Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:21]=2[CH3:22])[C:17]=1Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:35]([CH3:42])=[C:36]2[C:41]=1[O:40][CH2:39][CH2:38][CH2:37]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:21]=2[CH3:22])[C:17]=1[C:34]1[C:35]([CH3:42])=[C:36]2[C:41](=[C:32]([F:31])[CH:33]=1)[O:40][CH2:39][CH2:38][CH2:37]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 110 °C
Yield: 35.7 %

Procedure:
A solution of (S)-ethyl 2-(tert-butoxy)-2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.207 g, 0.460 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.151 g, 0.517 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.081 g, 0.070 mmol) in anhydrous DMF (4 mL) was treated with 2.0 M K2CO3 (0.55 mL, 1.100 mmol), degassed by nitrogen stream, then sealed and heated (110° C., microwave) for 60 min. The reaction slurry was filtered though a 0.45 micron syringe tip filter, and the filtrate was purified by biotage silica gel column, eluting with 0%-20% ethyl acetate in hexanes. Individual atropisomers eluted separately, and the early eluting isomer was concentrated under reduced pressure, affording the single isomer, (2S)-ethyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.095 g, 0.164 mmol, 35.7% yield) as a white glassy solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:12]=[C:13]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)c1Br
Yield: 83 %

Procedure:
3-Trifluoromethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-trifluoromethylbenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 113°-115° C., yield 83%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][CH:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.CCOC(C)=O>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([CH:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:9](=[O:10])[CH2:8][S:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: O=C1CSC(c2cccc(F)c2)N1CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CSC(c2cccc(F)c2)N1CCCN1CCOCC1
Temperature: 60 °C
Yield: 83.2 %

Procedure:
3-(3-Chloropropyl)-2-(3-fluorophenyl)-thiazolidin-4-one (1.15 mm, 0.315 g) and morpholine (1.15 mm, 0.1 g) are mixed in 20 mL DMF in the presence of N,N-diisopropylethylamine (1.15 mm, 0.2 mL) and a catalytic amount of KI. The mixture is heated at 60° C. for 24 hours, then 20 mL of EtOAc is added to the mixture. The organic layer is washed with brine and dried. The solvent is evaporated, and the residue is triturated with hexane, 0.31 g of the product is isolated (84%).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1cccc2ccccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCCCOc1cccc2ccccc12

Procedure:
A solution of 10.0 g N-[8-(1-naphthyloxy)octyl]phthalimide, prepared as above, and 200 ml of ethanol and 3.2 ml of hydrazine hydrate was refluxed for 18 hours. The solution was evaporated to about 100 ml, and diluted with 200 ml of water, then basified with aqueous potassium hydroxide and extracted with hexane. The extract was washed, dried and evaporated to give the title compound as an oil which was converted to the hydrochloride, mp 90.5°-92°.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][N:33]=3)=[CH:38][C:39]2=[O:55])=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Yield: 93 %

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 4-(5-fluoro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 2a) instead of preparation 1c.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=2[O:21][CH3:22])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]>CO.C1COCC1.[Pd]>[CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=2[O:21][CH3:22])[NH2:18])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CNC(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)cc1-c1cccc(CNC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
2-(3-(N-Isopropylamino)methylphenyl)-4-nitroanisole (120 mg, 0.39 mmol) was dissolved in MeOH/THF (5 mL:5 mL), and 10% Pd/C (20 mg) was added. The slurry was stirred at room temperature under an atmosphere of H2 for 16 h. The slurry was then filtered and evaporated to afford 3-[3-(N-isopropylamino)methylphenyl]-4-methoxyaniline as a brown oil (101 mg, 0.37 mmol, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[NH4+:23].[OH-]>O1CCOCC1.O>[NH2:23][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(NS(=O)(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Temperature: 95 °C

Procedure:
To a suspension of 4-chloro-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide (0.22 g) in dioxane (2 mL) was added NH4OH (3 mL). The reaction mixture was heated to 95° C. for 8 h. The mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The extract was dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 hexane/EtOAc) afforded 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]#[N:24])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:23]#[N:24])[CH:20]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C#N)cc(Br)c3O2)cc1
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C#N)cc(-c4ccccc4C)c3O2)cc1
Yield: 99 %

Procedure:
Treatment of 3-bromo-4-hydroxybenzonitrile (10.0 g, 50.0 mmol) with potassium carbonate (27.9 g, 200 mmol) and allyl bromide (7.96 g, 66.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromo-4-hydroxybenzonitrile. Treatment of 3-allyl-5-bromo-4-hydroxybenzonitrile (4.63 g, 19.0 mmol) with 3-chloroperoxybenzoic acid (6.2 g, 35.93 mmol, 77%) followed by potassium carbonate (6.56 g, 47.5 mmol) generally according to the procedure described for Intermediate 9 afforded 1.30 g (426) of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile (1.3 g, 5.0 mmol) with p-toluenesulfonyl chloride (1.02 g, 5.4 mol) generally according to the procedure described for Intermediate 10 gave 1.5 g (72%) of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.3 g, 2.20 mmol) generally according to the procedure described for Intermediate 35 afforded 0.33 g, (99%) of (±)-[5-cyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.26 g, 4.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (74%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of the azide with polymer-supported triphenylphosphine (0.24 g, 0.67 mmol) according to the procedure described in Example 154 afforded 0.118 g (53%) of (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile as a white solid, hydrochloride salt. mp 127-129° C.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][CH2:9][C@H:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C

Procedure:
A solution of 3.58 g of tert-butyl 4(S)-(2(S)-benzyloxymethyl-3-methylbutyl)-2,2-dimethyl-oxazolidine-3-carboxylate in 100 ml of tetrahydrofuran is hydrogenated at room temperature in the presence of 0.720 g of 10% Pd/C over 1 hour. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a yellowish oil. Rf=0.28 (1:2 EtOAc-heptane); Rt=4.48 (gradient I).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:30])([CH3:29])[C:23]=4[CH:31]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:32]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH3:29])([CH3:30])[C:23]=4[CH:31]=3)=[O:32])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=[CH:9][C:10](Cl)=[O:11].O1CCC[CH2:20]1.C[Mg]Br>C1(C)C=CC=CC=1>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]=[CH:9][C:10](=[O:11])[CH3:20]
Reactant: C1CCOC1
Reactant: O=C(Cl)C=CCc1ccccc1-c1ccccc1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: CC(=O)C=CCc1ccccc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
10.0 g. (0.039 mole) of crude acid chloride from Example 5, Step (c), is dissolved in 200 ml. of dry tetrahydrofuran and the solution placed in a 500 ml. round bottom flask fitted with a septum inlet and magnetic stirrer, and held under a nitrogen atmosphere. The solution is cooled to -30° C. in a dry ice/isopropanol bath and 19.5 ml (0.039 mole) of a commercial 2M methyl magnesium bromide solution in dry toluene is added, dropwise, over 30 minutes. After the addition is complete, the mixture is allowed to warm to room temperature and then stirred for 1 hour. The reaction is quenched by the addition of 20 ml. of saturated ammonium chloride solution and the organic layer is separated. The aqueous layer is extracted twice with 20 ml. portions of ether and the combined organic extracts are then dried over anhydrous magnesium sulphate and evaporated to yield the heading compound, m.p. 130° to 133° C., after recrystallization from petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=O)[CH2:12][N:13]([CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][N:13]([CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCCCCCCN(CC)CC(=O)Nc1ccc(OC)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCN(CC)CCNc1ccc(OC)c(Cl)c1

Procedure:
In a manner similar to Preparation 2 react N-(3-chloro-4-methoxyphenyl)-2-[ethyl(heptyl)amino]acetamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([N:32]=[C:33]=[O:34])=[CH:26][C:25]=2[O:24]1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([NH:32][C:33]([NH:2][CH2:3][C:4]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:5]=3[C:6](=[O:22])[N:7]([CH:14]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]3=[O:21])[C:8]4=[O:13])=[O:34])=[CH:26][C:25]=2[O:24]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc5c(c4)OCO5)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 77.7 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-methylenedioxyphenyl isocyanate (0.25 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.56 g of the product in 81% yield: mp 216-218° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.69 (d, J=5.8 Hz, 2H), 5.16 (dd, J=12.4 Hz, d=5.1 Hz, 1H), 5.93 (s, 2H), 6.67-6.70 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 7.75-7.88 (m, 3H), 8.67 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.7, 48.9, 100.5, 100.6, 108.0, 110.4, 121.8, 127.2, 131.6, 133.6, 134.7, 134.8, 140.3, 141.5, 147.1, 155.3, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C22H18N4O5: C, 58.67; H, 4.03; N, 12.44. Found: C, 58.35; H, 3.95; N, 12.25.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=[O:27])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1([CH2:37]N)[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[F:33][C:2]([F:1])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:28][CH2:37][CH:34]4[CH2:36][CH2:35]4)=[O:27])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: NCC1CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)OCC5CC5)c4)ccc32)c1
Temperature: 25 °C

Procedure:
To a solution of 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid (20.0 mg, 0.0440 mmol) and cyclopropylmethylamine (6.3 mg, 0.088 mmol Aldrich, Cat. No. 359521) in N,N-dimethylformamide (DMF) (1 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (23 mg, 0.053 mmol, Adv. ChemTech. Cat. No. RC8105) and N,N-diisopropylethylamine (23 μL, 0.13 mmol). The reaction mixture was stirred at r.t. 2 h., then diluted with MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=508.2.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.[F:37][C:38]([F:51])([F:50])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46]>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([N:47]=[C:48]=[S:49])=[O:46].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:48]([NH:47][C:45](=[O:46])[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[C:38]([F:37])([F:51])[F:50])=[S:49])=[C:31]([F:36])[CH:30]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 80%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][Mg]Br)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[S:20])[CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Br[Mg]CCC1C=CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: S=C(CCC1C=CCCC1)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The obtained THF solution of 2-(2-cyclohexene-1-yl)ethyl magnesium bromide was dropped into 25 ml of anhydrous THF solution including 1.8 g of p-chlorophenyl isothiocyanate at 0° C. The resulting solution was stirred at 0° C. for 30 minutes, and stirred at room temperature for an additional 30 minutes. The solution was added with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.2 g of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([N:7]4[CH2:8][CH2:9][CH2:10][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][CH2:6]4)=[CH:21][CH:20]=3)[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: C=CCN1CCCN(c2ccc(C(=O)OCC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCN1CCCN(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 14.5 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-prop-2-enyl-1,4-diazepan-1-yl)benzamide was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.288 g, 1 mmol, 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) and a 2M solution of trimethylaluminium (1.250 mL, 2.50 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum, which solidified on trituration with DCM/Ether to afford the title compound (0.071 g, 14.50%).