Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[NH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>C(N(CC)CC)C>[CH3:7][C:6]([OH:8])([CH3:9])[CH2:5][NH:4][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 150 mL of dichloromethane, 10 mL of triethylamine and 6.7 g (0.075 mole) of 1-amino-2-methyl-2-propanol was added 10.4 g (0.05 mole) of 4-chloro-3-nitroquinoline. The solution was heated on a steam bath for about one hour then evaporated to remove the solvent. The residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was made basic with concentrated ammonium hydroxide to reprecipitate the product. The product was separated by filtration and recrystallized twice from ethanol to provide the novel yellow solid 2-methyl-1-[(3-nitro-4-quinolinyl)amino]-2-propanol, m.p. 244°-246° C. (dec.). Analysis: Calculated for C13H15N3O3 : %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N 16.1.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.CNC.C1COCC1.[I:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>O>[I:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:3]([CH3:4])[CH3:2])=[O:25]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(I)c1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(I)c1
Reaction time: 18 h

Procedure:
EDCI (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: Nc1ccsc1-c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Add slowly to a solution of 2-(4-bromo-phenyl)-thiophen-3-yl amine(0.6 g, 2.36 mmol) in dry dichloromethane (10 mL) at 0° C., DBU 1.41 mL (9.45 mmol) and isopropylsulfonyl chloride (0.53 mL, 4.72 mmol) (Temp. always <0° C.). Remove the ice bath and stir the mixture at RT overnight. Add satd. aq. NH4Cl (10 mL) and extract the solution with EtOAc (2×10 mL). Dry the combined organic layers and concentrate under vacuum. Purify the crude residue by flash chromatography (Silica gel-Hexane /EtOAc 4:1) to give 0.8 g (94%) of propane-2-sulfonic acid [2-(4-bromo-phenyl)-thiophen-3-yl]-amide.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=[O:35])[OH:33].CO>O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([O-:40])=[O:39])([C:34]([O-:36])=[O:35])[OH:33]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (2.25 g, 5.65 mmol) and citric acid (1.09 g, 5.65 mmol) were dissolved while heating in the mixture of methanol (100 ml) and water (10 ml). The solution was left to cool to room temperature to give sunitinib citrate. Melting point: 168-173° C. (Form I).
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Br[CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C.O>C(O)C>[CH3:2][C:1]1[S:4][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g of ethanethioamide was suspended in 50 mL of ethanol, to which 9.3 mL of ethyl 3-bromo-2-oxopropanoate was added dropwise at room temperature, and this suspension was stirred for one hour while heating it under reflux. The reaction mixture was cooled to room temperature and added to a mixture of ethyl acetate and water, followed by separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 2.30 g of ethyl 2-methyl-1,3-thiazole-4-carboxylate as white solid.
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[P:2](=[O:9])([O:6]CC)[O:3]CC.O>CCOCC>[PH:2](=[O:3])([O-:9])[O-:6].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[C+4:1].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6].[PH:2](=[O:3])([O-:9])[O-:6]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Solvent: O
Solvent: CCOCC
Product: O=[PH]([O-])[O-]
Product: [C+4]
Temperature: 12.5 °C

Procedure:
A fixed amount of base and certain solvent (see the table below for the type of base and solvent) are added to a 100 ml three-necked bottle under the protection of nitrogen, 10 ml solvent (the same as the above solvent) with a fixed amount of tetraethyl methylenediphosphonate (see the table below for molar weight) dissolved therein is dropwise added on the condition that magnetic stirring is performed and cold water bath is maintained within a range from 10 to 15° C., gas is discharged, the addition can be finished about half an hour later, and stirring is continued for reaction for 20 minutes. Then, 10 ml solvent (the same as the above solvent), with 2.1 g C-14 aldehyde having a formula (3B) (prepared in the embodiment 7, 0.010 mol) dissolved therein, is dropwise added on the condition that cold water bath is maintained at a particular temperature, the addition can be finished about half an hour later, and stirring is continued while the temperature is maintained for reaction for 20 minutes. 10 ml water and 20 ml ether are added to the reaction mixture solution, which is followed by stirring for 10 minutes and layering, organic layer is rinsed by 20 ml sodium hydride aqueous solution with the concentration of 10%, dried by magnesium sulfate and filtered, the solvent is dried by evaporation under reduced pressure to obtain 3,7,11-trimethyl-1,3,6,10-tetraene-dodecyl diethyl phosphonate crude product, which is light brown liquid. Measurement for gas phase content and calculation for yield are carried out, and the results are shown in the table below.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8](O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O.CCCCCC>[CH2:17]([O:1][C:2]1[CH:9]=[C:8]([O:14][CH2:11][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:3]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1O
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 167.8 %

Procedure:
To a solution of 2,4-dihydroxybenzaldehyde (5.00 g, 36.2 mmol) in N,N-dimethylformamide (30 ml) were added potassium carbonate (12.0 g, 86.9 mmol) and benzyl bromide (9.48 ml, 79.6 mmol). After stirring at room temperature for 3 hr 30 min, water (100 ml) and hexane (50 ml) were added, and the precipitated solid was collected by filtration. The solid was washed with water (3 ml×3) and hexane (5 ml) and dried under reduced pressure to give 2,4-bisbenzyloxybenzaldehyde (9.67 g, yield 84%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:13][C:12]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)[CH2:11][CH2:10]1)=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Solvent: CO
Product: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 775.8 %

Procedure:
To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (4.5 g) in MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). The stirring was continued at 50° C. overnight before the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (2.1 g). 1H NMR (DMSO 300 MHz) δ 8.81 (brs, 2H), 6.66 (d, J=2.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.53 (dd, J=2.1, 8.1 Hz, 1H), 3.51 (s, 3H), 1.38-1.35 (m, 2H), 1.07-1.03 (m, 2H).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[CH:25][C:26]=1[CH2:27]Cl>O>[CH3:32][O:31][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][C:24]=1[O:29][CH3:30])[CH2:27][N:16]([S:13]([C:10]1[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=1)(=[O:15])=[O:14])[CH2:20]2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
100 ml of an N,N-dimethylformamide solution containing 34.2 g (0.20 mol) of p-toluenesulfonamide, was dropwise added over a period of 60 minutes under cooling with ice to a suspension comprising 19.7 g (0.41 mol) of 50% oily sodium hydride and 60 ml of N,N-dimethylformamide. The reaction solution was stirred at room temperature for 30 minutes at 60° C., and then 300 ml of an N,N-dimethylformamide solution containing 47 g (0.20 mol) of 4,5-bischloromethyl veratrol was dropwise added over a period of 90 minutes at 60° C. The reaction solution was stirred at room temperature for 3 hours, and then poured into 2000 ml of water. The precipitated crystals were collected and washed with water to obtain 60 g (yield: 90.0%) of the above identified compound.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:7][CH2:6][O:5][C:3]([C:2]([O:17][C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1)([CH3:9])[CH3:8])=[O:4]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-bromo-2-methyl-propanoate and p-chlorophenol was dissolved in dry acetone and treated with potassium carbonate. After stirring at rt for 30 min., the mixture was refluxed for 16 h. The reaction mixture was poured into water and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, hexanes:EtOAc, 9:1, 6:1 to 3:1) to give the desired product, which was used in the following step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl.Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of commercially-available 4-bromomethyl benzenesulfonyl chloride (1.0 g, 3.71 mmol) in dichloromethane (8 ml) at 0° C. under an argon atmosphere, is added triethylamine (0.575 ml, 4.1 mmol), in one portion, followed by morpholine (0.359 ml, 4.1 mmol). The reaction mixture is stirred for 20 h, warming up slowly to room temperature. The reaction mixture is then diluted with 2N HCl aq (40 ml) and extracted with dichloromethane (20 ml), dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound. Used crude in next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-chlorophenylboronic acid. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:24]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[CH:3]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1

Procedure:
In analogy to Example 70.4–6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, glutaric anhydride and Hünig's base in DMF there was obtained (RS)-4-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid, which was subsequently converted via (RS)-4-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid into (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenylcarbamoyl)-butyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C.O>[Br:15][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: COc1ccc(Br)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(Br)cc1Br
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 5-bromo-2-methoxypyridine (0.564 g, 3.0 mmol) and sodium acetate (0.246 g, 3.0 mmol) in acetic acid (3 mL) was added bromine (0.27 mL, 5.25 mmol), and the mixture was stirred at 80° C. for 3 hours, and then at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc, and the combined organic layers were washed with saturated aqueous Na2CO3 and saturated aqueous Na2S2O3. The organic layer was concentrated and dried under high vacuum to give 3,5-dibromo-2-methoxy-pyridine.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccc1
Product: O=C1C=CC(=O)N1c1ccccc1

Procedure:
Aniline, a primary aromatic amine, is a hazardous carcinogenic liquid. It is difficult to handle aniline safely during reactive extrusion, which is the most economical way to produce imides on a large scale. Often maleic anhydride is reacted with aniline to obtain the N-phenylmaleimide monomer, which is then copolymerized with other monomers in solution or emulsion polymerization processes.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8]2[O:13][C:11](=[O:12])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.C1(O)C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[C:4]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=Nc2ccccc2)O1
Solvent: Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
10 g (0.058mole) of N-phenyl isomaleimide is dissolved in 100 ml of methylene chloride. To the solution are added 0.400 g (0.004 mole) of phenol and 0.4 ml (0.290 g; 0.0029 mole) of triethylamine. The reaction mixture is stirred at 20-25° C. for 3 hours, and is then extracted by shaking twice with 10% aqueous NaOH solution; it is washed twice with water, dried over sodium sulphate and the solvent is removed in a rotary evaporator. The residue is dried at 40° C. in vacuo to obtain 9.7 g (97% of theory) of yellow crystalline N-phenyl maleimide, m.p. 85-86° C.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([C:35](=O)[CH2:36]Br)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[F:23][C:24]([F:39])([F:40])[C:25]1[CH:26]=[C:27]([C:35]2[N:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=3[CH3:17])[S:22][CH:36]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: Cc1ccc(C([O-])=S)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cs2)c(C)s1
Yield: 5 %

Procedure:
Methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl]1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate: A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 101 mg (0.3 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethane-1-one in a manner similar Example 8, step (a) to give methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (7 mg, 5%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ 8.75 (s, 1H), 8.73 (m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3.87 (s, 3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H11NO2S3F6, 484.0 (M+H), found 484.0.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])[CH3:3].[CH3:11][N:12]=[C:13]=[O:14]>CN(C)C1C=CN=CC=1.C1C=CC=CC=1>[CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:13]([NH:12][CH3:11])=[O:14])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CNC(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A 50 milliliter flask with a magnetic stirring bar, addition funnel, thermometer and condenser/drying tube was charged with 3.0 grams (0.021 mole) of 5-(1,1-dimethylethyl)-3-isoxazolamine, a few crystals of 4-dimethylaminopyridine and 20 milliliters of benzene. The funnel was charged with 2.3 grams (0.040 mole) of methyl isocyanate in 5 milliliters of benzene, which was added dropwise over five (5) minutes. After standing overnight, the mass of crystals which formed was isolated by filtration, washed with hexane, and air dried to give 3.0 grams of white powder of 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methylurea, M.P. 188°-189° C.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[S:36]([CH3:39])(=[O:38])=[O:37])=O.[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([NH:48][C:49]([NH2:51])=[O:50])[CH:45]=[CH:46][CH:47]=1.[C:54]([O:60][CH2:61][CH:62]=[CH2:63])(=[O:59])[CH2:55][C:56]([CH3:58])=O>CC(OC)(C)C>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH:26]2[C:55]([C:54]([O:60][CH2:61][CH:62]=[CH2:63])=[O:59])=[C:56]([CH3:58])[N:48]([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([C:41]([F:52])([F:53])[F:40])[CH:43]=3)[C:49](=[O:50])[NH:51]2)=[C:29]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:30]=1)#[N:33]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C=O
Reactant: C=CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: COC(C)(C)C
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
The reaction was carried out under argon. Triethyl phosphate (22.98 g, 126 mmol) and diphosphorus pentoxide (11.94 g, 84.1 mmol) were stirred at 50° C. overnight. The mixture was then diluted with MTBE (450 ml), and 4-formyl-3-(methylsulfonyl)benzonitrile (22.00 g, 105 mmol; Example 4A), 1-[3-(trifluoromethyl)phenyl]urea (21.47 g, 105 mmol) and allyl acetoacetate (22.42 g, 158 mmol) were added. The mixture was stirred under reflux overnight. Since the reaction was incomplete, the reaction mixture was concentrated by distillative removal of 350 ml of MTBE. The mixture was then heated under reflux for a further 4 h. For work-up, the solvent was removed under reduced pressure, and the residue was suspended in diethyl ether and then filtered off with suction. The solid was washed with dist. water (350 ml) and then with diethyl ether (50 ml). This gave 34.74 g (64% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O>[C:7]([C:5]1[S:6][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])=[CH:3][CH:4]=1)#[N:8]
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C#N)s1
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol) in 50 ml of dioxane is degassed with argon, tetralkis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid (2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) are successively added and the mixture is stirred for 16 hours at 85° C. Extractive work-up (2×50 ml dichloromethane and 2×30ml water). The organic phase is dried over sodium sulfate, filtrated and evaporated. The residue (4.05 g) is purified via flash chromatography on silica (eluent: 100% hexane>hexane/ethyl acetate 96:4 gradient) to give 1.37 g of 2-(5-cyanothien-2-yl)anisole (96%). M+=215.