Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9]([N:12]=[C:13](Cl)[CH3:14])(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:16].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C(Cl)Cl>[CH2:17]([N:19]([CH2:20][CH3:21])[C:13](=[N:12][S:9]([C:5]1[CH:6]=[C:7]([Br:8])[C:2]([NH2:1])=[C:3]([Br:16])[CH:4]=1)(=[O:11])=[O:10])[CH3:14])[CH3:18]
Reactant: CCNCC
Reactant: CC(Cl)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(C)=NS(=O)(=O)c1cc(Br)c(N)c(Br)c1

Procedure:
100 Mg. of crude N-(4-amino-3,5-dibromophenylsulfonyl) acetimidoyl chloride is stirred in 10 ml. of methylene chloride with 1 ml. of diethylamine at room temperature overnight. Volumes of water and methylene chloride equal to the volume of the reaction mixture are added, agitated and the layers separated. The organic layer is dried over magnesium sulfate and evaporated to dryness, in vacuo. The residue is taken up in 1 ml. of ethyl acetate and the dropwise addition of petroleum ether affords N,N-diethyl-N'-(4-amino-3,5-dibromophenylsulfonyl) acetamidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])C.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1B(O)O.[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:35]1[CH:36]=[CH:37][C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:33][CH:34]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Product: CC(C)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(Cl)cc4Cl)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 54 from 5-bromo-3-chloro-1H-indole-2-carboxylic acid ethyl ester, 2,4-dichlorophenyl boronic acid and 4-isopropoxyphenyl boronic acid, followed by ester hydrolysis.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]4[CH2:27][CH2:28][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:32]([CH3:34])[CH3:33])C.[CH2:38](Br)[CH:39]=[CH2:40]>C(Cl)Cl>[CH2:34]([N:1]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]4[CH2:27][CH2:28][C@H:13]4[C:12]=23)[O:5][N:4]=1)[CH2:40][CH:39]=[CH2:38])[CH:32]=[CH2:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCBr
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)n1
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)n1
Yield: 191.3 %

Procedure:
2 g (5.1mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 30 ml of methylene chloride, 6.2 ml (36 mmol) of N-ethyldiisopropylamine and 2.57 g (1.8 mmol) of allyl bromide were stirred at room temperature for 18 hours. The reaction solution was washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on 300 g of silica gel while eluting with ethyl acetate. There were obtained 1.62 g (67%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 147°-150°.
Reaction SMILES: S([CH:5](C)[C:6]([O:8][C:9](=[O:16])[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11])=[O:7])(O)(=O)=O.[C:18](OCC(O)C)(=[O:22])[C:19]([CH3:21])=[CH2:20].[CH3:28]OC.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[S:12]([CH:10]([CH3:11])[C:9]([O:8][C:6]([O:7][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])([CH3:5])[CH3:28])=[O:16])([OH:15])(=[O:13])=[O:14]
Reactant: COC
Reactant: C=C(C)C(=O)OCC(C)O
Reactant: CC(C(=O)OC(=O)C(C)S(=O)(=O)O)S(=O)(=O)O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC(C)(C)OC(=O)C(C)S(=O)(=O)O

Procedure:
To a reaction vessel fitted with an air-bleed tube, thermometer, stirrer, and condenser there are charged sulfopropionic anhydride (29.1 g.), 2-hydroxypropyl methacrylate (29.1 g.), the monomethyl ether of hydroquinone (0.1 g.) and toluene (60 g.). The mixture is stirred, sparged with dry air as in 1) above and heated. After 0.5 hour at 60° C. a solution containing 29% by weight of methacryloxyisopropyl sulfopropionate is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[NH:7]1[C:3]([CH2:2][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][N:5]=[N:6]1
Reactant: ClCc1nnn[nH]1
Reactant: C1COCCN1
Product: C1CN(Cc2nnn[nH]2)CCO1
Yield: 80.6 %

Procedure:
A solution of 5-(chloromethyl)-1H-tetrazole (260 mg, 2.2 mmol) in morpholine (1.5 mL, 17.2 mmol) was stirred at 25° C. for 20 minutes. The crude reaction mixture was purified by preparative LCMS using pH 2 buffer to yield the desired product (300 mg, 82%). MF=C6H11N5O; LCMS calculated for C6H12N5O (M+H)+: m/z=170.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2.C[Si](Cl)(C)C.[CH2:40](O)[CH2:41]CC>>[O:34]=[C:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([NH:23][C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:40][CH3:41])=[O:19])[CH2:13][CH2:12]4)[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:25]=2)[NH:30]1
Reactant: CCOC(=O)CC1CCN(c2nc(Cl)nc3[nH]ccc23)CC1
Reactant: CCCCO
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: C[Si](C)(C)Cl
Product: CCCCOC(=O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Temperature: 135 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 2-(1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetate (135 mg, 0.419 mmol), 6-amino-3,4-dihydroquinolin-2(1H)-one (97 mg, 0.600 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. More trimethylsilyl chloride (0.200 mL, 1.58 mmol) was added. It was stirred at 135° C. for another 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (54 mg). MS 477.3 (M+H); UV 200.0, 279.8 nm.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[OH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>ClCCl>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10])([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c(OC(C)(C)C)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
A stirred solution of isobutylene (33 mL) in dichloromethane (60 mL) at -70° C. is treated dropwise with a cooled solution of methyl 3-hydroxy-4-methoxybenzoate (6 g) in dichloromethane (60 mL), followed by trifluoromethanesulfonic acid (0.3 mL). The reaction mixture is vigorously stirred at -70° C. for 3 hours and then between -70° C. and -50° C. overnight. It is then treated with triethylamine (0.6 mL) and allowed to warm to room temperature. The resulting yellow solution is concentrated, and the residue is subjected by mplc, using diethyl ether as eluent, to give methyl 3-tert-butoxy-4-methoxybenzoate (4.93 g), m.p. 98-100° C. [Elemental analysis: C,65.7; H,7.8%; calculated: C,65.5; H,7.6%].
Reaction SMILES: [NH2:1][C@H:2]([C:4]1([OH:27])[CH2:7][N:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[C:11]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[O:9])[CH2:5]1)[CH3:3].[CH2:28]=O.[BH4-].[Na+]>CO.C=O>[F:17][C:12]1[C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:10]([C:8]([N:6]2[CH2:7][C:4]([C@@H:2]([NH:1][CH3:28])[CH3:3])([OH:27])[CH2:5]2)=[O:9])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: C=O
Reactant: C[C@H](N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN[C@@H](C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To 3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (87.4 mg, 0.18 mmol), prepared using similar procedures to those described in Example 28, was added formaldehyde (37% aqueous, 14 mg, 0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol). The mixture was stirred for 3 h at rt, after which sodium borohydride (16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, more formaldehyde (37% aqueous, 1 drop) was added, and the mixture was stirred 3 days at rt. A further small spatula (˜50 mg) of sodium borohydride was then added, and the mixture was stirred at rt for 30 min. After quenching with 1 N HCl, the reaction mixture was purified directly by preparative HPLC. The clean material was converted to its hydrochloride salt to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol as a yellow solid (21.7 mg, 0.040 mmol, 22% yield). 1H NMR (400 MHz, CD3OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62 (dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H), 1.29 (br m, 3H); MS (EI) for C19H19F3IN3O2: 506 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:16]=1[CH:17]=[O:18]>CC(C)=O>[CH:17]([C:16]1[CH:19]=[C:20]([CH3:24])[C:21]([CH3:23])=[CH:22][C:15]=1[O:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(O)c(C=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(C)cc1C=O

Procedure:
0.808 ml of ethyl bromoacetate and 1 g of potassium carbonate were added to a solution of 838 mg of 2-hydroxy-4,5-dimethylbenzaldehyde (J.Chem.Soc. (1953) 820) in 150 ml of acetone. The suspension obtained was heated to reflux overnight and then filtered. The filtrate was concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel and yielded 952 mg of ethyl (2-formyl-4,5-dimethyl-phenoxy)-acetate as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[Cl:18].[C:19]1(=O)[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]1>>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:3]3[C:4](=[O:8])[NH:5][N:6]([CH3:7])[C:2]=3[NH:1][C:19]3[CH2:23][CH2:22][C:21](=[O:24])[C:20]2=3)=[CH:12][C:11]=1[Cl:18]
Reactant: O=Cc1ccc(Br)c(Cl)c1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1CCC(=O)C1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(Br)c(Cl)c1
Yield: 67.6 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.84 g, 0.75 mmol), 4bromo-3-chlorobenzaldehyde (0.157 g, 0.75 mmol) from Example 40C, and 1,3-cyclopentanedione (0.074 g, 0.75 mmol) was processed as described in Example 1 to provide 0.20 g of the title compound. 1H NMR (DMSO-d6) δ 2.29 (t, 2H), 2.68 (m, 2H), 3.49 (s, 3H), 4.69 (s, 1H), 7.02 (dd, 1H), 7.33 (d, 1H), 7.6 (d, 1H), 9.55 (s, 1H), 10.41 (s, 1H); MS (ESI−) m/z 394 (M−H)−; Anal. Calcd for C16H13N3BrClO2: C, 48.66;H, 3.29; N, 10.64. Found: C, 48.92;H, 3.13; N, 10.72.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O[CH2:22][C:23](=[CH2:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=O)C.CN(C1C=CC=CN=1)C>ClCCl>[CH2:1]([O:17][CH2:29][C:23](=[CH2:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCO
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=C(COCCCCCCCCCCCCCCCC)C(=O)OCC
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a mixture of 1.1 g of 1-hexadecanol and 400 mg of 2-[(acetyloxy)methyl]-2-propenoic acid, ethyl ester in 15 ml of dichloromethane is added 550 mg of dimethylaminopyridine. This mixture is stirred overnight, then the solvent is evaporated and the residue subjected to preparative tlc (25% ethyl acetate/petroleum ether), to give 324 mg of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23]>CN(C=O)C>[N+:1]([C:4]1[N:5]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCn1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
A mixture of 5 g (44 mmol) of 2-nitroimidazole and 6.1 g of K2CO3 in 50 ml of DMF was heated at 60° C. for 0.5 hours; then 6.61 g (44 mmol) of 3-(2-chloroethyl)-2-oxazolidinone was added and stirring continued for 18 hours; at 60° C. The mixture was then cooled and concentrated. The residue was partitioned between CHCl3 and water, the organic layer was dried and concentrated to a solid. The solid was crystallized from ethanol to give 3.5 g (35%) of the desired product, 3-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-2-oxazolidinone; mp 103°-104° C.
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.[NH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:17]1(C)[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[N:3]1([CH2:2][N:12]([CH2:2][N:3]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:5]=[N:4]2)[CH2:13][C:14]([OH:16])=[O:15])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: NCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCn1nnc2ccccc21
Solvent: Cc1ccccc1
Product: O=C(O)CN(Cn1nnc2ccccc21)Cn1nnc2ccccc21
Reaction time: 4.5 h
Yield: 86 %

Procedure:
One hundred nineteen and three tenths parts of 1-(Hydroxymethyl) benzotriazole and glycine (30 parts) were added to 600 parts of dry toluene containing 1.7 parts of p-toluenesulfonic acid. The mixture was stirred and refluxed under a Dean-Stark trap. After about 4.5 hours, the theoretical amount of water (14.4 parts) had collected and heating was suspended. The reaction mixture was cooled in ice-water and the tan solid that had formed was filtered with suction. After washing the filter-cake consecutively with toluene and ether and drying it in vacuo, 116 parts of N,N-bis(benzotriazol-1-yl methyl) glycine were obtained and identified by 1H and 13C NMR spectral analysis. The product melted at 163°-6° C. and was obtained in 86% yield.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].N1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCCC1.O.Cl>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:22]
Reactant: O=C(O)c1ccccc1S
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)Sc1ccccc1C(=O)O
Yield: 80.2 %

Procedure:
Thiosalicylic acid (1.38 g, 9.0 mmol) was suspended in tetrahydrofuran (10 ml). While stirring under ice cooling, pyridine (1.77 g, 22 mmol) and then a tetrahydrofuran solution (5 ml) of 2-methoxybenzoyl chloride (1.68 g, 9.9 mmol) were dropwise added to the suspension. After the reaction mixture was stirred for 15 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (50 ml×2) with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was recrystallized from tetrahydrofuran-isopropyl ether to give the title compound (2.08 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:23]=1[NH2:24])[CH3:21]>>[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:23]=1[NH:24][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])[CH3:21]
Reactant: CCc1cccc(CC)c1N
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2ccc(C)cc21
Yield: 66.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.47 g of Compound A and 0.78 g of 2,6-diethylaniline in place of aniline to obtain 1.34 g of Compound 3.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.CCOC(C)=O.CCCCCCC>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
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: CCOC(C)=O
Solvent: COCCOC
Solvent: CCCCCCC
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4F)c3c2CC1
Yield: 42.9 %

Procedure:
A mixture of 3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.738 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol) in dimethoxyethane (5.0 mL) and a solution of 2-fluorophenylboronic acid (0.336 g, 2.4 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate (2 M, 7.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 20-50% EtOAc/heptane) afforded 0.33 g (43%) of the title compound as a solid: mp 241-244° C.; 1H NMR (400 MHz, CDCl3) δ 8.20, 8.04, 7.31, 7.15, 7.04, 3.96, 3.83, 3.62, 3.42, 3.14, 2.84, 2.71-2.69, 2.47, 2.31; IR (drift) 3236, 1603, 1501, 1485, 1469, 1456, 1434, 1249, 1217, 795, 786, 759, 746, 733, 706 cm−1; MS (EI) m/z 384 (M+); HRMS (FAB) calcd for C25H21,FN2O+H: 385.1716, found: 385.1721; Anal. Calcd for C25H21FN2O: C, 78.10; H, 5.51; N, 7.29. Found: C, 77.61; H, 5.60; N, 7.14.
Reaction SMILES: B(Br)(Br)[Br:2].[OH:5][CH:6]1[CH2:10][CH2:9][O:8][C:7]1=O.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([NH:20]C2C=CC=CC=2)[CH:17]=[CH:18][CH:19]=1.O>ClCCCl>[Br:2][CH2:9][CH2:10][CH:6]([OH:5])[C:7]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:28])([F:27])[F:12])[CH:15]=1)=[O:8]
Reactant: O=C1OCCC1O
Reactant: BrB(Br)Br
Reactant: FC(F)(F)c1cccc(Nc2ccccc2)c1
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(O)CCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron tribromide (11.0 ml, 1.0M solution in dichloromethane) was added dropwise to a stirred solution of 3-hydroxytetrahydrofuran-2-one (1.0 g) and 3-trifluoromethylphenylaniline (1.58 g) in 1,2-dichloroethane (20 ml). The mixture was stirred overnight at room temperature, poured on to water and extracted with dichloromethane. The extracts were washed with hydrochloric acid (2M) and brine, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give the title compound (0.74 g, m.p. 67°-69° C.). NMR (CDCl3): δ 2.3(1H,m); 2.6(1H,m); 3.5(1H,bs); 3.6(2H,dd); 4.5(1H,dd); 7.4(2H,m); 7.7 (1H,d); 7.9(1H,s); 8.7(1H,bs). MS: M+ 325, 327.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(C)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-methylpiperazine (Fluka) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H36N7O4SF2 [(M+H)+] 568.2512, observed 568.2519. CDK4 IC50=0.001; CDK1 IC50=0.039; CDK2 IC50=0.017; HCT IC90=0.274 μM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CO.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of methyl 4-(4-fluorophenylcarbamoyl)benzoate (2.98 g, 10.9 mmol) in THF (35 mL) was added MeOH (8 mL) and a solution of LiOH (1.79 g, 43.6 mmol) in H2O (8 mL). The reaction was stirred at room temperature for 2 h. The reaction was quenched upon the addition of 1N HCl (50 mL) and extracted with EtOAc (2×60 mL). The organic extracts were dried over MgSO4, and concentrated under vacuum to afford 4-(4-fluorophenylcarbamoyl)benzoic acid (2.43 g, 86%) as a white solid. 1H-nmr (400 MHz, d6-DMSO) δ 10.49 (s, 1H), 8.11-8.02 (m, 4H), 7.87-7.77 (m, 2H), 7.25-7.16 (m, 2H); MS (ESI) m/z 259.9.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(O)(C)C>[ClH:25].[Cl:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][C:15]=1[S:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2cc3ccncc3cc2Cl)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Clc1cc2cnccc2cc1SC1CCNCC1
Yield: 224.6 %

Procedure:
1.98 g of 4-(7-Chloro-isoquinolin-6-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (274) were dissolved in 7 ml dichloromethane and 5 ml 6N HCl in isopropanol. After 18 h at RT the volatiles were evaporated, water was added and lyophilized. 1.85 g of the expected compound were obtained. Rt=0.70 min (Method B). Detected mass: 279.1/281.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([CH:23]([C:27](Cl)=[O:28])[C:24](Cl)=[O:25])C.[O:30]1CC[CH2:32][CH2:31]1>C(OCC)C.O>[CH2:31]([O:30][C:27]([CH2:23][C:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:25])=[O:28])[CH3:32]
Reactant: C1CCOC1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)N(CC(=O)OCC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a 0° C solution of ethyl N-benzylglycinate (8 g) in tetrahydrofuran (4 ml) and diethyl ether (42 ml) was added simultaneously a solution of K2CO3 (5.72 g) in 20 ml of water and ethyl malonylchloride (6.54 g) in 20 ml diethyl ether. Following the addition the mixture was stirred at 0° for 1 hour then warmed to ambient temperature with stirring for 2 hours. The layers were separated with the organic phase washed once with brine. After drying (Na2SO4) and concentrating, there was obtained 12.5 g (98.8%) of the product as a viscous oil.