Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Li]CCCC.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]>CCOCC.N1C=CC=CC=1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:21][CH:16]=1
Reactant: c1ccc2occc2c1
Reactant: COc1ccccc1I
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
A solution of 46.0 g (0.39 mole) of benzofuran in 100 mL of Et2O was treated with 0.40 mol (1.6 M in hexanes) of n-BuLi at such a rate as to keep the reaction temperature below 25° C. The mixture was stirred for 15 min and was added to a 10° C. solution of 57.2 g (0.40 mole) of CuBr in 100 mL of Et2O at a rate so as to keep the reaction temperature below 10° C. The mixture was allowed to reach room temperature over 0.5 h and was treated with a solution of 93.6 g of iodoanisole in 300 mL of pyridine. The mixture was heated to 110° C. for 3 h, allowing the Et2O to boil off. The reaction mixture was concentrated in vacuo and the residue was dissolved in 3 L of EtOAc. The organic layer was washed several times with 2 N aqueous HCl and once with H2O, dried over MgSO4, and filtered. Concentration in vacuo afforded a residue which was recrystallized from MeOH to afford 44.5 g of the title compound as a solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[C:31](=[O:32])[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[O:23]=[C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH2:15][CH:16]([CH:30]1[C:28](=[O:29])[NH:27][C:25](=[O:26])[NH:24][C:31]1=[O:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: O=C(C=Cc1ccccc1)c1ccc(Oc2ccccc2)cc1
Product: O=C1NC(=O)C(C(CC(=O)c2ccc(Oc3ccccc3)cc2)c2ccccc2)C(=O)N1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(4-phenoxyphenyl)-3-phenylprop-2-en-1-one and barbituric acid, 5-(3-oxo-3-(4-phenoxyphenyl)-1-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione was obtained as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[C:4]([S:10][CH3:11])[N:3]=1.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[C:8]2[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1nc(C)n2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(SC)nc(C)n12
Reaction time: 0.67 h

Procedure:
5-Methyl-7-methylthioimidazo[5,1-b]thiazole (3.34 g) was dissolved in 150 ml of THF. A 1.59 N n-butyllithium/n-hexane solution (22.8 ml) was added dropwise to the solution in an argon atmosphere at −73° C. The mixture was stirred at the same temperature for 40 min. Tri-n-butylstannyl chloride (6.39 ml) was added thereto, followed by stirring at the same temperature for one hr. An ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:1). Of two main components, the fraction, which had been eluted earlier, was collected to give 598 mg of 5-methyl-7-methylthio-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:28][C:29]([NH2:32])([CH3:31])[CH3:30]>>[CH3:28][C:29]([NH:32][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24])([CH3:31])[CH3:30]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC(C)(C)N
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)C)cn2)CC1
Yield: 82 %

Procedure:
By the same procedure as described example 24, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-methyl-2-propaneamine. And then, the product was recrystallized with isopropanol to give a desired compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:12]=3[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:12]=3[C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-(indolin-1-yl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 2-((benzo-1,3-dioxol-5-yl)amino)-4-(indolin-1-yl)benzoic acid 31 mg of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cccnc1
Yield: 101.2 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) in DMF (100 mL) with triethylamine (8.53 mL, 61.2 mmol) and 3-aminomethylpyridine (4.16 mL, 40.8 mmol). After the precipitate was isolated by filtration, it was dried for three hours in a vacuum oven at 60° C. to provide 13.0 g of 2-chloro-3-nitro-N-(pyridin-3-ylmethyl)quinolin-4-amine as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([F:13])([C:9]([F:12])([F:11])[F:10])[C:4]([F:8])([F:7])[CH2:5][CH3:6].FC(F)(F)C(F)(C(F)(F)F)C(F)(F)[I:20].C=C>>[F:1][C:2]([F:14])([F:15])[C:3]([F:13])([C:9]([F:10])([F:11])[F:12])[C:4]([F:8])([F:7])[CH2:5][CH2:6][I:20]
Reactant: CCC(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)I
Agent: C=C
Product: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)CCI

Procedure:
1,1,1,2,3,3-Hexafluoro-2-(trifluoromethyl)-pentane ((CF3)2CFCF2CH2CH3) may be prepared by the reaction of 1,1,1,2,3,3-hexafluoro-2-(trifluoromethyl)-3-iodo-propane with ethylene to give 1,1,1,2,3,3-hexafluoro-2-(trifluoromethyl)-5-iodopentane followed by zinc reduction in an acid such as HCl or acetic acid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH3:28]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CCN
Product: CCNS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and ethylamine. MS (ESI): 422.3 (MH+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C@H:19]([CH2:22][OH:23])[O:18][C:17]=2[CH:24]=1.O>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:19]2[O:18][C:17]3[CH:24]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[O:21][CH2:20]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1COc2ccc(Cl)cc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(Cl)cc3O2)cc1
Reaction time: 4 h

Procedure:
4-Toluenesulphonyl chloride (5.9 g) was added to a solution of (S)-7-chloro-1,4-benzodioxan-2-ylmethanol (6.0 g; prepared by the method described above) in pyridine (40 ml) and the mixture stirred for 4 hours. More 4-toluenesulphonyl chloride (250 mg) was added, stirring continued for 2 hours, then further 4-toluenesulphonyl chloride (250 mg) was added and stirring continued for 1 hour. The mixture was poured into water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined extracts were washed with hydrochloric acid (2M; 2×200 ml), saturated aqueous sodium bicarbonate solution (2×200 ml) and brine (200 ml), then dried over magnesium sulphate. The solvent was removed in vacuo and the residue recrystallised from ether to give (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (7.00 g) m.p. 90-91° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH3:11][N:12]([CH3:39])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:24]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH3:39][N:12]([CH3:11])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:29][CH:28]=2)[CH:24]=1)=[O:17]
Reactant: ClCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(OCCCN2CCOCC2)cc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
4-(3-Chloropropyl)morpholine (0.1 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide (0.195 g), potassium carbonate (0.21 g) and DMA (5 ml). The mixture was then heated to 60° C. for 36 hours. The mixture was poured into water (150 ml) and the resultant solid was collected, washed with water and with diethyl ether. The product was dried under vacuum. There was thus obtained the title compound (0.203 g) as a colourless solid; NMR Spectrum: (DMSOd6) 1.88 (m, 2H), 2.18 (s, 3H), 2.36 (t, 4H), 2.41 (t, 2H), 2.96 (s, 6H), 3.58 (t, 4H), 4.08 (t, 2H), 6.9 (m, 1H), 7.01 (d, 2H), 7.19 (m, 3H), 7.26 (t, 1H), 7.58 (d, 1H), 7.78 (s, 1H), 7.98 (d, 2H), 9.72 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+ 517.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>O>[OH:10][CH:3]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(C(=O)c2ccccc2)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C(O)c2ccccc2)ccn1
Yield: 79.3 %

Procedure:
9.4 g of sodium borohydride was added little by little to a mixture of 130 g of 4-benzoyl-2-methoxypyridine and 300 ml of methanol under stirring in an ice bath. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was added to 1 L of water and then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then the solvent was removed, to give 104 g of the target compound.
Reaction SMILES: Cl.[NH:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:5][N:4]=[CH:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[NH:2]1[C:6]([CH2:7][CH2:8][C:9]([NH:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:15])=[O:11])=[CH:5][N:4]=[CH:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CCc1cnc[nH]1
Agent: Cl
Product: O=C(CCc1cnc[nH]1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 5 %

Procedure:
Proceeding as in Example 1, but substituting 3-(1H-imidazol-5-yl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 207, (S)-2-(3-(1H-imidazol-5-yl)propanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (18.4 mg, 5%). 1H-NMR (400 MHz, DMSO-D6): σ 10.19 (s, 1H), 8.29 (d, 1H), 7.60 (d, 2H), 7.46 (s, 1H), 7.29-7.16 (m, 6H), 7.01-6.94 (m, 4H), 6.73 (s, 1H), 4.70-4.64 (m, 1H), 4.50 (s, 2H), 2.73-2.67 (m, 2H), 2.48-2.43 (m, 4H). MS (EI) for C28H27FN4O4. found 503.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:30](Cl)=[O:31].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:27]([Cl:26])[CH:28]=1)[CH:13]=[C:12]2[CH:18]=[C:19]1[S:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2c[nH]c3ccc(OCc4ccccc4)cc23)S1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: O=C1NC(=O)C(=Cc2cn(C(=O)c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1
Reaction time: 18 h

Procedure:
5-Benzyloxy-3-(2,4-dioxo-thiazolidin-5-ylidene-methyl)-indole (Example 1, Step A; 10 mg) was dissolved in pyridine (1.5 mL) and 3,4-dichlorobenzoyl chloride (35 mg) and a trace of dimethylaminopyridine were added. The mixture was stirred at 50-60° for 18 hrs until the reaction was determined to be complete by TLC. Volatiles were removed under reduced pressure and the residue was washed with water and ether; 10 mg; consistent nmr and ms (m\e 525 (M+1); greater than 95% by HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH2:13])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:12]([NH:13][C:35]([CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[O:36])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1N
Reactant: O=C(Cl)C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.22 g (0.85 mmol) 4-(benzyloxy)-2-methyl-6-nitroaniline were placed in 5 mL DCM. 0.17 mL (1.00 mmol) DIPEA and 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.10 mL (1.00 mmol) tetrahydro-2H-pyran-4-carbonyl chloride were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.Cl>ClCCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:10]([C:9]2[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)=[O:11])=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(Br)ccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.3 %

Procedure:
To a suspension of AlCl3 (14.7 g, 110 mmol) in 250 mL of 1,2-dichloroethane was added 4-fluorobenzoyl chloride (11.8 mL, 100 mmol) at rt. The resulting mixture was stirred at rt for 15 min. and 3-bromoanisole (16.8 g, 90.0 mmol) in 20 mL of 1,2-dichloroethane was added. After 1 h at rt, the brown solution was poured into ice. 2N HCl was added to the aqueous layer followed by an extraction with CH2Cl2. The combined organics were dried (MgSO4), filtered and concentrated. The residue was subjected to chromatography on silica gel (EtOAc/hexane 5:95 to 7:93) affording 5.1 g of a solid that was triturated with 20 mL of EtOAc/hexane (10:90). The title compound was obtained from filtration, and additional product was recovered from the mother liquors.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[CH2:36]>C(O)(=O)C>[O:11]([C:10]1[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[S:1][CH2:36][CH2:35][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: C=Cc1ccncc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCCc2ccncc2)c1Oc1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (1.7 g), sodium hydrogen carbonate (1 g), sodium dithionite (1 g), 4-vinylpyridine (0.8 ml) and saturated aqueous sodium hydrogen carbonate (17 ml) is stirred at 70°C. for 4 hours. After cooling, pH of the mixture is adjusted to 4.5 by addition of acetic acid. The precipitated material is collected by filtration, washed with water, and recrystallized from aqueous ethanol to yield 4-phenoxy-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[OH:38])[CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[CH:31][C:32]([C:34]([F:35])([F:36])[F:37])=[CH:33][C:28]=3[CH2:25][CH2:26][CH3:27])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCCc1cc(C(F)(F)F)ccc1O
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CCCc1cc(C(F)(F)F)ccc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 56.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 2-propyl-4-trifluoromethylphenol (37 mg, 0.18 mmol) to give the title compound (40 mg, 55%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: I[CH3:2].[C:3]([O:7][C:8](=[O:25])[CH2:9][CH2:10][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:12][OH:13])([CH3:6])([CH3:5])[CH3:4]>C(#N)C.[Ag-]=O>[C:3]([O:7][C:8](=[O:25])[CH2:9][CH2:10][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:12][O:13][CH3:2])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=[Ag-]
Solvent: CC#N
Product: COC[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.4 %

Procedure:
A solution of 4.82 ml (77.3 mmol) of iodomethane and 2.50 g (7.7 mmol) (S)-4-Benzyloxycarbonylamino-5-hydroxy-pentanoic acid tert-butyl ester in 25 ml of acetonitrile was cooled (0° C.) and treated with 2.72 g (11.8 mmol) of silver(I) oxide. The reaction mixture was stirred at RT for 3 days. The reaction was filtered and evaporated to yield after flash chromatography (SiO2, dichloromethane/ether 2.5%) 1.70 g (65%) of the titled compound as light yellow oil. MS: 360.18 (M+Na).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][N:20]=2)[N:9]=1)=[O:7])C.Cl>CO.O1CCCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:10]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[N:9]2)=[N:20][CH:21]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(OC)cn2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Aqueous 1N sodium hydroxide (3.5 mL) was added to the above-obtained 1-(5-methoxy-2-pyridyl)-5-phenylpyrazole-3-carboxylic acid ethyl ester (700 mg) in a mixture of methanol (7 mL) and tetrahydrofuran (7 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture, under cooling with ice, aqueous 1N hydrochloric acid (3.6 mL) was added. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as a solid (602 mg, 94%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:18]([OH:20])=O)=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].CN.[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:18]([NH:28][CH3:27])=[O:20])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(NC(C)C)nncc2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoic acid (0.22 g, 0.7 mmol) in DMF (2 mL) at RT was treated with a 2 M solution of methylamine (2 mL, 3 mmol), and HATU (0.4 g, 1 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4, concentrated in vacuo and purified by column eluting with 2-3% 2M ammonia MeOH/DCM to give the title compound. MS (ES+): 335 (M+H)+.