Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]1=[O:25]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[C:5]([NH:11][CH2:12][C:13]#[CH:14])=[CH:4][C:3]([N:15]2[C:16](=[O:25])[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[C:23]2=[O:24])=[C:2]([F:1])[CH:7]=1
Reactant: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1N
Temperature: 80 °C
Yield: 86.2 %

Procedure:
Iron powder (1.22 g) was suspended in a 5% aqueous acetic acid solution, followed by heating at 80° C. A solution of 2-[2-fluoro-4-nitro-5-(2-propynyl)aminophenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.75 g) in a mixture of acetic acid (2.2 ml) and ethyl acetate (2.2 ml) was dropwise added to the suspension, and the resultant mixture was heated at 70° C. for 3 hours. After removal of the precipitate by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-[4-amino-2-fluoro-5-(2-propynyl)amino-phenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). m.p., 182.2° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][Cl:22])[CH:5]=1
Reactant: O=C(Cl)CCCCl
Reactant: CCOc1cc(N)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 113.9 %

Procedure:
3-Amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) was suspended in CH2Cl2 (40 ml) and treated at room temperature with NEt3 (2.32 g, 23 mmol, 1.1 equiv). The resulting solution was cooled to 0° C. and 4-chlorobutyryl chloride (3.1 g, 22 mmol, 1.1 equiv) was added dropwise. The resulting mixture was stirred at 0° C. for 3 h then allowed to warm to room temperature. The solution was washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo to give of 3-(4-chloro-butanoylamino)-5-ethoxy-benzoic acid methyl ester (D51) (7.0 g, 115%) as a brown oil.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].Br[C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([Br:16])[C:9]=2[N:10]=1.[OH-].[Na+].O1CCCC1>O>[Br:16][C:11]1[C:9]2[N:10]=[C:6]([S:4][CH2:1][CH:2]=[CH2:3])[S:7][C:8]=2[CH:14]=[C:13]([CH3:15])[CH:12]=1
Reactant: C=CCS
Reactant: Cc1cc(Br)c2nc(Br)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCSc1nc2c(Br)cc(C)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1.0 g of allyl mercaptan prepared above, 3.1 g of 2,4-dibromo-6-methyl-benzothiazole, 0.4 g of sodium hydroxide, 10 ml of tetrahydrofuran and 10 ml of water were mixed together and the obtained mixture was stirred for 3 hours at room temperature and then extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and evaporated to obtain the title compound in a liquid state (Yield: 92.5%).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34](I)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH:46]1(B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34]([CH:46]2[CH2:48][CH2:47]2)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([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
Reactant: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-{5-[3-(2-ethylbutyl)cyclobutyl]-4-iodoisoxazol-3-yl}valerate (4.96 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.68 g), tripotassium phosphate (5.66 g), PdCl2(PPh3)2 (468 mg) and N,N-dimethylacetamide (50 mL) were mixed. The mixture was stirred at 80° C. for 5 hr. To the reaction mixture were added ethyl acetate (50 mL) and Celite at RT, and the mixture was filtered. The collected solid was washed with ethyl acetate (50 mL×2). The filtrate was washed with water/brine=1/1 (100 mL×2) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/50→1/40→1/30→1/20) to give the title compound (2.86 g).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]([C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(O)C>[O:9]([C:16]1[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH:22]=[N:2][OH:3])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CCOc1ccc(Oc2ccccc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=CCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 25 g of hydroxylamine hydrochloride and 29.4 g of anhydrous sodium acetate in 100 ml of water is added dropwise at room temperature to a solution of 68.5 g of 4-phenoxyphenoxyacetaldehyde in 300 ml ethanol. After the slightly exothermic reaction has subsided, the mixture is stirred for 2 hours at reflux temperature. The mixture is then cooled to 0° C. and stirred for 3 hours at this temperature, whereupon the resultant oxime crystallises. The crystallised 4-phenoxyphenoxyacetaldehyde oxime is isolated by suction filtration, repeatedly washed thoroughly with water and dried in a vacuum cabinet at 40° C. Melting point: 102°-105° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13](Br)=[C:12]([F:19])[C:11]=1[F:20].B(O)(O)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9]([C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=2)=[C:12]([F:19])[C:11]=1[F:20])=[O:21]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(F)c(F)c(Br)c(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(F)c(F)c(-c2ccc(C=O)cc2)c(F)c1F
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A toluene/Water (175 mL+25 mL) mixture was degassed with nitrogen for 30 minutes. Cesium carbonate (14.9 g, 43.55 mmol) was added followed by 4-bromo-2,3,5,6-tetrafluoro-benzoic acid methyl ester (5.0 g, 17.42 mmol), 4-formyl boronic acid (3.4 g, 22.64 mmol) and dichlorobis(triphenylphosphine)-palladium(II) catalyst (0.611 g, 0.87 mmol). The reaction mixture was refluxed for 15 h. TLC shows completion of the reaction. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 5% ethyl acetate in hexane to get colorless solid (3.0 g, 55.24%).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[K+].[Br-]>>[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:26])([O:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=4)[C:4]([OH:3])=[O:27])=[CH:8][CH:9]=3)[N:38]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 42. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.4 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.90 (d, 2H, J=8.4 Hz), 6.79 (d, 2H, J=8.4 Hz), 4.43 (bs, 1H), 4.16 (t, 2H, J=6.0 Hz), 3.25 and 3.13 (d of Abq, 2H, J=14.0 Hz), 3.02 (t, 2H, J=6.0 Hz), 3.02-2.98 (m, 1H), 2.36 (s, 3H), 2.09-2.00 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.69 (m, 1H), 1.64-1.52 (m, 2H), 1.43 (s, 3H), 1.40-1.23 (m, 3H). IR (KBr) 3600, 2980, 1725, 1601, 1500, 1268 cm−1. HRMS (ES+) m/z exact mass calcd for C29H33NO6F3 548.2260, found 548.2274.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:14])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1ccccc1)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595 mg) in THF (5 mL) at −78° C. was added phenyl magnesium bromide (4.6 mL of 1 M in THF) dropwise. The resulting mixture was stirred at 0° C. for 4 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[N:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1>C(#N)C>[CH:12]1([CH2:11][C:10]([NH:9][C:5]2[C:4]([CH3:18])=[CH:3][C:2]([NH:1][CH2:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:22][CH:23]=3)=[CH:7][C:6]=2[CH3:8])=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cc(N)cc(C)c1NC(=O)CC1CCCC1
Solvent: CC#N
Product: Cc1cc(NCc2ccc(C(F)(F)F)nc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (204 mg) and 6-trifluoromethyl-pyridine-3-carbaldehyde (163 mg) were dissolved in acetonitrile (3 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo, redissolved in methanol (5 mL) followed by addition of acetic acid (0.5 mL) and sodium cyanoborohydride (244 mg) and stirred at 25° C. for 16 hours. Aqueous sodium carbonate (10%, 25 mL) was added, and the product was collected by filtration to furnish 0.311 g (92% yield) of the title compound as a white solid. LC-MS (m/z) 406 (MH+); tR=2.90, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.20 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.97 (s, 6H), 2.22 (m, 3H), 4.39 (d, 2H), 6.20 (t, 1H), 6.28 (s, 2H), 7.85 (d, 1H), 7.99 (d, 1H), 8.75 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cccc(CCN2CCCC2)c1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1cccc(CCN2CCCC2)c1
Yield: 92.2 %

Procedure:
Prepared from a solution of 0.256 g (1.26 mmol) of 4-methoxymethylene-4H-isoquinoline-1,3-dione and 0.240 g (1.26 mmol) of 3-(2-pyrrolidin-1-yl-ethyl)-phenylamine in 4 mL of N,N-dimethylformamide (DMF) at 100° C. under N2 as described for example 21. After heating for 1 h, solvent is removed and the residue is filtered through Magnesol (20% MeOH in CHCl3). Solvent evaporation gave 0.420 g (92%) of a red glass: 1H NMR (DMSO-d6) δ 12.40 (d, 1H, J=9.0 Hz), 11.33 (s, 1H), 8.90 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=6.0 Hz), 8.03 (d, 1H, J=6.0 Hz), 7.62 (m, 1H), 7.46 (s, 1H), 7.30 (m, 3H), 7.04 (d, 1H, J=6.0 Hz), 2.70 (m, 4H), 2.50 (m, 4H), 1.67 (m, 4H); HRMS (ESI) m/z calcd for C22H23N3O2 362.18631. found 362.18574 (M+H)−1; Analysis for C22H23N3O2.0.75H2O; Calcd: C, 70.46; H, 6.60; N, 11.21. Found: C, 70.83; 6.61; N, 11.24.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=[O:16].O>C(O)(=O)C>[CH:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6](=[O:16])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Solvent: O
Solvent: CC(=O)O
Product: O=S1c2ccccc2Sc2ccccc21
Reaction time: 5 h

Procedure:
In 300 ml of acetic acid was refluxed 20 g of thianthrene and 36 ml of diluted nitric acid was gradually added dropwise thereto. After reacting for 5 hours, the reaction solution was poured into 1.2 liters of water to deposit crystals. The crystals were collected by filtration and recrystallized from acetonitrile to obtain 12 g of thianthrene-S-oxide. 1H-NMR (400 MHz, CDCl3): σ 7.42 (t, 2H), 7.56 (t, 2H), 7.63 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:29])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5]([Cl:29])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a mixture of 50.0 g of product from Example 37 in 700 ml of chloroform and 10 drops of dimethylformamide is added, dropwise, 25.8 g of oxalyl chloride. The reaction is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is dissolved in diethyl ether, filtered and concentrated in vacuo to give 51.1 g of the desired product as white crystals.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20]([OH:22])=O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:22])[NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: Nc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)Nc1ccccc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 45 %

Procedure:
The title compound (25 mg, 45%) was prepared from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and aniline as in Example 1, Part C. HPLC: RT=10.81 min. MS (ESI−): mass calcd. for C28H20Cl3N5O4S2, 660.98; m/z found, 658/660 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.54 (s, 1H), 8.39 (dd, J=7.1, 1.0, 1H), 8.19 (dd, J=8.8, 0.8, 1H), 7.75-7.67 (m, 2H), 7.67-7.62 (m, 1H), 7.47-7.42 (m, 2H), 7.42-7.33 (m, 4H), 7.26-7.23 (m, 1H), 7.11-7.09 (m, 1H), 6.96-6.90 (m, 2H), 4.84-4.77 (m, 1H), 3.23-3.10 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(O)C>[CH:25]1([NH:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (295 mg, 2.32 mmol) and cyclohexylamine (288 mg, 2.32 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crystals that were purified by silica gel column chromatography to yield the title compound (191 mg, 48% yield) as orange crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.CS([C:18]1[N:23]=[C:22]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)(=O)=O>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([NH:3][C:18]2[N:23]=[C:22]([C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1nccc(-c2ccnn2-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2nccc(-c3ccnn3-c3ccccc3)n2)cc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (22 mg, 0.93 mmol, 2.0 equiv) was added to a solution of methyl 4-aminobenzoate (140 mg, 0.93 mmol, 2.0 equiv) in DMF (5 mL) at 23° C. The resulting yellow solution was stirred for 15 minutes before 2-(methylsulfonyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-7, 140 mg, 0.47 mmol, 1 equiv) was added. The resulting red mixture was stirred for 30 minutes, then partitioned between brine (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes, initially, grading to 40% hexanes in ethyl acetate) to give methyl 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino}benzoate (2-1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.41 (d, 1H, J=4.9 Hz), 7.86 (d, 2H, J=8.8 Hz), 7.78 (d, 1H, J=1.8 Hz), 7.52–7.33 (m, 5H), 7.28 (d, 2H, J=8.6 Hz), 6.90 (d, 1H, J=1.8 Hz), 6.78 (d, 1H, J=4.9 Hz), 3.90 (s, 3H)
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][CH2:14][CH:15]1[CH2:23][CH:22]2[CH:18]([CH2:19][NH:20][CH2:21]2)[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])([OH:24])[CH2:16]1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43]>ClCCl>[OH:13][CH2:14][CH:15]1[CH2:23][CH:22]2[CH:18]([CH2:19][N:20]([C:42](=[O:43])[CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:21]2)[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])([OH:24])[CH2:16]1
Reactant: COc1ccccc1C1(O)CC(CO)CC2CNCC21
Reactant: COc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 45.6 %

Procedure:
2.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to a solution of 3 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol and 1.8 g of (2-methoxyphenyl)acetic acid in 60 cm3 of dichloromethane. The reaction mixture is stirred at 20° C. for 20 hours and then washed with 30 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, height [lacuna]cm) in ethyl acetate and then in a mixture of ethyl acetate and methanol (95:5 by volume). Drying under reduced pressure gives a white solid which, after recrystallization from a mixture of ethyl ether and acetonitrile, gives 2.1 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol in the form of white crystals. M.p.=162° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[N:34]=[CH:35][NH:36][CH:37]=1>>[NH:36]1[CH:37]=[C:33]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]=2[CH3:29])[N:34]=[CH:35]1
Reactant: Brc1c[nH]cn1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1c[nH]cn1)OCC2c1ccc(C(C)C)cc1
Yield: 48 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 4-bromoimidazole, the title compound was obtained in the same manner as in Example 107. Yield: 48%. Melting point: 277-279° C. (ethyl acetate).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1I)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:31]=[N:32]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(I)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-iodo-4',6'-dinitrophenylazo)-N,N-diethylaniline (4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 10 hours when thin layer chromatography showed reaction to be complete. Isolation of the product as in Example 1 gave 3-acetylamino 4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline (infra red spectrum identical with that of authentic material).