Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=O>CC(O)=O>[N+:23]([C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[N:10]=2)[CH:22]=[CH:21][CH:20]=1)([O-:25])=[O:24]
Reactant: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccn3c(n2)nc2ccccc23)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a round bottomed flask equipped with a magnetic stir bar, containing AcOH (20 mL) was placed 1H-benzoimidazol-2-amine (1 g, 7.5 mmol, 1.0 equiv). To this solution was added (E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one (1.7 g, 7.5 mmol, 1 equiv) and the reaction was allowed to stir at 120° C. for 24 h. After the reaction was complete by LCMS, the solvent was completely evaporated and the reaction mixture was neutralized with NaHCO3 solution. Yellow solid was filtered and washed with DCM to give the nitro compound DHK-7-16 0.83 g (39%). MS (ESI, Pos.) m/z: 291.1 M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:41].Cl([O-])=O.[Na+].S(=O)(=O)(O)N>ClCCl.O>[C:2]([CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[C:36]([OH:38])=[O:37])([OH:41])=[O:1]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCCO)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCC(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
(1RS, 2SR, 3RS)-3-[2-(3-Hydroxyprop-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (0.07 g, 0.13 mmol) was dissolved in dry dichloromethane (0.5 ml) and Dess-Martin periodinane (0.07 g, 0.17 mmol) added in dry dichloromethane (1 ml). After 2h. the product was partitioned between ether and saturated aqueous sodium carbonate solution containing sodium thiosulfate. The ether extract was washed with water then brine, dried (MgSO4 anhydrous), filtered and evaporated to give an oil which was used without purification. The crude product was dissolved in t-butanol (5 ml) and to this was added a solution of sodium chlorite (1 8 mg, 0.2 mmol) and sulfamic acid (21 mg, 0.22 mmol) in water (1.5 ml). After 1 h. stirring at ambient temperature the product was extracted into ethyl acetate. The organic layer was washed with water then brine then dried (MgSO4 anhyd.) filtered and evaporated to give an oil. The product was purified by column chromatography on silica-gel (eluant: ethyl acetate/hexane/3% acetic acid) to give 12 mg of free acid which was converted to its bis-dicyclohexylamine salt.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26](Br)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Br)c1C(=O)Nc1cc(O)cc(F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3cc(O)cc(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.37 mmol), 4-amino-6-bromo-N-(3-fluoro-5-hydroxyphenyl)pyrimidine-5-carboxamide (183 mg, 0.56 mmol), DIEA (325 μl, 1.87 mmol) and cesium fluoride (113 mg, 0.74 mmol) were suspended in tert-butanol (5 ml) and the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 15 mg (8% yield) as a solid. Purity 97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[O:26][C:27]=1[CH3:28].ClC1C=C(C=CC=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=Cc1cccc(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 47 c]) was reacted with 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole (prepared from 3-chloro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in N,N-dimethylformamide in the presence of potassium carbonate to yield [rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-ethoxy-phenyl}-2-ethoxy-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: NC1C=C(N2C3C4C=CC=CC=4SCC=3C([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=N2)C=CC=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>CN(C)C=O>[C:32]([CH:22]([CH:21]=[O:34])[C:23]([NH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:24])#[N:33]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2cccc(N)c2)c2c1CSc1ccccc1-2
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: N#CC(C=O)C(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
3-[1-(3-amino-phenyl)-1,4-dihydro-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide (1.9 g) dissolved in dimethylformamide (25 ml) is reacted with acetic anhydride (5 ml) in the presence of pyridine (5 ml) at room temperature for 20 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water: crystallization from dimethylformamide-ethanol gives 1.6 g of 3-[1-(3-acetylamino-)phenyl)-1,4-dihydro-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[N:22]=2)=[CH:14]\[C@@H:15]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:30]I.O>O1CCCC1.C(OCC)(=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[N:22]=2)=[CH:14]\[C@@H:15]2[N:19]([CH3:30])[C:18](=[O:20])[CH2:17][CH2:16]2)=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2C)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
60% sodium hydride (27 mg) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (185 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 20 minutes. Methyl iodide (60 μL) was then added and the mixture was stirred at room temperature for 4.5 hours. Water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=80:20) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]-1-methylpyrrolidin-2-one as a colorless powder (180 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OC)c(N)c1
Yield: 92.7 %

Procedure:
A solution of methyl 6-methoxy-5-nitronicotinate (5.4 g) in ethyl acetate (120 mL) is hydrogenated using 5% palladium on carbon (1 g) as catalyst. When hydrogen uptake ceased the mixture is filtered through a pad of diatomaceous earth and the filtrate evaporated. The residue is triturated with n-pentane and methyl t-butyl ether to give methyl 5-amino-6-methoxynicotinoate (4.3 g) as a light-brown solid, m.p.108-9° C. [Elemental analysis: C, 52.99; H, 5.49; N, 15.25%. calculated: C, 52.74; H, 5.53; N, 15.38%.]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:28]=[C:14]2[C:15]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:16][CH:17]=[C:18]([F:19])[C:13]2=[N:12]1.I([O-])(=O)(=O)=[O:30].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:28]=[C:14]2[C:15]([NH:20][C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23][N:22]=3)=[N:16][CH:17]=[C:18]([F:19])[C:13]2=[N:12]1)[CH:8]=[O:30]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(Cl)c(-n2cc3c(Nc4cc(C)ncn4)ncc(F)c3n2)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4Cl)cc23)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of [2-(2,6-dichloro-4-vinylphenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)amine (193 mg, 0.47 mmol) in acetone (10 mL) and water (2.5 mL) was added osmium (VIII) oxide (2.5% wt in tert-butanol, 0.465 mL), followed by sodium periodate (257 mg, 1.2 mmol) and the reaction mixture was stirred at room temperature overnight. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (80% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (129 mg, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 10.10 (s, 1H), 9.35 (d, J=2.6 Hz, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.31 (s, 2H), 8.01 (d, J=3.5 Hz, 1H), 2.45 (s, 3H).
Reaction SMILES: O=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl.[NH2:21][OH:22].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[OH:22][N:21]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC(=NO)c1ccccc1
Yield: 94.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-4-phenylbutylcarbamate (2.4 g, 9.1 mmol), hydroxylamine hydrochloride (1.27 g, 2 equiv.) and sodium acetate trihydrate (2.5 g, 2 equiv.) was stirred and heated under reflux in 20% aqueous ethanol (60 ml) for 7 h. The reaction mixture was then concentrated and the residue partitioned between saturated aqueous sodium bicarbonate (100 ml) and ethyl acetate (200 ml). The organic extract was dried over magnesium sulphate and concentrated to afford a colourless solid (2.4 g, 95%).
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](N)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-trifluoromethyl-phenylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][N:25](C)[CH:26]=O.CNC>C1C=CC=CC=1.O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][C:10]=1[C:11]([N:25]([CH3:26])[CH3:24])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: CN(C)C=O
Agent: CNC
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=Cc1ccc(OCc2ccccc2)c(C(=O)N(C)C)c1

Procedure:
To a solution of 2-benzyloxy-5-vinylbenzoic acid (607 mg) in benzene (10 ml) were added thionyl chloride (350 μl) and a catalytic amount of N,N-dimethylformamide, and the mixture was heated under reflux for 1 hour with stirring. After concentration of the reaction mixture under reduced pressure, the residue was dissolved in tetrahydrofuran (5 ml), and an excess amount of 50% aqueous dimethylamine solution was added to the stirred solution under ice-cooling. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent:hexane/diethyl ether/dichloromethane=1/2/2) gave 2-benzyloxy-N,N-dimethyl-5-vinylbenzamide (548 mg).
Reaction SMILES: S1[C:5]([C:6](=[O:34])/[CH:7]=[CH:8]/[C@H:9]2[C@@H:13]([F:14])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[CH:4][C:3]2[CH:35]=[CH:36][CH:37]=[CH:38][C:2]1=2.[BH4-].[Na+].[CH3:41]O>>[CH2:41]1[C:2]2[C:3](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:4][CH:5]1[C@H:6]([OH:34])/[CH:7]=[CH:8]/[C@H:9]1[C@@H:13]([F:14])[CH2:12][C@H:11]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C@@H:10]1[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(=O)c2cc3ccccc3s2)[C@@H](F)C[C@@H]1OC1CCCCO1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: -40 °C

Procedure:
To a stirring mixture consisting of (Z)-isopropyl 7-((1R,2R,3S,5S)-2-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step H, 13.4 g) in methanol (325 mL) cooled to −40° C. was added CeCl3 heptahydrate (9.46 g). The reaction mixture was further cooled to −78° C. and was stirred for an additional hour. Sodium borohydride (1.89 g) was added and the reaction mixture was stirred for one hour at −78° C. Upon completion (as visualized by TLC), the reaction was quenched by the addition of acetone and the mixture was warmed to room temperature. The mixture was subsequently acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title intermediate (15.2 g). The crude intermediate was carried on with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[S:23](N)(N)(=[O:25])=[O:24]>N1C=CC=CC=1>[O:24]=[S:23]1(=[O:25])[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 11.0 g (0.0372 mol) of 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenemethanamine in 200 ml of pyridine was added dropwise within 1.5 hours and at reflux temperature to a solution of 3.4 g (0.0354 mol) of sulphamide in 200 ml of pyridine and the mixture was then refluxed for 6 hours. The mixture was freed from solvent, the residue was purified by column chromatography using ethyl acetate/methanol 9/1 (v/v) as eluant. 5.5 g (43.5% of theory) of a colourless amorphous substance were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=4[CH3:34])[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH3:37]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[C:28]([CH3:34])=[CH:29][C:30]([O:33][CH3:37])=[CH:31][N:32]=4)[CH2:25][CH2:26]3)[N:12]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CI
Reactant: Cc1cc(O)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(N2CCN(c3cc(-c4ccc(F)c(Cl)c4)nc(N4CCCC4C)n3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-{4-[6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-5-methyl-pyridin-3-ol (50 mg, 0.10 mmol) in DMF add 60% NaH (12 mg, 0.30 mmol). Stir the solution at room temperature for 30 minutes. Add methyl iodide (0.3 mmol) and stir the solution at room temperature for 2 hours. Partition between EtOAc and water. Wash with brine, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc:Hexanes (1:4) to afford 4-(3-chloro-4-fluoro-phenyl)-6-[4-(5-methoxy-3-methyl-pyridin-2-yl)-piperazin-1-yl]-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine as a solid. 1H NMR (300 MHz, CDCl3): δ1.30 (t, 3H, J=6.3 Hz, CH3); 1.70 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 2.33 (s, 3H, Ar—CH3); 3.13 (m, 4H); 3.67 (m, 2H); 3.78 (m, 4H); 3.80 (s, OCH3); 4.33 (m, 1H); 6.25 (s, 1H, Ar—H); 7.06 (d, J=2.4 Hz, 1H); 7.18 (m, 1H); 7.88 (m, 2 H); 7.86 (m, 1H); 8.07 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH:27][CH3:26])=[O:29])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Product: CNC(=O)c1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-(methyl-carbamoyl)phenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 499.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]1[CH2:12][CH2:11][CH:10]1[C:13](Cl)=[O:14].[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]1[CH2:12][CH2:11][CH:10]1[C:13]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)=[O:14].[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27]
Reactant: Cc1cc(C)c(C2CCC2C(=O)Cl)c(C)c1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c(C2CCC2C(=O)[c-]2cccc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
1-Mesityl-cyclobutan-2-oic acid chloride (assumed to be 0.1 mole) and ferrocene (18.6g; 0.1 mole) in dry methylene chloride (200 ml) were stirred at 0°-5° and aluminium chloride (20g; 0.15 mole) was added. The mixture was stirred at 0°-5° for 30 minutes and at room temperature for 1 hr; ice was added slowly and the organic fraction was separated. The aqueous fraction was extracted with chloroform, and the combined organic fractions were washed with water and dried (magnesium sulphate). The solvent was evaporated under reduced pressure to yield a red oil which was purified by column chromatography on silica using 10:1 petroleum ether/ethyl acetate as eluent. The major band gave a red oil which was recrystallised from petroleum ether to give orange crystals of 1-mesityl-2-ferrocenoyl cyclobutane mp 113°-114.5° (20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[CH:28]=1
Reactant: CN1CCN(CCc2cccc(N)c2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN1CCN(CCc2cccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)c2)CC1
Yield: 55.8 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (240 mg, 0.77 mmol) was reacted with 3-(2-(4-methylpiperazin-1-yl)ethyl)aniline (170 mg, 0.77 mmol) to afford the desired product (212 mg, 55%) as a yellow solid: ESI MS m/z 493 [C26H29BrN4O+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)[CH:3]=1.C(C1[S:32]C(N)=NC=1)C>>[CH2:2]([C:7]1[S:32][C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)=[N:5][CH:6]=1)[CH3:3]
Reactant: CCc1cnc(N)s1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Product: CCc1cnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)s1
Yield: 34.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 4, starting from 5-ethylthiazol-2-amine, to afford the title compound (191 mg, 34.2%).