Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]#[N:7])[CH3:2].C([Li])CCC.[C:13]1([CH2:23][CH2:24][CH2:25]I)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(Cl)Cl>O1CCCC1>[CH2:1]([O:3][CH:4]=[C:5]([C:6]#[N:7])[CH2:25][CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: ICCCc1cccc2ccccc12
Reactant: CCOC=CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC=C(C#N)CCCc1cccc2ccccc12
Temperature: 25 °C
Yield: 26.9 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 1.5 mL (0.014 mole) of 3-ethoxyacrylonitrile in 45 mL of tetrahydrofuran was cooled to about -110° C., and 6.2 mL (0.015 mole) of 2.5M n-butyllithium in hexanes was added dropwise at a rate to keep the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was stirred for about ten minutes, and then a solution of 4.0 grams (0.014 mole) of 3-(naphth-1-yl)propyl iodide in 15 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at about -78° C. for two hours. After this time the reaction mixture was allowed to warm to ambient temperature as it stirred for about 16 hours. The reaction mixture was concentrated under reduced pressure, yielding a dark residual oil. The oil was passed through a short column of silica gel using methylene chloride as the eluant. The eluate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 2:1 methylene chloride and petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.0 gram of 1-ethoxy-2-cyano-5-(naphth-1-yl)-1-pentene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.044 g, 0.11 mmol) and EtOH (4.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 6%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.020 g, 33%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.5 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.78 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H) and 3.53 (s, 2H) (C6H4CH2N and NCH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 7.24 (d, J=3.5 Hz, 1H, thiazole-H), 7.48 (m, 3H, 3,5-C6H4— and thiazole-H), 8.12 (d, J=9.7 Hz, 2H, 2,6-C6H4—), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.46 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:27]#[N:28])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:29])(OC)=O.CS(C)=O.[Cl-].[Na+]>O>[C:27]([C:9]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:19])[F:20])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:12]=2)[CH2:10][CH2:5][C:6](=[O:29])[CH2:7][CH2:8]1)#[N:28]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC(=O)CC1
Temperature: 145 °C
Yield: 23.9 %

Procedure:
A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one (0.98 g, 2.4 mmole), dimethyl sulfoxide (10 mL), water (0.62 mL) and sodium chloride (0.62 g) under an argon atmosphere was heated at 145° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer washed with water, was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 20-30% ethyl acetate/hexanes. The isolated residue was dissolved in ethyl acetate, this was washed twice with dilute sodium hydroxide, once with water, once with brine and then was dried and evaporated to yield a solid (0.2 g, 23.6%): m.p. 76°-78.5° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:33]1[N:38]=[CH:37][N:36]=[CH:35][CH:34]=1>CN(C=O)C>[N:36]1[CH:35]=[CH:34][CH:33]=[N:38][C:37]=1[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1
Reactant: Clc1ccncn1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(c3ncccn3)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (6 mL) were added diisopropylethylamine (366 mg, 2.84 mmol) and 6-chloropyrimidine (128 mg, 1.11 mmol) at ambient temperature and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5/hexane-EtOAc=¼) to give ethyl (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (141 mg, 46%) as an amorphous powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:21][C:22]2[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=2[Cl:29])=[N:11][N:10]=1>CN(C=O)C>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:10][N:11]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3ccnc3)c2c1
Temperature: 80 °C
Yield: 41.3 %

Procedure:
A solution of imidazole (0.814 g, 11.21 mmoles) in dry DMF (30 ml) was stirred under N2 at room temperature and added with NaH (8.46 mmoles). After 30 minutes 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (2 g, 5.64 mmoles), prepared as described in example 45, in dry DMF (30 ml) was added. The mixture was heated at 80° C. for 3.5 hours, cooled, poured into water/ice and extracted three times with CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: ethyl acetate) yielding 0.9 g of the title compound (yield: 50%). m.p. 250° C.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH2:38])=[CH:26]2>C(O)CCC>[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)=[CH:26]2
Reactant: NCc1cc2cccc(F)c2nc1-c1ccccc1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3)nc12
Temperature: 110 °C

Procedure:
To a reaction flask was added 6-bromopurine (19 mg, 95 μmol, 1.2 eq), diisopropylethylamine (42 μl, 238 μmol, 3 eq), (8-fluoro-2-phenylquinolin-3-yl)-methanamine (20 mg, 79 μmol, 1 eq), and n-butanol (0.75 mL). The reaction was heated to 110° C. for 8 h. The reaction was cooled to rt and the solvent was removed in vacuo. The compound was purified by reverse phase HPLC. The fractions were concentrated and freebased with sat. NaHCO3. The organic layer was extracted into DCM, dried over MgSO4, filtered, and concentrated to afford a white solid,
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14].[OH-].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>CS(C)=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13](=[O:15])[CH3:14]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)c1c(C)nc2ccccc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-amino-2-methyl-3-quinolinyl)-ethanone in dimethylsulfoxide (150 ml) was added to a stirred slurry of pulverized 85% potassium hydroxide (7 g) in dimethylsulfoxide (40 ml). This mixture was stirred at ambient temperature for twenty minutes, and thereafter a solution of o-fluorobenzylchloride (15.2 g) in dimethylsulfoxide (40 ml) was added dropwise. The mixture was stirred for two hours and allowed to stand overnight at room temperature. Thereafter, it was poured onto ice and diluted with water to form a tacky lump. This was allowed to stand for fifteen minutes, and the aqueous dimethylsulfoxide was decanted. The tacky precipitate was dissolved in dichloromethane, washed with water (3×) and saturated sodium chloride solution, and dried over sodium sulfate. Removal of the sodium sulfate by filtration and the solvent by evaporation gave 26.5 g of viscous oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9](=S)([S:15]CC(O)=O)[S:10][CH2:11][C:12](O)=[O:13].C(N(CC)CC)C>CC(O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[S:15])[CH3:3]
Reactant: O=C(O)CSC(=S)SCC(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)CN1C(=O)CSC1=S
Yield: 80.8 %

Procedure:
Separately, glycine ethyl ester hydrochloride (140 mg, 1 mmol) and bis(carboxymethyl) trithiocarbonate (224 mg, 1 mmol) were dissolved in 2-propanol (6 mL), triethylamine (0.6 mL) was added thereto, and the mixture was heated to reflux for 1 hour while stirring. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/1 (volume ratio)) as an eluent, to give ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate in a yield of 177 mg (yield 80.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.CS(C)=O.CC(C)([O-])C.[Na+]>O>[Cl:16][C:17]1[C:22]([O:15][CH:13]2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1nccnc1Cl
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CC(Oc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 3-hydroxy-azetidine-1-carboxylic acid benzyl ester (5.19 g, 27.4 mmol, purchased from Ace Synthesis), 2,3-dichloropyrazine (4.116 g, 27.6 mmol, Oakwood) and DMSO (40 mL) was added sodium tert-butoxide (2.64 g, 27.4 mmol) in three portions. The solution was allowed to stir at room temperature. After 2 hours, the reaction was poured into water (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ether layers were washed with water (50 mL), brine (50 mL), and then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with 0% to 20% EtOAc in hexane, to provide benzyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (5.4 g, 61.6% yield), as a yellow oil. MS (ESI) m/z 320.1 (MH+). ICSO (uM): 1.33.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].[CH3:23][N:24](C)[CH:25]=O>>[CH3:23][N:24]([CH3:25])[C:20](=[O:21])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1]
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: CN(C)C=O
Product: CN(C)C(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl

Procedure:
A solution of 3.5 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride in 35 ml dimethylformamide is heated at 100° C. for 4 hr. The reaction mixture is then poured into ice, acidified and extracted with ether (4×200 ml). The organic extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to afford an oil which crystallizes on trituration with ether/petroleum ether. Chromatography on silica gel affords N,N-dimethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide mp 116° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[CH3:9])=[CH:13][CH:12]=1
Reactant: CN1CCCC1CCCl
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCSc1ccc(O)cc1
Yield: 44.3 %

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (2.0 g, 13.5 mmole), 4-hydroxythiophenol (1.7 g, 13.5 mmole), potassium carbonate (18.7 g, 135.4 mmole) and DMF (26 mL) were combined, yielding 1.42 g (5.98 mmole, 44%) of the desired compound.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.C[O-].[Na+]>CO.O1CCOCC1>[NH:31]1[CH2:32][CH2:33][CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:41])([F:1])[F:42])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.965 g, 1.65 mmol) was dissolved in methanol (1.0 mL). To the solution was added 4 N HCl in dioxane (1.5 mL). The mixture was stirred at r.t. for 2 h. The mixture was cooled with ice-water, and was carefully neutralized with sodium methoxide in methanol solution (25% w/w, about 4.375 M, 1.38 mL) to pH about 8. The volatiles were removed under reduced pressure. The residue was dried in vacuo to afford the desired product which contained residual NaCl, and was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=485.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19](O)[CH3:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]([N:50]1[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]1=[O:51])[CH3:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2
Reactant: CC(O)c1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2c(Cl)cccc2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol (0.9927 g, 3.290 mmol) in tetrahydrofuran (32.90 mL, 3.290 mmol) were added triphenylphosphine (2.589 g, 9.870 mmol), phthalimide (1.452 g, 9.870 mmol), and diisopropyl azodicarboxylate (1.943 mL, 9.870 mmol). The reaction mixture was stirred at room temperature. After 1.5 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc for 10 min as eluent to give 2-(1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (1 H, s), 7.98-8.04 (1 H, m), 7.85-7.90 (1 H, m), 7.82 (1 H, s), 7.74-7.81 (2 H, m), 7.65-7.71 (2 H, m), 7.21-7.33 (2 H, m), 7.12-7.19 (2 H, m), 5.76-5.82 (1 H, m), 1.83 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 431.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[O:16]=[C:13]1[CH:12]=[N:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:15]=2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1)c1cccc(OC(F)(F)F)c1
Yield: 20 %

Procedure:
Method G1 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-trifluoromethoxybenzoyl chloride to afford the title compound as a white solid (35 mg, 20%).
Reaction SMILES: FC1C=CC=C(F)C=1O[C:5]1[O:6][C:7]([CH3:16])([CH3:15])[C:8]([CH3:14])([CH3:13])[S:9](=[O:12])(=[O:11])[N:10]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C@@H:28]([NH:30][C:5]2[O:6][C:7]([CH3:15])([CH3:16])[C:8]([CH3:13])([CH3:14])[S:9](=[O:11])(=[O:12])[N:10]=2)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CC1(C)OC(Oc2c(F)cccc2F)=NS(=O)(=O)C1(C)C
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A mixture of 194 mg of 2-(2,6-difluorophenoxy)-5,5,6,6-tetramethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 737 mg of (S)-1-phenylethylamine was stirred at room temperature for 16 hours and then purified in a purification laboratory by means of preparative HPLC. The combined product-containing fractions were alkalized with 25% aqueous ammonia solution and extracted three times with 30 ml of ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. This gave the product (96 mg) with a molecular weight of 310.4 g/mol (C15H22N2O3S); MS (ESI): m/e=311 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:17][C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=C1C(Cc2ccncc2)c2cccnc2N1c1ccc(Cl)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1N(c2ccc(Cl)cc2)c2ncccc2C1(Cc1ccccc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1,3-dihydro-1-(4-chlorophenyl)-3-(4-pyridinylmethyl)-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g, 8.93 mmol) and 20 ml 1N NaOH was treated with enough MeOH to effect solution. The mixture was treated with benzyl chloride (1.24 g, 9.82 mmol) and stirred at room temperature for 24 h. The resulting solid was collected by filtration, washed with water, and dried in vacuo to give the desired product in 87% (3.30 g) yield; mp 182°-185° C.; IR(nujol): 1727 cm-1 (CO); 1H NMR(CDCl3TMS): d 3.29 (dd, 2H, Phe-CH2), 3.4-3.-7 (g, 2H, Pyr-CH2), [6.75 (d, J=8.8, 2H), 6.9 (m, 2H), 7.1 (m, 6H), 7.35 (d, J=8.4, 2H), 7.61 (d, J=7.3, 1H), 8.05 (d, J=6.6, 1H), 8.33 (d, J=6.2, 2H), Ar]; mass spec m/e 426(M+1). Anal calcd for C26H20N3OCl, MW 425.92: C, 73.32; H, 4.73; N,
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:32]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:34])([F:35])[F:23])[CH:26]=3)=[O:33])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and α,α,α-trifluoro-m-tolyl-isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-(3-trifluoromethyl-phenyl)-urea (0.58 g, 66%): mp 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.91 (98%); 1H NMR (DMSO-d6): δ 2.00-2.05 (m, 1H), 2.28-2.39 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.93 (m, 1H), 3.01 (s, 3H), 4.32-4.53 (dd, J=8, 20 Hz, 2H), 4.67 (s, 2H), 5.11-5.18 (dd, J=5.9, 15.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.44-7.57 (m, 3H), 7.65 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 8.81 (s, 1H), 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 22.56, 31.17, 34.76, 46.25, 48.36, 51.60, 115.71, 118.50, 121.78, 123.15, 126.42, 128.49, 128.83, 129.44, 129.81, 131.94, 133.59, 140.14, 141.33, 155.41, 168.00, 171.01, 172.82. Anal Calcd for C23H21F3N4O4: C, 58.23; H, 4.46; N, 11.81, F, 12.01. Found: C, 58.06; H, 4.30; N, 12.09, F, 11.59.