Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=[CH:12][C:4]=2[O:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:3]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=[CH:12][C:4]=2[O:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCCCCCCCc1ccc2oc(C(=O)OCC)c(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCc1ccc2oc(C(=O)O)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of Ethyl 3-methyl-5-octylbenzo[b]furan-2-carboxylate (1.44 g) in ethanol (20 ml) was added 10% NaOH aqueous solution (2.2 ml), and stirred for 2 hours at ambient temperature, and evaporated under reduced pressure. The residue was adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3-Methyl-5-octylbenzo[b]furan-2-carboxylic acid (1.00 g).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:12]=1.[N+:21]([C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([C:33]([F:36])([F:35])[F:34])[C:25]=1Cl)([O-:23])=[O:22].O1CCCC1.C(O)(C)(C)C>C(O)(C)(C)C.O.C(O)(=O)C>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:25]2[C:26]([C:33]([F:35])([F:36])[F:34])=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])[S:9][CH:10]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2nc(-c3ccc(Cl)cc3Cl)cs2)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 7.4 g (66 mmol) of potassium tert-butylate in 50 ml of tert-butanol was added dropwise to a vigorously stirred mixture of 8.0 g (33 mmol) of 2-amino-4-(2,4-dichlorophenyl)thiazole, 9.8 g (37 mmol) of 2,4-dinitro-6-trifluoromethylchlorobenzene and 100 ml of tetrahydrofuran/tert-butanol (1:2) at 0° to 5° C. in such a way that addition was complete after 1 hour. After a further hour at 0° C., the mixture was slowly warmed, over the course of about 2 hours, to 20° C. The mixture was then adjusted to pH 4 with glacial acetic acid and diluted with about 1 l of water. The precipitate was separated off, washed with water until neutral and dried. Yield: 90%; melting point 125° to 130° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1-n1cncn1
Temperature: 50 °C

Procedure:
2-Fluoro-5-nitro-benzonitrile (1.0 g, 6.0 mmol) was dissolved in anhydrous DMF (6 mL), then treated with [1,2,4]-triazole (0.46 g, 6.7 mmol), cesium carbonate (2.9 g, 8.9 mmol), and heated (50° C.) overnight. After cooling to RT, the mixture was treated with water and the solid title compound collected by filtration (1.14 g). MS (ESI+) for m/z 216 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH3:26])[C:4](=[O:27])[CH:3]=1.[CH2:28]([SH:31])[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[C:2]([S:31][CH2:28][CH2:29][CH3:30])=[CH:3][C:4](=[O:27])[N:5]([CH2:24][CH2:25][CH3:26])[C:6]2=[O:23])=[CH:10][CH:11]=1)#[N:22]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 6-chloro-1-(2'-cyanobiphenyl-4-yl)methyl-3-propylpyrimidine-2,4(1H,3H)-dione (0.7 g), propylmercaptan (0.2 ml) and potassium carbonate (0.51 g) in acetonitrile (12 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness to give colorless syrups (0.77 g, 100%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:42])[CH2:40][CH3:41]>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([C:39](=[O:42])[CH2:40][CH3:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)CC)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To 2 g (4.5 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide Example (586) dissolved in 25 ml of ethyl acetate and cooled to -5° C., was added 0.8 g (9 mmole) of pyridine and, finally, 0.8 g (9 mmole) of propionyl chloride was added. After 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 0.5 g of the desired compound, mp 152°-154° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:18]([CH3:19])[CH2:17][NH:16][CH:15]([CH2:20][CH2:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>CN(C=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:16]2[CH2:17][C@H:18]([CH3:19])[N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:23])[C@@H:15]2[CH2:20][CH2:21][CH3:22])=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Solvent: CN(C)C=O
Product: CCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)[C@@H](C)CN1C(=O)Nc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 4-[4-Amino-quinazolin-7-ylmethyl]-5-methyl-3-oxo-2-propyl-piperazine (12 mg, 0.04 mmol, EXAMPLE 888) in 2 mL of DMF is added 4-chlorophenyl isocyanate (9 mg, 0.06 mmol). After stirring at 100° C. for 1 h, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyophilized to provide the title compound (16 mg, 0.03 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.74 (bs, 2H), 8.77 (m, 2H), 8.35 (m, 1H), 7.56 (m, 2H), 7.46 (d, 2H), 7.21 (d, 2H), 5.00-4.38 (m, 3H, rotamers), 4.20 (m, 1H, rotamers), 3.58 (m, 1H, rotamers), 3.10 (m, 1H), 1.86 (m, 2H), 1.33 (m, 2H), 1.08 (m, 3H, rotamers), 0.90 (t, 3H). ISP MS, [M+H]+=467, 469 (Cl pattern).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phenoxy-acetic acid ethyl ester (9.1 mL) is added to chlorosulfonic acid (15 mL) at 0° C. dropwise. The reaction is stirred at 0° C. for 30 min, it is allowed to warm to room temperature. After 2 hrs, the reaction mixture is poured into ice, solid product is collected by filtration and dried under vacuum.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](N(C)C)=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C(OC(=O)C)(=O)C>[CH2:2]1[N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:17](=[O:18])[NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=32)[CH2:3]1
Reactant: CN(C)C(=O)Nc1ccccc1N1CCc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: O=C1Nc2ccccc2N2CCc3cccc1c32

Procedure:
N-[2-(Indolin-1-yl)phenyl]-dimethylaminocarboxamide (37 gm; 0.13 moles) in acetic anhydride (140 ml) was refluxed for 30 minutes. The mixture was cooled to ~50° C., and thereafter concentrated on a rotary evaporator to about 80 ml while crystallization occurred. The red solid was filtered and washed with ether. Recrystallization from chloroform (500 ml) afforded red-orange crystals: 21.3 gm (68%), m.p. 213.5°-214.5° C.
Reaction SMILES: [O-2:1].[La+3:2].[O-2:3].[O-2:4].[La+3].[O-2].[Cr+3:7].[O-2].[O-2].[Cr+3]>O>[Cr:7]([O-:4])([O-:3])=[O:1].[La+3:2].[Cr:7]([O-:4])([O-:3])=[O:1].[Cr:7]([O-:4])([O-:3])=[O:1].[La+3:2]
Reactant: [O-2]
Reactant: [Cr+3]
Agent: *CC*
Agent: [La+3]
Solvent: O
Product: O=[Cr]([O-])[O-]

Procedure:
A hundred parts of lanthanum oxide having an average particle diameter of 1 μm, 125 parts of chromium oxide having an average diameter of 1 μm, and 100 parts of ion-exchanged water were put into a polyethylene pot together with zirconia balls, subjected to pulverization and mixing for 20 hours, and then dehydrated by filter pressing. A resultant cake was dried in a drying chamber at 120° C. for 24 hours. The dried cake was ground coarsely, and placed in an aluminacrucible, and heated in air at 1,200° C. for 2 hours to form lanthanum chromite. A hundred parts of the lanthanum chromite powder thus obtained and 100 parts of ion-exchanged water were put into a polyethylene pot together with 200 parts of zirconia balls, and pulverized for 48 hours to provide an average particle diameter of 0.5 μm.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C>C(O)C.C1COCC1.[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[C:5]2=[N:6][CH:7]=[CH:2][CH:3]=[C:4]2[NH:10][N:9]=1
Reactant: Fc1ccccc1Cc1n[nH]c2cc(Cl)cnc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1ccccc1Cc1n[nH]c2cccnc12
Reaction time: 2 h

Procedure:
411 mg (1.57 mmol) of 6-chloro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine from example 3A are dissolved in a mixture of 4 ml of ethanol and 4 ml of THF, and, after addition of 159 mg (1.57 mmol) of triethylamine and 140 mg of 10% palladium on carbon, the mixture is hydrogenated under a hydrogen atmosphere at atmospheric pressure for 2 h. It is then filtered to remove the catalyst, concentrated in vacuo and taken up in water. The mixture is extracted with dichloromethane, and the organic phase is dried over sodium sulfate. Concentration results in 334 mg (94% of theory) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](Br)[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]([C:18](=[S:22])[O:19]CC)[NH2:17]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[S:22][C:18](=[O:19])[NH:16][N:17]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(Br)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=S)NN
Solvent: O
Solvent: CCO
Product: CC1SC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 23 %

Procedure:
22 g (75 mM) of 1-(4-chloro-3-nitrophenyl)-2-bromopropan-1-one and 8 ml (75 mM) of O-ethyl hydrazinecarbothioate in 150 ml of ethanol are refluxed for 16 hours with stirring. The reaction medium is then concentrated under vacuum and the residue obtained is taken up in water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and then dried over anhydrous sodium sulfate. The solvent is evaporated off under vacuum to give an oil, which is purified on a column of silica using a dichloromethane/acetone mixture (95/5) as eluent. 5 g of 5-(4-chloro-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one are obtained.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C(OCC)(=O)C>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OO
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 40 mmol of benzhydrol, 4 mmol of N-hydroxyphthalimide, and 20 ml of ethyl acetate was stirred at 75° C. in an oxygen atmosphere (1 atm) for 12 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 60% (selectivity: 85%). Separately, as a result of a gas chromatographic analysis of the reaction mixture, the conversion rate from benzhydrol was 71%, and benzophenone was formed in yield of 70%.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:13]1(C2N=CNC=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrC1C=C(OC)C=CC=1>>[C:13]1([C:4]2[N:3]=[CH:2][N:1]([C:6]3[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=3)[CH:5]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Oc1cccc(-n2ccnc2)c1
Agent: COc1cccc(Br)c1
Product: Oc1cccc(-n2cnc(-c3ccccc3)c2)c1
Yield: 57 %

Procedure:
Following the procedure for preparation of 3-(1H-imidazol-1-yl)phenol (preparation 29), 4-phenylimidazole (20 g, 0.138 mole) and 3-bromoanisole (32 ml, 0.25 mole) were reacted to give the title compound in 57% yield; mp 195°-197° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)Cl.[CH3:18][NH2:19]>CN(C)C=O>[CH3:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
10 g (0.034 mol) 4-Iodo-3-nitrobenzoic acid (Compound VI-1) and 50 ml N,N-dimethylformamide were added into a reaction flask, stirred to dissolve, and cooled to below 10° C., and 7.5 ml (0.10 mol) sulfoxide chloride was added. After completion of the dropwise addition, the mixture was warmed to room temperature and reacted for one hour. The reaction mixture was poured into 200 ml aqueous solution of 30% methylamine with low temperature, stirred for 5 minutes to precipitate a solid, and then the mixture was added with 500 ml ice-water, stirred for 10 minutes, filtered. The solid was washed with water and dried to obtain N-methyl-4-iodo-3-nitrobenzamide (Compound VII-1), 6.5 g (0.021 mol), yield 62.3%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[C:34]([F:33])([F:43])[F:44])=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1

Procedure:
A solution of trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid as TFA salt (18.4 mg, 0.04 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (10.5 mg, 0.06 mmol, 1.5 equivalents) and DMAP (1.3 mg, 0.26 equivalents) in dichloromethane (1 ml) was cooled with stirring in an ice bath. EDCl (12.7 mg, 0.066 mmol, 1.65 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The solvent was removed to give the crude product, which was further purified by RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 5-40% CH3CN/H2O, 0.1% TFA, 25 min) to give the final product (5.33 mg, 21.5%). MS (ES+): m/e 507.21 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([C:7]2[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:10])[CH:6]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 36.6 %

Procedure:
The title compound (0.219 g) was prepared from 2,6-difluoro-4-bromo aniline (0.5 g, 2.4 mmol) and 3-ethoxyphenylboronic acid (0.517 g, 3.12 mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.30-7.24 (m, 3H), 7.14 (d, J 7.9, 1H), 7.11 (s, 1H), 6.82 (dd, J 2.1, 8.1, 1H), 5.31 (s, 2H), 4.07 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:4]=1[CH:5]=[O:6].C(N(CC)CC)C.[C:19]([O:23]C)(=[O:22])[CH:20]=[CH2:21]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:21]=[CH:20][C:19]([OH:23])=[O:22])=[O:6]
Reactant: COc1ccc(I)cc1C=O
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)O)cc1C=O
Temperature: 67.5 °C

Procedure:
2-Methoxy-5-iodobenzaldehyde (1.0 g, 3.82 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (3.71 ml, 26.7 mmol) and methyl acrylate (0.686, ml, 7.63 mmol) are added dropwise with stirring to the solution, followed by four portions of 0.0214 g of tri-o-tolylphosphine (0.095 mmol) and 0.008 g of palladium (II) acetate (0.047 mmol) at 1 hour intervals. The mixture is then heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is dissolved in dichloromethane. The resulting solution is percolated through silica gel eluting with a mixture of hexane-ethyl acetate (6:4). The percolate is evaporated to dryness, re-dissolved in 20 ml of methanol and 10 ml of 20% aqueous potassium carbonate solution added. The mixture is stirred for 6 hours at room temperature and concentrated under reduced pressure to a third of its volume. The solution is taken to a pH value of 1 with concentrated hydrochloride acid and the precipitate is filtered and recrystallized from isopropanol, to give 0.472 g of 3-formyl-4-methoxycinnamic acid (2.29 mmol) as a crystalline white solid. A second harvest obtained by concentration of the mother liquor gave an additional 0.105 g.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH3:6][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[CH2:9]Cl.CCCCCC.C1C=CC=CC=1>C(O)(=O)C>[C:1]([O:4][CH2:9][C:8]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=1[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1CCl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(=O)OCc1cc([N+](=O)[O-])ccc1C
Temperature: 115 °C

Procedure:
A slurry of anhydrous sodium acetate (60.0 g; 0.73 mol) in acetic acid (400 ml) is stirred and 2-methyl-5-nitrobenzyl chloride (45.3 g; 0.24 mol) added. The resulting reaction mixture is heated to reflux and is heated overnight at 115° C., after which time tlc (silica gel; 75/25 hexane/benzene) indicates that no starting material is present. The mixture is cooled down, concentrated in vacuo, and diluted with water. The precipitated solid (48.9 g; 95.8%) is collected and dried. A sample recrystallized from hexane has a melting point of 52°-53.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20](O)=[O:21])=[O:17])[CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:41]([O:43][C:44](=[O:48])[N:45]([CH3:47])[NH2:46])[CH3:42]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:41]([O:43][C:44](=[O:48])[N:45]([CH3:47])[NH:46][C:20](=[O:21])[C@@H:19]1[CH2:23][CH2:24][CH2:25][N:18]1[C:16](=[O:17])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:42]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 0.009 moles of t-butyloxycarbonylalanylalanylproline in 80 ml of dry tetrahydrofuran which has been cooled to -20° to -30° is added 1.0 ml of N-methylmorpholine and 1.2 ml of isobutylchloroformate. After stirring for 10 minutes there is added 0.009 moles of 2-azaalanine ethyl ester in 50 ml of chloroform. The reaction mixture is stirred overnight at room temperature and then concentrated in vacuo. The residue is taken up between ethyl acetate and 0.25 N hydrochloric acid. The organic layer is separated, washed with saturated sodium bicarbonate solution, water, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel. Elution with ethyl acetate gives t-butyloxycarbonylalanylalanylprolyl-2-azaalanine ethyl ester.