyl 2-hydroxy-5-iodobenzoate (70.2 g, 0.22 mol) and 4-ethenyl-N-(3-methyl-2pyridinyl)benzensulfonamide (54.8 g, 0.20 mol) were suspended in a solution of tributylamine (55.5 g, 0.3 mol) and palladium(II) acetate (0.44 g 0.0022 mol) in dimethylacetamide (200 ml)
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)CCN(C)C.CN1CCCC1=O.[Br:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[C:42]([F:48])[CH:41]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:16]([CH:15]([CH:44]([C:43]1[CH:46]=[CH:47][C:40]([Br:39])=[CH:41][C:42]=1[F:48])[OH:45])[C:14]([N:3]1[CH:2]([CH3:1])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC1C(c2ccccc2)OC(=O)N1C(=O)C(Cc1ccccc1)C(O)c1ccc(Br)cc1F
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4R, 5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1.50 g, 4.8 mmol) in dichloromethane (23 mL) at −70° C. was added titanium tetrachloride (0.6 mL, 5.3 mmol) giving a yellow-orange solution which was stirred for 15 minutes at −70° C. N,N,N′,N′-Tetramethylethylenediamine(2.2 mL, 15 mmol) was added over 10 minutes giving a dark red reaction mixture which was stirred for 70 minutes at −78° C. 1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes at −70° C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol) in dichloromethane (5 mL) was added dropwise while maintaining a reaction temperature of less than or equal to −68° C. The reaction mixture was stirred at −70° C. for 60 minutes and then allowed to warm to 0 C. over 90 minutes, at which point it was quenched with 15 mL of saturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixture was stirred overnight at room temperature and filtered. The phases were separated and the organic phase was washed three times with water and once with brine, dried over magnesium sulfate, and concentrated under vacuum to 2.76 g of an oil containing the title compound and 1.2 equivalents of 1 -methyl-2-pyrrolidinone: 1H NMR (400 MHz, CDCl3) 67 7.48 (t, J=8.1 Hz, 1 H), 7.09-7.34 (m, 1 2H), 5.35 (d, J=7.3 Hz, 1 H), 5.32 (d, J=4.9 Hz, 1 H), 4.89-4.92 (m, 1 H), 4.51-4.55 (m, 1 H), 3.65 (bs, 1 H), 3.35 (dd, J=7.1, 7.1 Hz, 2H), 3.03-3.06 (m, 2 H), 2.81 (s, 3H), 2.34 (dd, J=8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3 H).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.[CH2:27]([N:29]([CH2:32]C)[CH2:30]C)C.ClC(Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.Cl>ClCCl>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27]([N:29]([CH3:32])[CH3:30])=[O:37])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reaction time: 20 h

Procedure:
0.56 g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine trihydrochloride was suspended in dry dichloromethane (50 ml), triethylamine 0.77 ml, 6 mmol) was added and 0.13 g (0.44 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature dimetilamine hydrochloride (0.49 g, 6 mmol) followed by triethylamine (0.84 ml, 6 mmol) was added and the stirring was continued for 20 hours. The mixture was filtered, the filtrate washed with water, dried and evaporated in vacuo. Recrystallizing the product from methanol gave the title compound (0.27 g, 52%). Melting point: 212-4° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl.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>[CH3:14][O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 90 °C

Procedure:
2-Bromo-5-trifluoromethyl-benzaldehyde (4.152 g, 16.41 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (4.988 g, 16.41 mmol), and potassium carbonate (5.67 g, 41.03 mmol) were combined in DME (40 mL) and H2O (20 mL) under N2. The mixture was purged with N2, and then tetrakis(triphenylphosphine)palladium(0) (1.9 g, 1.64 mmol) was added, and the reaction was heated to 90° C. for 10 hours. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and diluted with CH2Cl2 and H2O. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16](Br)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:35]3[CH:36]=[CH:37][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ccccc2)CC1
Yield: 50.1 %

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate D) (4.3 g, 11.10 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.61 g, 12.21 mmol), palladium tetrakistriphenyphosphine(0.77 g, 0.67 mmol) and sodium carbonate(2.82 g, 26.65 mmol) were mixed with ethylene glycol dimethyl ether(100 ml) and water(50 ml). The reaction mixture was heated to reflux overnight. Organic solvent was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography using ethyl acetate/methanol (98/2) as mobile phase to give 2.65 g of 1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.99 (d, J=1.02 Hz, 2H), 2.25(m, 2H), 2.47 (m, 2H), 3.07 (d, J=1.12 Hz), 3.59 (s, 2H), 4.80 (m, 1H), 5.52 (s, 2H), 7.07 (d, J=0.67, 1H), 7.15 (m, 3H), 7.37 (m, 6H), 7.66 (d, J=8.51, 2H), 8.37 (s,1H); LC/MS (MH+=477).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[OH2:26].NN.Cl>C(Cl)(Cl)Cl.CO.O1CCCC1>[CH2:16]([C:14]1[CH:13]=[CH:12][C:3]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:1][CH:2]([CH3:15])[C:3](=[O:26])[NH:1][C:2]=2[CH:15]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O
Reactant: CCCCCCCCCCc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCc1ccc2c(c1)NC(=O)C(C)N=C2c1ccccc1
Temperature: 25 °C
Yield: 132.9 %

Procedure:
2-Amino-4-decylbenzophenone (4.16 g) was dissolved in chloroform (40 ml) and phthaloylalanyl chloride (3.22 g) was added thereto with stirring at room temperature. The mixture was stirred for 0.5 hour. The reaction mixture was washed with 5% aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography and the oily substance obtained was dissolved in a mixed solvent of methanol (20 ml) and tetrahydrofuran (40 ml). Thereto was added hydrazine monohydrate (1.56 g) with stirring under ice-cooling and the mixture was stirred for 2 hours. Conc. hydrochloric acid (1 ml) was added thereto with stirring at room temperature and the mixture was stirred at 60° C. for 2 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was extracted with chloroform and washed with 5% aqueous sodium hydrogencarbonate and water. The residue was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Isopropyl alcohol (60 ml) and acetic acid (1 ml) were added to the concentrate and the mixture was stirred at 70° C. for 1 hour. After cooling, the residue obtained by concentration under reduced pressure was extracted with chloroform and washed with 5% aqueous sodium hydrogencarbonate and water. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give 3.2 g of 8-decyl-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one as crystals.
Reaction SMILES: [OH-:1].[Na+].OO.CS(C)=O.[CH3:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:20]([F:38])=[CH:19][C:18]=2[C:39]#[N:40])[CH:13]=[N:14][CH:15]=1>O.C(O)C>[NH2:40][C:39]([C:18]1[CH:19]=[C:20]([F:38])[C:21]([NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[N:22][C:17]=1[NH:16][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([CH3:9])[CH:11]=1)=[O:1]
Reactant: [OH-]
Reactant: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(F)cc2C#N)c1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(F)cc2C(N)=O)c1
Temperature: 34 °C
Reaction time: 0.5 h

Procedure:
A 5N sodium hydroxide aqueous solution (1.18 ml) and 30% hydrogen peroxide solution (0.70 ml) were added to a solution of dimethyl sulfoxide (10 ml) and ethanol (10 ml) containing tert-butyl cis-2-(6-(5-methylpyridin-3-ylamino)-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (520 mg), followed by stirring at 34° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water was added. Solid matter was collected by filtration, dissolved in ethyl acetate and tetrahydrofuran, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was added to diisopropylether, solid matter was collected by filtration and washed with diisopropylether and hexane, and a light yellow solid of tert-butyl cis-2-(5-aminocarbonyl-3-fluoro-6-(5-methylpyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate (506 mg) was thus obtained.
Reaction SMILES: ClC1N=CC=C[C:3]=1[C:4]([O:6][CH3:7])=O.[C:12](=[O:15])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]1[O:6][CH2:4][CH2:3][O:15][CH2:12][CH2:7][O:6][CH2:4][CH2:3][O:15][CH2:12][CH2:7][O:6][CH2:4][CH2:3][O:15][CH2:12]1
Reactant: COC(=O)c1cccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1COCCOCCOCCOCCOCCO1

Procedure:
3.4 g of methyl 2-chloronicotinate were reacted with 3.4 g of 4-piperidinopideridine in 75 ml of DMF in the presence of 5.5 g of potassium carbonate and a spatula tipful of 18-crown-6 analogously to Example 1a, 5.9 g (97%) of the product being obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Li]CCCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>>[B:14]([OH:19])([OH:15])[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccc(F)nc1
Yield: 74 %

Procedure:
5-Bromo-2-fluoropyridine was treated with n-BuLi (1.6 M in hexanes, 19.5 mL, 31.3 mmol), triisopropyl borate (7.9 mL, 34.1 mmol) and HCl(aq) (2.7 N, 28.4 mL) as for 1 to give the title compound 2 (3.0 g, 74% yield) as a brown semi-solid: 1H NMR (CD3OD) δ 8.45 (br s, 1H), 8.21 (br s, 1H), 7.01 (m, 1H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: [CH3:1][CH:2](O)[CH3:3].[Bi](Br)(Br)Br.[OH:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11]>ClC(Cl)(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([CH:10]([O:9][CH:2]([CH3:3])[CH3:1])[CH3:11])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: CC(C)O
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To the solution of propan-2-ol (100 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth(III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, then methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added to the solution, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl4-(1-isopropoxyethyl)benzoate (161 mg, 43%) as oil. 1H-NMR (300 MHz, CD3OD) δ 7.96 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 4.68-4.61 (m, 1H), 3.54-3.46 (m, 1H), 1.38 (d, 3H), 1.15 (d, 3H), 1.06 (d, 3H),