Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:17]=[CH:16][C:9]2[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[O:13][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].C(Cl)Cl.CO>C(O)(=O)C>[C:3]([C:6]1[CH:17]=[CH:16][C:9]2[C:10](=[O:15])[C:11]([Br:1])=[C:12]([CH3:14])[O:13][C:8]=2[CH:7]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1ccc2c(=O)cc(C)oc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc2c(=O)c(Br)c(C)oc2c1
Reaction time: 2 h
Yield: 19 %

Procedure:
77.5 ml of a 10% solution of bromine in acetic acid are added at 60° C., under an inert atmosphere, to a solution of 8.8 g (40.10-3 mol) of 7-acetyl-2-methyl-4H-1-benzopyran-4-one in 80 ml of acetic acid. The reaction mixture is kept at 60° C. for 2 hours and is then left to stand for 12 hours. It is concentrated under reduced pressure and the residue is then neutralized with a saturated solution of sodium bicarbonate. After extraction with ethyl acetate, the organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and concentrated to dryness. After chromatography on silica gel using a methylene chloride/methanol mixture (12/1 v/v) as the eluent, 2.3 g (yield: 19%) of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)[N:3]=1.O.[NH2:28][NH2:29]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:20][CH2:19]4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:29][N:28]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NC3CCc4ccccc43)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(NC2CCc3ccccc32)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
To 4-[2-amino-6-(2,3-dihydro-1H-inden-1-ylamino)-4-pyrimidinyl]-2-fluorobenzonitrile (500 mg, 1.45 mmol) in ethanol (2 mL) was added hydrazine monohydrate (3 mL, 74.0 mmol), and the reaction mixture was heated to 100° C. for 1 hour in a BiotageInitiator® microwave synthesizer. Upon cooling, the reaction mixture was concentrated in vacuum and purified by HPLC to afford the title compound (100 mg) as a brown solid. LC-MS (ES) m/z=358 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.81 (s, 1H), 1.90-1.92 (m, 1H), 2.84-3.051 (m, 2H), 5.43 (s, 2H), 5.71 (s, 1H), 6.12 (s, 2H), 6.40 (s, 1H), 7.23-7.48 (m, 6H), 7.75 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 11.58 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C@@H:7]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:15]=[C:16](I)[CH:17]=1)=[O:11])[CH3:8].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][C:27]1=[O:35].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC>C1(C)C=CC=CC=1.[Cu]I>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C@@H:7]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:15]=[C:16]([N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[NH:28][C:27]2=[O:35])[CH:17]=1)=[O:11])[CH3:8]
Reactant: Cc1ccc(-c2cc(I)cc(C(=O)N[C@@H](C)c3cnccn3)c2)cc1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)c3cnccn3)cc(-n3c(=O)[nH]c4ccccc43)c2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
5-Iodo-4′-methyl-biphenyl-3-carboxylic acid ((S)-1-pyrazin-2-yl-ethyl)-amide (110 mg, 0.25 mmol) was dissolved in toluene (3 mL) and 1,3-dihydro-benzoimidazol-2-one (135 mg, 1.0 mmol), and CuI (15 mg), K3PO4 (212 mg, 1.0 mmol) and 1,2-bis(methylamino)cyclohexane (0.1 mL) were added. The reaction mixture was stirred at 110° C. overnight, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography (7% methanol in dichloromethane) to give 20 mg (185 yield overall) of 4′-methyl-5-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-biphenyl-3-carboxylic acid ((S)-1-pyrazin-2-yl-ethyl)-amide MS (M+H)=450.
Reaction SMILES: C([Sn](CCCC)(CCCC)/[C:6](/[F:14])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)CCC.Br[C:24]1[C:25]([NH2:42])=[N:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[N:29]=1>C1COCC1.[Pd]>[F:14]/[C:6](/[C:24]1[C:25]([NH2:42])=[N:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])=[CH:32][CH:31]=2)[N:29]=1)=[CH:7]\[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(F)=C/c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(/C(F)=C/c3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
tributyl-[(E)-1-fluoro-2-phenyl-vinyl]stannane (190 mg, 0.4621 mmol), 3-bromo-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (164.6 mg, 0.4621 mmol), palladium (9.835 mg, 0.09242 mmol) and cuprous iodide (83.61 mg, 14.85 μL, 0.4390 mmol) were combined in THF (5 mL) and was stirred at 80° C. for 1 hour under microwave conditions. After this time the mixture was filtered over celite, concentrated in vacuo, and the residue was triturated twice in petroleum ether and dried. This material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (44 mg, 18.92% Yield). H1 NMR (400.0 MHz, DMSO) H NMR (400.0 MHz, DMSO) δ 1.16-1.19 (d, 6H), 3.45 (m, 1H), 6.88 (d, J=40.7 Hz, 1H), 6.96 (s, 2H), 7.35 (t, J=7.4 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.73 (d, J=7.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 8.32 (d, J=8.5 Hz, 2H) and 8.82 (s, 1H) ppm. MS (ES+) 398.0
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:21]([C:20]2[CH:19]=[N:18][CH:17]=[CH:16][C:15]=2[Cl:14])=[O:22])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1NC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A mixture of 524 mg of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 500 mg of 4-chloronicotinic acid, 790 mg of EDCI hydrochloride, 37 mg of HOBt and 4 ml of pyridine was stirred at room temperature for 4 hours. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 828 mg of 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-chloropyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)#N>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: COc1ccnc(C#N)c1
Product: COc1ccnc(-c2cc3ccccc3c(=O)[nH]2)c1
Yield: 29.9 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (4.96 g) and 2-cyano-4-methoxypyridine (4.46 g) were reacted, to give 3-(4-methoxypyridin-2-yl)isoquinolin-1-one (2.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Product: CN1CCN(C2Cc3cc(Cl)ccc3Sc3cc(F)ccc32)CC1

Procedure:
12 g of 2,10-dichloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin are heated for 10 minutes together with 16 g of N-methylpiperazine at an external temperature of 120°-130°. After cooling the reaction mixture is poured on water and extracted with ether. The organic phase is washed with water and subsequently treated with 2 N hydrochloric acid. A precipitate is obtained. The mixture is extracted with ether, made alkaline and subsequently again extracted with ether. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The so-obtained raw 1-(2-chloro-7-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-4-methylpiperazine is converted to the corresponding maleate by treatment with maleic acid. The maleat melts at 200° with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[NH:6][C:5]=2[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:20])=O>C1COCC1>[Cl:20][C:7]1[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:15]([CH3:17])[CH3:16])[C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(C(C)C)c2[nH]c(=O)cc(C(=O)O)c12
Solvent: C1CCOC1
Product: Cc1nn(C(C)C)c2nc(Cl)cc(C(=O)O)c12
Temperature: 105 °C
Reaction time: 24 h

Procedure:
3-Methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1.5 g, 6.38 mmol) was added to a solution of THF (15 mL) followed by addition of phosphorous oxychloride (8.9 mL, 96 mmol), and the contents heated at 105° C. overnight. After cooling to room temperature, the contents were concentrated in vacuo to remove most of the volatiles. The residual contents were slowly poured into a solution of iced water and 1N NaOH (10 mL), and the contents were stirred at room temperature for 24 h, during which time solid precipitation ensued. Additional 1N NaOH was added, upon which the solids went into solution. After stirring at room temperature for an additional 30 min., the contents were cooled in an ice bath and the mixture slowly acidified to pH=3-4 by slow addition of 6N HCl, to afford a heterogenous mixture. The mixture was filtered and a white solid set aside. The aq. layer was further extracted with EtOAc and DCM. The combined organic layers dried were dried over MgSO4, filtered and concentrated in vacuo. The resultant light brown solid was triturated in EtOAc/EtOH (1:1) and filtered to afford a first crop of white solid product, which was set aside. The filtrate was again concentrated in vacuo. The residue was diluted with EtOAc, sonicated, treated with hexanes, and filtered. The process was repeated. The isolated solid product crops were dried under vacuum (3 h) and collected as 1.33 g (80%). LCMS E-S (M+H): 254.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, 6 H), 2.60 (s, 3 H), 5.10 (quin, J=6.63 Hz, 1 H), 7.50 (s, 1 H), 14.17 (br. s., 1 H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][N:5]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]([C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)=[O:11])=[CH:13]1
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)ccn1

Procedure:
Compound 4ee was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 53 mg (0.20 mmol) of 3-(2-methyl-pyridine-4-carbonyl)-1H-quinolin-4-one 3h, 3 mL of anhydrous dimethylformamide, and 49 mg (0.26 mmol) of 2-fluorobenzylbromide. The crude product 4ee was purified by flash chromatography to yield 21 mg of a colorless solid 4ee: LC-MSD, m/z for C23H17FN2O2, [M+H]+=373.5, [M+2H]+=374.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.296 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.60 (s, 3H), 5.43 (s, 2H), 7.02-7.20 (m, 3H), 7.32-7.40 (m, 2H), 7.40-7.47 (m, 3H), 7.64 (t, 1H), 8.44 (m, 2H), 8.60 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:48])(=[O:47])[C@H:41]([CH2:43][C:44]([OH:46])=[O:45])[OH:42]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:48])(=[O:47])[C@H:41]([CH2:43][C:44]([O-:46])=[O:45])[OH:42]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])C[C@H](O)C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of L-malic acid (0.038 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 2 h and it was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight while stirring and then a sample (1 ml) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give amorphous Nilotinib L-malate as characterized by the powder X-ray diffractogram depicted in FIG. 44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26]C)=[C:6]([C:8]2[C:17]([C:18](OC)=[O:19])=[C:16]3[C:11]([NH:12][C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]3[CH3:22])=[CH:10][CH:9]=2)[CH:7]=1.B(Br)(Br)Br.C(OCC)(=O)C.[H-].[Na+]>ClCCl.O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([O:26][C:18](=[O:19])[C:17]3[C:8]2=[CH:9][CH:10]=[C:11]2[C:16]=3[N:15]([CH3:22])[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[NH:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2cc(Cl)ccc2OC)ccc2c1N(C)C(=O)C(C)(C)N2
Agent: BrB(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CN1C(=O)C(C)(C)Nc2ccc3c(c21)c(=O)oc1ccc(Cl)cc13
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
7-(5-Chloro-2-methoxyphenyl)-8-methoxycarbonyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 10-1, 3.81 g, 9.80 mmol) was dissolved in anhydrous dichloromethane (30 mL), boron tribromide (7.62 g, 30.4 mmol) was added thereto at −78° C., and then stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (500 mL), ethyl acetate (500 mL) was added thereto and partitioned. The organic layer was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL), 60% sodium hydride (23.1 mg, 0.578 mmol) was added thereto, and then stirred at 70° C. overnight. 60% sodium hydride (31.2 mg, 0.780 mmol) was added more thereto and stirred at 80° C. overnight. After cooling down, ethyl acetate (200 mL), diethylether (200 mL) and water (300 mL) were added and partitioned. The organic layer was washed with water (200 mL) and saturated brine (200 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was filtered with ethyl acetate/hexane (1/4, 30 mL) to give the titled reference compound (2.04 g) as a pale yellow solid. (Yield 61%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[S:18]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:17](=[S:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1ccccc1C(=S)Cl
Reactant: COc1ccc(CCN)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCNC(=S)c2ccccc2C)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)ethylamine (4.8 ml), poly(4-vinylpyridine) (PVP) (5.7 g) and 2-methylthiobenzoyl chloride (5.3 g) were stirred in dichloromethane (50 ml) with cooling in a water bath at 20° for one night. The PVP was filtered off and washed with CHCl3. Evaporation of the extracts followed by flash chromatography (ethyl acetate/petroleum ether) gave the sub-title compound, mp 94°-95°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (65.75 g, 0.232 mol) in THF (470 mL) and EtOAc (770 mL) was added Et3N (39 mL, 0.28 mol). The solution was cooled in an ice-bath and a solution of methanesulphonyl chloride (19 mL, 0.245 mol) dissolved in EtOAc (50 mL) was added (so that the internal temp<12° C.). After stiffing for 2 h in the ice-bath further additions of methanesulphonyl chloride (1.9 mL and 0.95 mL) and Et3N (3.9 mL) were made (so that by tlc there was no remaining starting material after a further 1 h of stiffing). NaHCO3 (550 mL) was added and the solution stirred for 20 mins then saturated brine (200 mL) was added and the phases were separated. The organic phase was dried (MgSO4) and evaporated with seeding to give a damp solid which was used in the next step without thorough drying.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][CH:25]=1)[CH2:9][CH:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[O:13]C(=O)[NH:11]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[NH2:11][CH:10]([CH2:9][C:8]1[CH:23]=[CH:24][CH:25]=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:7]=1)[CH:14]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[OH:13]
Reactant: CC(C)(C)Oc1cccc(CC2NC(=O)OC2c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1

Procedure:
To a solution of (4RS,5SR)-4-[3-(tert-butyloxy)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (6.6 g, 19.2 mmol) in ethanol (30 ml) was added 8N aqueous sodium hydroxide solution (9.6 ml, 76.9 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated under reduced pressure. Water (150 ml) was added, and the mixture was extracted with ethyl acetate (200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to give the objective substance (5.86 g, 96%).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2N)=[CH:11][CH:10]=1)=[O:8].[BrH:24]>CS(C)=O.C(=O)([O-])[O-].[K+].[K+].O>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[Br:24])=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2N)cc1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of sodium nitrite (1.40 g) in dimethyl sulfoxide (50 mL) is added 2′-amino-4′-methoxy-biphenyl-4-carboxylic acid methyl ester (2.61 g). After 5 minutes, the reaction mixture is treated with a solution of 4.7 mL hydrobromic acid (48%) in 50 mL dimethyl sulfoxide. The reaction is allowed to stir at room temperature for 2 h. The reaction mixture is diluted with a solution of 20.0 g potassium carbonate dissolved in 400 mL water. The product is extracted five times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with hexanes/ethyl acetate (99:1 to 86:14) to afford the title compound (1.00 g, 31%) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[NH:29]1[C:33]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)=[N:32][N:31]=[N:30]1>>[NH:32]1[C:33]([C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:36][CH:35]=2)=[N:29][N:30]=[N:31]1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(tetrazol-5-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/ethanol=5:1) C25H20N6O3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[CH3:25][C@H:23]1[NH:24][C@@H:19]([CH3:18])[CH2:20][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:31][CH:32]=2)=[O:27])[CH2:22]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (57.8 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Solvent: CCCCO
Product: Clc1nc(NCc2ccccc2)c2ncn(C3CCOC3)c2n1
Temperature: 95 °C

Procedure:
139 mg of the product obtained in Stage 1 above, 2 ml of butanol and 0.06 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 95° C. for 5 hours 30. The reaction medium is then left to return to ambient temperature and to crystallize, followed by separating, washing with 10 ml of isopropanol and drying under vacuum at approximately 50° C. In this way 157 mg of expected product is obtained in the form of white crystals.