Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2].CS(C)=O.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:28][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cccc(Br)c3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cccc(Br)c3nc21
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-8-bromo-1H-pyrazolo[3,4-b]quinoline (2.0 g, 6.44 mmol), DMSO (5 mL) and cyclohexylmethylamine (1.46 g, 12.9 mmol) was heated at 80°-90° C. for 3 hours. The reaction mixture was cooled to room temperature and then was poured into water. The resulting solid was collected by filtration, washed with water and evaporated. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 2.0 g (80%) of 1-ethyl-8-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 160°-162° C.
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1)=[O:16])=[O:6]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.50 g, 1.71 mmol) was reacted at ca. 0° C. with benzyl bromide (BnBr) (0.243 mL, 0.35 g, 2.05 mmol) and diisopropylethylamine (DIEA) (1.00 mL, 0.74 g, 5.76 mmol) in dichloromethane (DCM) followed by warming to room temperature. After aqueous work-up, the crude product was purified by mass-guided preparative HPLC to afford 0.18 g (27% yield) of the title compound (15) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.08-7.01 (m, 5H), 6.72-6.71 (m, 2H), 4.60 (s, 2H), 3.58-3.57 (s, 3H), 3.23-3.19 (br S, 2H), 3.30 (s, 2H), 3.1.19-3.11 (br S, 2H), 2.23 (br S, 4H); MS (ESI) m/z 347.13 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:6][C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:5])[CH3:4].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1>>[F:1][CH2:2][C:3]([NH:6][C:7]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[C:10]([C:27]3[NH:26][C:25]4[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=4[CH:28]=3)[CH:11]=[CH:12][CH:13]=2)[N:8]=1)([CH3:5])[CH3:4]
Reactant: Cn1c(NC(C)(C)CF)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC(C)(C)CF)nc34)[nH]c21
Yield: 34 %

Procedure:
This compound (77 mg, 34% yield) as a brown solid was prepared according to the procedure described for Example 448, using 24(1-fluoro-2-methylpropan-2-yl)amino)-8-iodo-3-methylquinazolin-4(3H)-one (712) (221 mg, 0.59 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (193 mg, 0.74 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (1H, br.), 7.94 (1H, d, J=7.4 Hz), 7.80 (1H, d, J=6.8 Hz), 7.60 (1H, br.), 7.22 (1H, t, J=7.1 Hz), 6.52 (1H, s), 6.02 (1H, s), 4.74 (1H, s), 4.62 (1H, s), 4.51 (1H, m), 3.51 (3H, s), 1.45 (6H, s), 1.38 (3H, d, J=5.9 Hz). m/z (ESI, +ve) 383.9 (M+H)+.
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].Br[CH2:34][CH:35]1[CH2:37][C:36]1([F:39])[F:38]>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:34][CH:35]3[CH2:37][C:36]3([F:39])[F:38])[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: FC1(F)CC1CBr
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Yield: 49 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with bromomethyl-2,2-difluorocyclopropane, the title compound was obtained as a yellow solid in 49% yield: mp 146-148° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.00 (t, J=9.0 Hz, 2H), 3.65-3.48 (m, 2H), 3.20-3.13 (m, 2H), 2.51 (s, 3H), 2.41 (s, 3H), 2.05-2.18 (m, 1H), 1.68-1.56 (m, 1H), 1.38-1.27 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 190.8, 160.1, 155.1, 154.9, 125.8, 114.8 (t), 42.4, 42.1, 41.1 (d), 30.4, 20.2 (t), 18.6, 14.9 (t); MS (ES+) m/z 316.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH3:10].N1C[CH2:47][O:46][CH2:45]C1.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:41]([S:38]([N:35]1[CH2:36][CH2:37][CH:32]([C:23]2[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=[C:20]([C:14]4[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH2:11][N:9]5[CH2:10][CH2:47][O:46][CH2:45][CH2:8]5)[CH:13]=4)[CH:21]=3)[NH:25][CH:24]=2)[CH2:33][CH2:34]1)(=[O:40])=[O:39])[CH3:42]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN(C)C)c4)cc23)CC1
Reactant: C1COCCN1
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(OC)c(CN5CCOCC5)c4)cc23)CC1
Yield: 17 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (20 μL, 0.214 mmol) for the dimethylamine to afford 12 mg of the title compound (17%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=[CH:4][C:5]=4[CH3:24])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (72.6 mg, 0.224 mmol) in tetrahydrofuran (4.0 mL) were added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (46.3 mg, 0.29 mmol) in tetrahydrofuran (0.5 mL) and triethylamine (68 mg, 0.672 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, washed with ethyl acetate/hexane to give the title compound (64 mg, 64%) as a brown powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+].[OH-].[Na+]>CN(C)C=O.O>[F:18][CH:14]([F:19])[O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)F)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (500 mg) in N,N-dimethylformamide (4.3 mL) were added sodium chlorodifluoroacetate (456 mg), sodium hydroxide (120 mg) and water (0.060 mL) at room temperature, and the mixture was stirred at 125° C. for one hour. The reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (240 mg).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:23]=[CH:24][C:18]=3[N:17]=2)=[C:11]([Cl:37])[CH:10]=1)(C)(C)C.Cl>C1(OC)C=CC=CC=1.O1CCOCC1>[Cl:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])[CH:10]=[C:11]([Cl:37])[C:12]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]3[O:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[N:28][N:29]=3)[CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: O=C(O)CCc1cc(Cl)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 100 ml rbf was added 0.090 g (0.157 mmol) of 3-(3,5-Dichloro-4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-phenyl)-propionic acid tert-butyl ester, a few drops of anisole, and 3 mL 4M HCl in 1,4-dioxane. The purple solution was allowed to stir at r.t. for 72 h. The reaction mixture was concentrated and the residue purified by basic HPLC (ACN/0.005 mM H2O—NH4OH, 2.5:7.5 to 8:2) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (t, J=7.45 Hz, 2H) 3.07 (t, J=7.33 Hz, 2H) 7.75 (s, 2H) 7.84-7.89 (m, 2H) 7.99 (d, J=7.45 Hz, 1H) 8.20 (dd, J=8.46, 1.39 Hz, 1H) 8.32-8.37 (m, 2H) 8.56 (br. s., 1H). MS (m/z) 515.0 M (+1), tR=1.19, Meth 10
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][CH:34]([CH2:36]Br)[CH2:33][C:32]=2[CH:38]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:19][C:2]([F:18])([F:1])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][N:12]([CH2:36][CH:34]3[CH2:33][C:32]4[CH:38]=[C:28]([O:27][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:29]=[CH:30][C:31]=4[O:35]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: OC1(Cc2ccc(OC(F)(F)F)cc2)CCNCC1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: OC1(Cc2ccc(OC(F)(F)F)cc2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=514.6 (M+H+) was prepared from 4-(4-trifluoromethoxy-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[OH:16].Cl.[CH:18](OCC)(OCC)OCC>CO>[CH3:8][C:7]1[C:2]2[N:1]=[CH:18][O:16][C:3]=2[CH:4]=[CH:5][C:6]=1[NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1c(NC(=O)C(F)(F)F)ccc(O)c1N
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CO
Product: Cc1c(NC(=O)C(F)(F)F)ccc2ocnc12
Temperature: 90 °C
Yield: 76.7 %

Procedure:
A solution of 2-amino-3-methyl-4-trifluoroacetamidophenol (4.25 g, 18.15 mmol) and concentrated hydrochloric acid (45 mL) in methanol (5.2 mL) is treated with triethyl orthoformate (2.98 mL, 27.2 mmol). A simple distillation apparatus is attached and the mixture is heated with an oil bath to 90° C. and methanol is distilled from the reaction. The reaction mixture is cooled to room temperature and distributed between ethyl ether (200 mL) and water (20 mL). The ether layer is washed with a 0.1 M aqueous solution of sodium hydroxide (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield 3.40 g of 4-methyl-5-trifluoroacetamidobenzoxazole as an orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.CC(C)CCN.[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([C:28]3[S:32][C:31]([C:33]([O-])=[O:34])=[CH:30][CH:29]=3)=[O:27])=[CH:20][C:19]=12.[Li+].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]([C:28]3[S:32][C:31]([C:33]([N:5]4[CH2:6][CH2:7][CH2:8][C@@H:4]4[CH2:3][O:2][CH3:1])=[O:34])=[CH:30][CH:29]=3)=[O:27])=[CH:20][C:19]=12
Reactant: O=C([O-])c1ccc(C(=O)NCc2ccn3ccnc3c2)s1
Reactant: COC[C@H]1CCCN1
Agent: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Product: COC[C@H]1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting), (R)-2-(methoxymethyl)pyrrolidine for 3-methylbutan-1-amine and lithium 5-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)thiophene-2-carboxylate for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6). δ ppm 9.23 (t, J=6.0 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.42-7.39 (m, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 4.35-4.23 (m, 1H), 3.78-3.65 (m, 2H), 3.26 (s, 3H), 2.02-1.81 (m, 4H); MS (ESI(+)) m/e 399 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=[C:61]3C=2N=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[CH:83]=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.CN(C)[C@@H]1CCNC1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:61][N:60]([CH3:59])[C@@H:74]1[CH2:78][CH2:77][N:79]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:3]=2)[CH2:83]1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethyl-amino)pyrrolidine. MS (ES+) m/e 622.40 (MH+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClC(Cl)C>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH:19]([C:20]([CH:19]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reaction time: 1 h
Yield: 90.9 %

Procedure:
55 g (0.5 mole) of resorcinol were suspended in 250 ml of dichloro ethane and at 20° C. 67 g (0.502 mole) of anhydrous aluminum chloride were added. To the obtained homogeneous dark solution, containing the hydrogen-aluminum-trichloro-3-hydroxy-phenolate, 77.2 g (0.5 mole) of phenyl-acetyl chloride in 100 ml of dichloro ethane were added over one hour while the temperature raised to 35°-40° C. The reaction mixture was stirred for one hour, the solution thus obtained was added to an aqueous hydrochloric acid solution, the two layers were separated, the organic layer was washed with water to neutral, the solvent was distilled off and the residue was optionally crystallized from toluene. 96.9 g of 2,4-dihydroxy-phenyl-benzyl-ketone were obtained, m.p.: 112°-114° C., yield: 85%. After an optional recrystallization from toluene the melting point was 113°-114° C. Elemental analysis for C14H12O3 (Mw: 228):
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Maleic acid (1.161 g, dissolved in 35 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The mixture is stirred for 3 hours at room temperature and concentrated at vacuum to give the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][CH2:10][CH2:11][NH2:12].Cl[C:14]1[C:23]([C:24]([C:26](=[CH:32]N(C)C)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][C:18]([Cl:37])=[C:19]([F:36])[CH:20]=2)[N:15]=1>ClC(Cl)Cl>[Cl:37][C:18]1[C:19]([F:36])=[CH:20][C:21]2[C:16]([CH:17]=1)=[N:15][C:14]1[N:12]([CH2:11][CH2:10][F:9])[CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:24](=[O:25])[C:23]=1[CH:22]=2
Reactant: NCCF
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2.7 cm3 of triethylamine are added to a suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 cm3 of trichloromethane. 3.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are added to the solution obtained at about 20° C. After stirring at this temperature for 16 hours, the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue is taken up in 20 cm3 of ethanol and 3 cm3 of triethylamine and heated at about 75° C., with stirring, for 2 hours. After cooling to about 20° C. the insoluble matter is drained and washed with twice 10 cm3 of ethanol and twice 10 cm3 of diisopropyl ether. 1.9 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 268° C., which is used for the subsequent step without further purification
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3,5-dibromopyridine (1.00 g) in toluene (10 mL) and ethanol (5 mL) was added phenylboronic acid (515 mg), sodium carbonate (1.34 g) and tetrakis (triphenylphosphine)palladium(0) (24 mg) and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted into ethylacetate (2×30 mL). The organic layers were washed with brine (40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-bromo-5-phenyl-pyridine as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[CH:17][N:16]=1.O>O1CCCC1>[O:7]([C:19]1[C:20]([F:21])=[C:15]([F:14])[N:16]=[CH:17][N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ncnc(F)c1F
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ncnc(Oc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
A solution of 42.4 g (0.45 mol) of phenol and 50.4 g (0.45 mol) of potassium tert-butoxide in 400 ml of tetrahydrofuran is added dropwise at 0° C. to a solution of 80 g (0.6 mol) of 4,5,6-trifluoropyrimidine in 1 of tetrahydrofuran. When the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. and then poured into water and extracted using ethyl acetate. The organic phase is dried over sodium sulphate and concentrated in vacuo, and the residue is stirred with low-boiling petroleum ether. 63.8 g (68.1% of theory) of 4-phenoxy-5,6-difluoropyrimidine of melting point 65-66° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1>C(O)C.CO>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:22])[CH2:16][C:15]=4[CH:35]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCCC3c3ccccc3)CCO4)cc2[nH]1
Solvent: CCO
Solvent: CO
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCC[C@H]3c3ccccc3)CCO4)cc2[nH]1

Procedure:
Prepared by chiral preparative HPLC separation of racemic 7-(2-methyl-1H-benzimidazol-6-yl)-4-[(2-phenylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 18.0 mL/min and detection at 220 nm. The isomer with retention time 11.20 min. was assigned as the (5)-enantiomer. Chiral analytical HPLC was carried out using a SHIMADZU LC-20AD apparatus equipped with a Chiralpak AD-H, 25 cm×4.6 mm column using a mobile phase of ethanol:methanol 1:1 and flow rate of 0.7 mL/min with detection at 254/220 nm. This isomer gave a retention time 13.30 min and ee>99%. MS (EI) C29H30N4O2: 467 (MH+).