Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.O>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)CCl
Reaction time: 1.5 h
Yield: 95 %

Procedure:
In 3 l of toluene was dissolved 182 g of 2,6-xylidine, and in 1.5 l of water was dissolved 159 g of sodium carbonate. The two solutions were combined, and 203 g of chloroacetyl chloride was added thereto dropwise over 1.5 hours at an inner temperature of from 20° to 35° C., followed by stirring at that temperature for 1.5 hours. The reaction mixture was cooled with ice, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 282 g (95%) of the titled compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:26])[N:6]=1)[CH:2]([CH3:4])[CH3:3].[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[OH:30][CH2:29][CH:28]([NH:27][C:23](=[O:25])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:9]3[CH:8]=[C:7]([CH3:26])[N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:10]=3)[O:15][N:14]=2)=[CH:17][CH:18]=1)[CH2:31][OH:32]
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(CC(C)C)n1
Reactant: NC(CO)CO
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)NC(CO)CO)cc3)no2)cc(CC(C)C)n1

Procedure:
N-(2-Hydroxy-1-hydroxymethyl-ethyl)-2-{4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide is prepared from {4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid and 2-amino-propane-1,3-diol in analogy to Example 65; LC-MS: tR=0.73, [M+1-1]+=425.06.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N+:23]([O-])=O)[C:14]1=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:23][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[CH:22][N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:14]2=[O:26]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Temperature: 25 °C
Yield: 93.5 %

Procedure:
Tin(II) chloride dihydrate (1.21 g, 5.36 mmol) was added to a stirred solution of 2-benzyl-5-nitroisoquinolin-1(2H)-one (300 mg, 1.07 mmol) in anhydrous ethanol (20 mL). The reaction mixture was stirred at reflux for 20 h. The resulting mixture was cooled to room temperature, treated with saturated aqueous sodium bicarbonate to pH=11 and diluted with water (100 mL). The obtained mixture was extracted with ethyl acetate (3×70 mL). The combined organic fractions were dried over anhydrous Na2SO4, filtered and evaporated to give 5-amino-2-benzylisoquinolin-1(2H)-one (248 mg, 1.0 mmol, 93% yield) as an orange foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:17])[CH:12]1[O:16][CH2:15][CH2:14][CH2:13]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCC1CCCO1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC2CCCO2)cc1
Temperature: 0 °C

Procedure:
0.3 mol (46.2 g) of para-chloronitrobenzene and 1 mol (101 g) of tetrahydrofurfurylamine are heated for three hours in an oil bath at 150° C. The reaction medium is then poured into 500 ml of ice-cooled water. The expected product initially precipitates in the form of a thick oil which rapidly crystallises. After it has been filtered off, washed with water, recrystallised from ethanol and dried in vacuo, the product melts at 74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:29])[C:22]([CH:27]=O)=[CH:23][CH:24]=[CH:25][CH:26]=1.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH2:13]([C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:29][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[CH:3][CH:4]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)[CH3:14]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: Cc1ccccc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (300 mg, 1.14 mmol) and o-tolualdehyde (260 mg, 2.25 mmol) in 5% HOAc/MeOH (6 mL) at room temperature under argon, sodium cyanoborohydride (200 mg, 3.18 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then concentrated, diluted with water, extracted into ethyl acetate, washed with brine. The residue obtained on concentration was chromatographed on silica gel (eluant, gradient of 25-50% EtOAc in hexane) to provide the title compound as an oil that solidified on trituration with ether/petroleum ether (97 mg, 23%), m.p. 117-9° C. NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.5 (br, 1H); 8.1 (br, 1H); 7.4-7.2 (overlapping m, 7H), 6.7 (d,2H), 6.5 (s, 1H), 4.4 (s, 2H), 4.1 (br, 1H), 2.7 (q, 2H), 2.4 (s, 3H), 1.3 (t, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([CH2:27][OH:28])[O:16][C@@:10]2([OH:15])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC(O)=O)=O.C(O)(=O)C>C[O-].[Na+].CO>[C:1]1([CH2:7][O:8][C@H:9]2[C@H:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([CH2:27][OH:28])[O:16][C:10]2([OH:15])[C:11]([O:13][CH3:14])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@]1(O)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(=O)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(O)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A solution of 4.25 g of 3,4-bis-O-(phenylmethyl)-alpha-D-arabino-hexulofuranosonic acid, methyl ester, diacetate in 45 ml of 1.0M sodium methoxide in methanol was stirred at 25° for 20 minutes, treated with 4.1 ml of acetic acid, and concentrated. The residue was partitioned with ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was subjected to chromatography on silica gel to give an oil, CMR δ 53.3 (CH3OCO).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:27])[C@@H:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[O:13][C:14]([CH3:17])([CH3:16])[O:15][C:11]=2[CH:10]=1)(=[O:3])[CH3:2].[Li].CC([O-])(C)C.CC([O-])(C)C.CC([O-])(C)C.[Al+3]>C(O)C>[C:1]([O:4][CH2:5][C@@H:6]([OH:27])[C@@H:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]2[O:13][C:14]([CH3:16])([CH3:17])[O:15][C:11]=2[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Agent: [Li]
Solvent: CCO
Product: CC(=O)OC[C@@H](O)[C@H](Cc1ccc2c(c1)OC(C)(C)O2)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
A solution of (S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-oxobutyl acetate (3270 mg, 8311 μmol) in 100 mL of ethanol was cooled to −78° C. and added to a solution of lithium aluminum tri-tert-butoxyhydride (16623 μl, 16623 μmol) in 45 mL of ethanol at −78 C dropwise via a cannula over 10 minutes. After stirring at −78° C. for 2 hours the reaction was quenched with 25 mL of 1 N HCl and diluted with ethyl acetate (500 mL). The mixture was poured into 200 mL of water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water, brine, and dried over sodium sulfate and concentrated to provide (2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-hydroxybutyl acetate (3220 mg, 98% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH:16]1([CH2:19][NH:20][C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[O:37])=[CH:23][CH:24]=3)[C:13]([CH3:14])=[C:12]([F:15])[CH:11]=2)=[O:6])[CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 80 °C
Yield: 61.9 %

Procedure:
3-Bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide (Intermediate 1, 40 mg, 0.15 mmol), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (45 mg, 0.15 mmol) and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol) were dissolved in DME (3 ml) and aqueous sodium carbonate (1M, 150 μl) was added. The mixture was refluxed at 80° C. for 16 hours. Solvent was removed in vacuo and the residue was purified by silica biotage chromatography, eluting with ethyl acetate:cyclohexane (2:) then 100% ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-5-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide (34 mg, 62%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[C:11]2[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Product: COc1ccc(C(=O)Nc2ccc3[nH]cc(C4=CCN(C)CC4)c3c2)cc1
Yield: 20.3 %

Procedure:
Beginning with 1.13 gm (5.0 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.853 gm (5.0 mMol) 4-methoxybenzoyl chloride, 0.367 gm (20.4%) of the title compound were recovered as a light yellow solid.
Reaction SMILES: Cl[CH:2]([Cl:4])[CH3:3].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[S:16]1C2C(=O)[CH:22]=[CH:21][NH:20][C:19]=2[CH:18]=[CH:17]1>ClCCl>[Cl:4][C:2]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[CH:17][S:16][C:3]=12
Reactant: O=c1cc[nH]c2ccsc12
Reactant: CC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccnc2ccsc12

Procedure:
30 ml of dichloromethane and 20 ml of dichloroethane in 250 ml round bottom flask were added with dimethylformamide (1.8 ml, 23.28 mmol) and oxalylchloride (2.9 ml, 33.86 mmol) was slowly dropped to the mixture at 0° C. After 4H-thieno[3,2-b]pyridine-7-one (1.6 g, 10.58 mmol) was added, the mixture was refluxed for 6 hours. After lowering the temperature to room temperature, the title compound of yellowish solid (1.7 g, 90%) was obtained.
Reaction SMILES: [C:1]1([CH:7]([O:37]C(=O)C)[C:8](=[O:36])[NH:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[N:23]=[CH:22][N:21]=4)[C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:37][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:10]1[S:11][C:12]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)[N:23]=[CH:22][N:21]=3)[C:13]=2[N:14]=1)=[O:36]
Reactant: CC(=O)OC(C(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1)C(O)c1ccccc1

Procedure:
This material was prepared according to the procedure described in Example 68(b) using acetic acid phenyl-{4-[6-(4trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-methyl ester, (Example 79), (0.44 g, 0.78 mmol) and potassium carbonate (0.22 g, 1.6 mmol) in MeOH (8 mL). Purification by silica gel chromatography (1:2 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 523 (M+1). Mp: 197.7–205.4° C.
Reaction SMILES: OO.[ClH:3].[ClH:4].[Cl:5][C:6]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]([S:13](=[O:22])(=[O:21])[N:14]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH3:15])[C:7]=1[O:23][C:24](=[O:46])[C:25]([O:27][C:28]1[C:33]([S:34](=[O:43])(=[O:42])[N:35]([CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH3:36])=[CH:32][C:31](Cl)=[CH:30][C:29]=1[Cl:45])=[O:26]>>[ClH:5].[ClH:3].[Cl:5][C:6]1[CH:7]([O:23][C:24](=[O:46])[C:25]([O:27][CH:28]2[C:33]([Cl:4])([S:34](=[O:42])(=[O:43])[N:35]([CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH3:36])[CH:32]=[CH:31][CH:30]=[C:29]2[Cl:45])=[O:26])[C:8]([Cl:3])([S:13](=[O:21])(=[O:22])[N:14]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCN(C)S(=O)(=O)c1cc(Cl)cc(Cl)c1OC(=O)C(=O)Oc1c(Cl)cc(Cl)cc1S(=O)(=O)N(C)CCN(C)C
Agent: Cl
Agent: OO
Product: CN(C)CCN(C)S(=O)(=O)C1(Cl)C=CC=C(Cl)C1OC(=O)C(=O)OC1C(Cl)=CC=CC1(Cl)S(=O)(=O)N(C)CCN(C)C

Procedure:
An aqueous solution of hydrogen peroxide (2.8 mls) is added to a cuvette containing 0.0178 gram of the product of Example 1, 0.0859 gram of bis{2,4-dichloro-6-[(2-dimethylaminoethyl)methylsulfamoyl]phenyl}oxalate dihydrochloride, and 0.0221 gram of DECERESOL® Surfactant NI Conc. The materials are mixed thoroughly at ambient temperature to provide an initial concentration of 0.04M for the bis{2,6-dichloro-6-[(2-dimethylaminoethyl)methylsulfamoyl]phenyl}oxalate dihydrochloride, and a concentration of 0.01M for the product of Example 1. A comparison determination is also carried out without the surfactant. The results obtained are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].CC[O:16]C(C)=O>CO>[CH2:12]1[CH:10]([NH:9][C:7]([C:6]2[CH:5]=[N+:4]([O-:16])[CH:3]=[C:2]([Br:1])[CH:13]=2)=[O:8])[CH2:11]1
Reactant: CCOC(C)=O
Reactant: O=C(NC1CC1)c1cncc(Br)c1
Solvent: CO
Product: O=C(NC1CC1)c1cc(Br)c[n+]([O-])c1

Procedure:
Prepared according to the procedure described in EXAMPLE 9 (Step 4) but using 5-bromo-N-cyclopropyl-nicotinamide from Step 1 as starting material. Flash chromatography (EtOAc:MeOH; 9:1) afforded the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1>>[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[CH3:28])[CH2:9]/[C:10](/[C:13]3[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=3)=[N:11]\[OH:12])=[CH:6][CH:7]=2)=[CH:34][CH:35]=1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(N)cc2)cc1

Procedure:
In analogy to example 166, from (E)-5-(3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (example 224) and 4-aminophenylboronic acid pinacol ester (CAS RN: [214360-73-3]) was prepared the title compound as a light brown foam, MS (ESI+): m/z=456.21 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[CH2:10][CH:9]([NH:11]C(=O)OC(C)(C)C)[CH2:8]1.[ClH:24]>CO.O1CCOCC1>[ClH:24].[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[CH2:8][CH:9]([NH2:11])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CN(Cc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product from Example 180A (0.14 g) in methanol (5 mL) was added 4 N HCl in dioxane (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.81 (bs, 2H), 7.95 (m, 1H), 7.84 (m, 2H), 7.71 (t, J=7.73 Hz, 1H), 4.63 (s, 2H), 4.23 (m, 5H); MS (DCI) m/z 231 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O>[N+:21]([C:12]1[CH:13]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:23])=[O:22]
Reactant: Oc1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Oc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
Phenol (1.282 g, 13.63 mmol) in dimethylformamide (20 mL) was treated with 60% sodium hydride (0.545 g, 13.63 mmol). The reaction mixture was stirred for 10 minutes. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (0.75 g, 3.41 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (1:1 ethyl acetate/hexanes) on silica gel to give 0.96 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C1COCC1>[CH2:31]([NH:33][C:34]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:35])[CH3:32]
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)ONC(=O)CCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (0.5 g) in THF was added a THF (2 ml) solution of ethyl isocyanate (0.1 g) at room temperature and the mixture was stirred for 2 hours. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1). The resulting oil was crystallized from hexane to provide the title compound (0.29 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C@@H:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:16]=1)[CH3:2].[CH3:30]O>S(=O)(=O)(O)O>[CH3:30][O:27][C:26](=[O:28])[C@@H:25]([C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[CH2:4][NH:3][CH2:1][CH3:2])[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[CH3:29]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)OC)cc(C(F)(F)F)c1

Procedure:
(R)-2-(2′-Ethylaminomethyl-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-propionic acid (0.04 g, 0.10 mmol) in MeOH (2 mL) was treated with 2 drops of sulfuric acid at room temperature overnight. The mixture was concentrated, and the crude material was used directly in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([O:17][CH3:18])[C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])N.Cl.N([O-])=O.[Na+].[I-:24].[K+]>O>[I:24][C:6]1[CH:5]=[C:4]([O:3][CH3:2])[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: COc1cc(N)cc(OC)c1OCC(F)(F)F
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(I)cc(OC)c1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
The crude 3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)-aniline hydrochloride prepared by the above-described procedure was suspended in water (16 mL), and to the ice-cold suspension were added concentrated hydrochloric acid (0.26 mL, 3.1 mmol) and a solution of sodium nitrite (227.0 mg, 3.29 mmol) in water (2.0 mL) dropwise over about 5 minutes. The resulting mixture was stirred for 15 minutes, and a solution of potassium iodide (562.0 mg, 3.44 mmol) in water (2.0 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and at 50° C. for 15 minutes, then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 1-iodo-3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)benzene as a colorless oil [1.00 g, yield: 88% based on N-t-butoxy-carbonyl-3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)aniline].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].O>COCCOC.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.[Zn]>[CH3:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CBr)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(CC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of Pd(PPh3)2Cl2 (0.86 g, 1.22 mmol) and zinc powder (3.19 g, 48.8 mmol) in 1,2-dimethoxyethane (DME, 100 mL) at room temperature was slowly added a solution of 3-methoxybenzyl bromide (5.0 g, 24.4 mmol) and isobutyryl chloride in DME (25 mL). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with ether. The combined ether extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (20:1) to give 3.03 g (64) of compound (§4 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.09 (d, J=7.0 Hz, 6H), 2.70-2.75 (m, 1H), 3.70 (s, 2H), 3.79 (s, 3H), 6.70-6.85 (m, 3H), 7.23 (t, J=8.0 Hz, 1H).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[O:16]=[C:17]1[S:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18]1.CO>C(OCC)C.CN(C1C=CC=CN=1)C>[CH3:1][O:23][C:22]([CH:19]1[CH2:18][C:17](=[O:16])[S:21][CH2:20]1)=[O:24]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CC(C(=O)O)CS1
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CSC(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
225 g (1.09 mol) of dicyclohexylcarbodiimide (DCC) are added in portions, while cooling with ice, to a solution of 160 g (1.095 mol) of tetrahydro-5-oxo-3-thiophenecarboxylic acid, 70 g (2.19 mol) of methanol and 4 g (32.8 mmol) of dimethylaminopyridine (DMAP) in 2.5 litres of diethyl ether. After 4 hours' stirring at room temperature, the dicyclohexylurea is filtered off and the filtrate is extracted with 500 ml of 2N hydrochloric acid and 500 ml of saturated sodium hydrogen carbonate solution, is washed with water and is dried over sodium sulfate. There are obtained 149 g of solid product having a melting point of 33°-35° C.