Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(=O)[O:18][C:16](=[O:17])C2=CC=CC=C12.C1(C[C@H](N2C(=O)C3=CC=CC=C3C2=O)C(O)=O)C=CC=CC=1.C1(C[C@H](N2C(=O)C3=CC=CC=C3C2=O)C(Cl)=O)C=CC=CC=1.C1(C[C@H](N2C(=O)C3=CC=CC=C3C2=O)C=O)C=CC=CC=1.C(C(O)[C@@H](N1C(=O)C2=CC=CC=C2C1=O)CC1C=CC=CC=1)#N>>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:10]([OH:12])[C:16]([OH:18])=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N#CC(O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=C(O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Product: N[C@@H](Cc1ccccc1)C(O)C(=O)O

Procedure:
L-phenylalanine of the formula ##STR2## is reacted with phthalic anhydride, b) the resultant 3-phenyl-2(S)-phthalimidopropionic acid of the formula ##STR3## is converted into the corresponding acid chloride, c) the resultant 3-phenyl-2(S)-phthalimidopropionic acid chloride of the formula ##STR4## is reduced, d) the resultant 3-phenyl-2(S)-phthalimidopropan-1-al of the formula ##STR5## is transformed into the 1-cyano-3-phenyl-2(S)-phthalimidopropan-1-ol of the formula ##STR6## e) the resultant nitrile of the formula VI is hydrolysed, f) the 3(S)-amino-2-hydroxy-4-phenylbutyric acid formed of the formula ##STR7## is reacted with a low alkyl ester or the phenyl or benzyl ester of chloroformic acid,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[Cl:11].C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[Cl:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Ni]
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(Cl)c1Cl
Reaction time: 1 h

Procedure:
48.0 g of 1,2-dichloro-3-nitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 12 bar and a temperature of 80° C. The hydrogenation time is 1 hour. 1,2-Dichloro-3-aminobenzene, 99.7% pure (analysed by gas chromatography), is obtained in quantitative yield.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([C:27](=[O:28])[N:26]([CH3:38])[CH3:25])=[CH:37][CH:36]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:12])[F:13]
Reactant: CN(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1C(=O)c1ccc(C(=O)N(C)C)cc1
Yield: 17.8 %

Procedure:
To a stirred solution of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (400 mg, 1.57 mmol) and triethylamine (0.4 ml, 2.84 mmol) in EtOAc (25 ml) was added a solution of 4-dimethylcarbamoylbenzoyl chloride (350 mg, 1.66 mmol) in EtOAc (25 ml). The resultant mixture was stirred at ambient temperature for 24 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with EtOAc as eluent to give the title compound as a solid (120 mg, 0.28 mmol). NMR: 1.1-1.13 (m, 6H), 1.6 (s, 3H), 2.9 (s, 3H), 3.1 (s, 3H), 3.25 (m, 1H), 3.4 (m, 1H), 4.25 (s, 2H), 4.65 (s, 1H), 4.9 (s, 1H), 5.2 (s, 1H), 7.3-7.4 (dd, 4H); m/z 428.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17]>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:17][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: CN(C)CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1nccc(N)n1
Temperature: 180 °C
Yield: 26.3 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), sodium ethoxide (189 mg, 2.78 mmol) and 2-(dimethylamino)ethanol (349 μl, 3.47 mmol) in N,N-dimethylformamide (DMF) (2.9 mL) was heated to 180° C. via a microwave reactor for min. The reaction was purified by RP-HPLC to yield 2-{[2-(dimethylamino)ethyl]oxy}-4-pyrimidinamine (111 mg, 0.609 mmol, 26% yield). MS (ES+) m/z 183.0 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:17])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[NH:22][N:21]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:17][N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=3[C:20]([C:19]([F:18])([F:30])[F:29])=[N:21]2)=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CN(Cc1ccc(Br)cc1)C(=O)N1CCCC1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CN(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C(=O)N1CCCC1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
A mixture of N-[(4-bromophenyl)methyl]-N-methyl-1-pyrrolidinecarboxamide (250 mg, crude), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg, 0.8 mmol), N,N-dimethylglycine (20 mol %, 16.5 mg, 0.16 mmol), copper (I) iodide (10 mol %, 15 mg, 0.08 mmol) and potassium carbonate (1.6 mmol, 221 mg) in dimethylsulfoxide (4 ml) was stirred at 190° C. in a microwave reactor for 30 minutes. The reaction mix was treated with fresh N,N-dimethylglycine and copper (I) iodide and heated at 190° C. in a microwave reactor for a further 30 minutes. The reaction mix was partitioned between dichloromethane (5 ml) and water (5 ml). The organic layer was added to a 5 g isolute silica sep-pak column and eluted with ethyl acetate. The solvent was removed under reduced pressure and the residue purified by mass directed auto-prep (MDAP) to give the title compound as a brown oil (12 mg, 4%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:17][C:18]1([CH3:49])[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=3)[CH:24]=2)[S:19]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:36]#[C:37][C:38]4[CH:48]=[CH:47][C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][CH:39]=4)[CH:24]=3)[S:19][C:18]([CH3:17])([CH3:49])[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CC(C)(C)S3)cc1
Temperature: 25 °C

Procedure:
A solution of 4-tert-butylbromobenzene (149.0 mg, 0.70 mmol) in 2.0 mL of THF was cooled to -78° C. and tert-butyllithium (92.6 mg, 1.44 mmol, 0.85 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (133.0 mg, 0.98 mmol) in 4.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-ylethynyl) benzoate (Compound 224, 140.0 mg, 0.28 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 94.0 mg (70%), was isolated by column chromatography (5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.98 (2H, d, J=8.3 Hz), 7.52 (2H, d, J=8.3 Hz), 7.43-7.22 (7H, m), 5.86 (1H, s), 4.38 (2H, q, J=7.1 Hz), 1.47 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.38 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:15]([C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH:14]=1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccccc1C(F)(F)F
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 2-bromobenzotrifluoride 0.11 mL, cesium carbonate 0.22 g, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.5 mg, tris(dibenzylideneacetone)dipalladium(0) 3.0 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.0 mg were added to it, and it was stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-phenethyl-2-(2-(trifluoromethyl)anilino)benzoate.
Reaction SMILES: CN(C)C=O.O[CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccccc2)c(CCO)o1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(CCCl)o1

Procedure:
N,N-Dimethylformamide (4.0 ml) was added to a solution of 5-(2-hydroxyethyl)-2-methyl-4-phenyloxazole (10.5 g) in chloroform (100 ml) and, under ice-cooling and stirring, thionyl chloride (11.4 ml) was added dropwise. The mixture was refluxed for 30 minutes and the solvent was distilled off. Then, ice water was added and the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-chloroethyl)-2-methyl-4-phenyloxazole, yield 11.0 g (96.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>ClCCl>[Br:22][C:21]1[N:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1Br

Procedure:
A suspension of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine (300 mg., 1 mmole) in 20 ml. of dichloromethane is treated with N-bromosuccinimide (220 mg., 1.24 mmole). The resultant solution is stirred at room temperature for 48 hours. The precipitate is collected by filtration, washed with dichloromethane and dried to yield 3-bromo-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 165°-168° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[N:18]1[CH2:24][CH2:25][NH:26][C:27]1[N:28]=[N+:29]([O-:40])[C:30]2[CH:39]=[C:38]3[C:34]([CH2:35][CH2:36][CH2:37]3)=[CH:33][C:31]=2[N:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[N:18]1[CH2:24][CH2:25][NH:26][C:27]1[N:28]=[N+:29]([O-:40])[C:30]2[CH:39]=[C:38]3[C:34]([CH2:35][CH2:36][CH2:37]3)=[CH:33][C:31]=2[N+:32]=1[O-:4]
Reactant: CC1CCCC(C)N1CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCC(C)N1CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
H2O2 (70%, 0.46 mL, ca. 9.2 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 38 (314 mg, 0.9 mmol) and TFA (0.35 mL, 4.6 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 39 (118 mg, 36%) as a red solid: mp (MeOH) 170-172° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.21 (br s, 1H, NH), 3.56-3.63 (m, 2H, CH2N), 3.12 (br dd, J=7.6, 7.3 Hz, 2H, CH2), 3.07 (br dd, J=7.5, 7.4 Hz, 2H, CH2N), 2.95 (br dd, J=7.5, 7.1 Hz, 2H, CH2N), 2.49-2.57 (m, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, CH2), 1.65-1.70 (m, 1H, CH2), 1.53-1.59 (m, 2H, CH2), 1.25-1.40 (m, 3H, CH2), 1.18 (d, J=6.3 Hz, 6H, 2×CH3); 13C NMR δ 155.7, 149.4, 145.7, 137.9, 129.7, 115.8, 111.5, 57.1 (2), 47.2, 39.3, 34.2, 33.4 (2), 32.4, 25.6, 24.4, 21.7 (2). Anal. calcd for C19H27N5O2: C, 63.8; H, 7.6; N, 19.6. Found: C, 64.0; H, 7.6; N, 19.8%.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8]C2(O)C3C(=CC=C(C)C=3)N(CCC(C)C)C2=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:31](=[O:44])[C:30]2=[O:45].CC1C=CC=CN=1>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:31](=[O:44])[C:30]2([OH:45])[CH2:8][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1C(=O)N(CCN2CCCCC2)c2ccc(Cl)cc21
Reactant: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Solvent: Cc1ccccn1
Product: O=C1N(CCN2CCCCC2)c2ccc(Cl)cc2C1(O)Cc1ccccn1

Procedure:
This compound was prepared in an analogous manner to 3-((3-bromopyridin-2-yl)methyl)-3-hydroxy-1-isopentyl-5-methylindolin-2-one using 5-chloro-1-(2-(piperidin-1-yl)ethyl)indoline-2,3-dione and 2-methylpyridine (purchased from Fisher Scientific). 1H-NMR δ 8.61 (d, 1H), 7.70 (m, 2H), 7.32 (dd, 1H), 7.24 (dd, 1H), 7.10 (d, 1H), 6.82 (m, 2H), 3.87-3.75 (m, 2H), 3.33 (d, 1H), 3.11 (d, 1H), 2.62-2.47 (m, 6H), 1.57 (m, 4H), 1.45 (m, 2H). Calculated mass for C21H24ClN3O2, 385.16, observed, 386.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1cc(O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (3.20 g, 16.7 mmol) in methanol (60 mL) was added 20 wt % palladium hydroxide on carbon (1.60 g) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 8 hr under hydrogen atmosphere. After nitrogen replacement, triethylamine (2.32 mL, 16.7 mmol) was added to the reaction mixture, and the mixture was filtered through a kiriyama funnel. Saturated brine was added to the filtrate, and the mixture was extracted twice with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was recrystallized from diethyl ether/hexane to give the title compound (1.40 g, 66%) as pale-brown crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5].[Mg].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:23])[C:15]3[N:16]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:17]=2[CH:18]=1.[Cl-].[NH4+]>CCOCC.ClCCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]([OH:23])([CH2:2][CH2:3][CH:4]([O:6][CH3:7])[CH3:5])[C:15]3[N:16]([CH2:19][CH2:20][CH2:21][N:22]=3)[C:17]=2[CH:18]=1
Reactant: O=C1C2=NCCCN2c2cc(Cl)ccc21
Reactant: COC(C)CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: COC(C)CCC1(O)C2=NCCCN2c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-bromo-3-methoxybutane (2.0 g) in dry ether (20 ml) was added dropwise under a nitrogen atmosphere to magnesium turnings (0.3 g) at such a rate as to maintain gentle reflux. After 0.5 hour the reaction mixture was cooled and a solution of 7-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (1.0 g) in dry 1,2-dichloroethane (50 ml) was added dropwise. After stirring the reaction mixture for one hour at room temperature it was cooled and excess saturated ammonium chloride solution was added dropwise. The organic phase was separated and the aqueous phase was extracted with chloroform. The extracts were combined with the organic phase, dried (MgSO4) and the solution evaporated in vacuo to leave an oil which was triturated with ether to give a solid. Recrystallisation from ethyl acetate gave the title compound as crystals m.p. 146.5°-148°. A solution of these crystals in warm propan-2-ol was treated with ethereal hydrogen chloride. Evaporation in vacuo followed by recrystallisation from propan-2-ol gave the title compound as the hydrochloride, colourless needles, m.p. 226°-8°.
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][N+:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt](=O)=O.CO>[C:2]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc[n+](CCc2ccccc2)cc1
Agent: O=[Pt]=O
Agent: [Br-]
Solvent: CO
Product: CCOC(=O)C1CCN(CCc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
A mixture of 5.90 g (17.5 mmol) of 1-(2-phenylethyl)-4-carboethoxypyridinium bromide, 0.60 g of platinum (IV) oxide and 100 mL of methanol was hydrogenated at 50 p.s.i. and room temperature for 1.5 hours. The reaction mixture was filtered, concentrated and the residue dissolved in water. The aqueous solution was made alkaline to pH 9-10 with aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried and evaporated to afford 4.11 g of 1-(2-phenylethyl)-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.16-7.32 (m, 5H); 4.08-4.19 (q, 2H); 2.91-3.02 (m, 2H); 2.77-2.88 (m, 2H); 2.53-2.65 (m, 2H); 2.23-2.35 (m, 1H); 2.03-2.15 (m, 2H); 1.87-1.98 (m, 2H); 1.72-1.88 (m, 4H); 1.20-1.30 (t,3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
Into a 5 mL microwave tube was charged 4-fluoro-2-methoxy-1-nitrobenzene (1 g, 0.584 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.321 g, 1.753 mmol), triethylamine (0.244 mL, 1.753 mmol), and acetonitrile (1.948 mL). The reaction was heated in Biotage microwave reactor at 130° C. for 40 minutes. The solvent was removed under reduced pressure, and the reaction purified by flash chromatography using a gradient 100% CH2Cl2 to 1:1 CH2Cl2/methanol to provide the title compound. MS (ESI) m/e 335 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[O:24])[C:7]2(O)[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (64%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ9.53 (s, 1H), 7.44-7.20 (m, 13H), 7.01-6.91 (m, 2H), 6.22 (s, 1H), 4.82 (s, 1H), 4.48 (t, J=8.5 Hz, 2H), 3.03 (t, J=8.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:7]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(F)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (98%, 530 mg, 0.74 mmol) was added to a mixture of (5-fluoro-2-methoxyphenyl)boronic acid (10.0 g, 58.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (6.75 mL, 65.0 mmol) and potassium carbonate (16.3 g, 118 mmol) in tetrahydrofuran (100 mL) and water (30 mL), and the reaction mixture was stirred for 18 hours at room temperature. The aqueous layer was extracted with diethyl ether (100 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo, while keeping the bath temperature at <30° C. Pentane (200 mL) was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure; the residue was subjected to silica gel chromatography (Eluent: pentane) to afford the product as a colorless oil. Yield: 9.08 g, 41.2 mmol, 70%. 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 5.69-5.70 (m, 1H), 6.12-6.13 (m, 1H), 6.88 (dd, J=9.0, 4.5 Hz, 1H), 6.98 (br dd, J=8.8, 3.1 Hz, 1H), 7.05 (ddd, J=9.0, 7.8, 3.1 Hz, 1H).