Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:18]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N+:11]2([O-])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([CH:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCC[N+]2([O-])CCOCC2)ncc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCCN2CCOCC2)ncc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
The 4-[2-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine-N-oxide (78 mg, 0.14 mmol) obtained in Example 61 was dissolved in a mixed solvent of acetic acid (2.0 ml) and water (2.0 ml). The resulting solution was heated to 60° C. and iron powder (40 mg, 0.72 mmol) was added thereto. The resulting mixture was stirred for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous solution of potassium carbonate, followed by extraction with ethyl acetate (60 ml). The extract was washed with brine, dried and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (3% methanol/chloroform solution) to give the title compound (30 mg, 40%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 98.5 %

Procedure:
Following a procedure similar to that described in Example 74(c), but using 1.00 g of 2-butyl-4-(1-hydroxy-2,2-dimethyl propyl)-1-{4-[2-(trityltetrazol-5-yl)-phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (b) above] in 75% v/v aqueous acetic acid, 0.65 g of the title compound was obtained as a glass.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:40]/[O:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)/[C:37](O)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:76][CH:77]1[C:107](=[O:108])[N:79]2[C:80]([C:91]([O:93][CH:94]([C:101]3[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=3)[C:95]3[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=3)=[O:92])=[C:81](/[CH:84]=[CH:85]/[CH2:86][O:87][C:88](=[O:90])[CH3:89])[CH2:82][S:83][C@H:78]12>C1COCC1>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:40]/[O:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)/[C:37]([NH:76][CH:77]2[C:107](=[O:108])[N:79]3[C:80]([C:91]([O:93][CH:94]([C:95]4[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=4)[C:101]4[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=4)=[O:92])=[C:81](/[CH:84]=[CH:85]/[CH2:86][O:87][C:88](=[O:90])[CH3:89])[CH2:82][S:83][C@H:78]23)=[O:38])[N:35]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OC/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)OC/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 1-hydroxybenzotriazole (223 mg, 1.44 mmol) and (Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (1.06 g, 1.44 mmol) in THF (14 ml) was added DCC (300 mg, 1.44 mmol) and the mixture was stirred for 1 hr at 5° C. Diphenylmethyl 7-amino-3-[(E)-acetoxy-1-propenyl]-3-cephem-4-carboxylate (670 mg, 1.44 mmol) was added to the mixture. After stirring for 4 hr at ambient temperature, the reaction mixture was filtered, diluted with ethyl acetate (50 ml) and washed with water. Concentration of the organic layer gave an oil, which was chromatographed on a column of silica gel. Elution with toluene-ethyl acetate (10:1) gave 1.607 g (99%) of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(E)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate as an amorphous powder. IR νmax (KBr) cm-1 1770, 1730. 1H NMR (CDCl3) δ 2.0 (3H, s, OAc), 3.33 (2H, s, 2-H), 4.54 (2H, ABq, CH2OAc), 5.04 (1H, d, J=5 Hz, 6-H), 6.0 (1H, m, vinyl-H), 6.02 (1H, dd, J=5 & 7 Hz, 7-H), 6.40 (1H, s, thiazole-H), 6.82 (1H, d, J=15 Hz, vinyl-H), 7.00 (1H, s, Ph2CH), 7.3 (25H, s, Ph).
Reaction SMILES: B.CSC.[CH3:5][C:6]([NH:9][CH2:10][CH:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18](OC)=[O:19])[OH:12])([CH3:8])[CH3:7].C1(C)C(C([C@@](C(O)=O)(O)[C@@](C(C2C(C)=CC=CC=2)=O)(O)C(O)=O)=O)=CC=CC=1.C1(C)C(C([C@](C(O)=O)(O)[C@](C(C2C(C)=CC=CC=2)=O)(O)C(O)=O)=O)=CC=CC=1>CO>[CH3:8][C:6]([NH:9][CH2:10][C@H:11]([OH:12])[C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH2:18][OH:19])[CH:22]=1)([CH3:5])[CH3:7]
Reactant: COC(=O)c1cc(C(O)CNC(C)(C)C)ccc1O
Agent: B
Agent: Cc1ccccc1C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c1ccccc1C
Agent: Cc1ccccc1C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c1ccccc1C
Solvent: CSC
Solvent: CO
Product: CC(C)(C)NC[C@H](O)c1ccc(O)c(CO)c1

Procedure:
Several patents report synthetic routes using enantiomeric separation, however, the synthetic routes result in low yields of the enantiomerically pure product. Optically pure levalbuterol was synthesized by the borane-methylsulfide reduction of the enantiomerically pure precursor (Formula 2) as described in U.S. Pat. No. 5,399,765. The reaction dissolved a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from (−)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol, upon cooling one stereoisomer crystallized, which was separated, and recrystallized as a diastereomer from methanol, the diastereomer was separated, treated with base, and upon reduction formed optically active levalbuterol.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][N:17]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]([CH2:20][C@H:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18]1>>[C:23]([C@H:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]([CH3:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cn1cc(C[C@@H](N)C(=O)O)c2ccccc21
Product: Cn1cc(C[C@@H](Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c2ccccc21
Yield: 87 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 1-methyl-D-tryptophan to provide the title compound in 87% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=[O:18])[CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[CH:10]([OH:18])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)C(=O)CC2c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(c1)C(O)CC2c1ccc(F)cc1

Procedure:
A solution of 225 grams of 3-(4'-fluorophenyl)-6-methyl-1-indanone in 2.3 liters of methanol was treated with 90 grams of sodium borohydride while cooling and stirring and keeping the temperature below 20 degrees Centigrade.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([NH:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[I:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([I:21])=[CH:23][CH:24]=2)=[O:30])[CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C=Nc1ccc(I)cc1
Reactant: CCCNN(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Solvent: c1ccncc1
Product: CCCN(C(=O)Nc1ccc(I)cc1)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Yield: 84.6 %

Procedure:
2.0 g (7.273 mmol) of 404 are stirred at RT for 1.5 h in 5.0 ml of pyridine with 1.78 g (7.265 mmol) of 4-iodophenyl isocyanate. After customary work-up, 3.2 g (84.7%) of 405 are thus obtained as crystals having a melting point of 184-185° C.; MS(FAB)=521.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Temperature: 50 °C

Procedure:
A solution of quinoline-4-carboxylic acid (173 mg, 1 mmol), and 1,1′-carbonyldiimidazole (162 mg, 1 mmol) in dimethylformamide (2 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (150 mg, 1 mmol), and N,N-diisopropylethylamine (0.262 mL, 1.5 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with chloroform (10 mL). The organic solution was washed with water (3×10 mL), 1 N NaOH (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 156 mg (58%) of 403:
Reaction SMILES: [S:1]1[C:13]2[N:5]([C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=3)[CH2:4][CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[S:1]1[C:13]2[N:5]([C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([CH:14]=[O:15])[CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccc2nc3n(c2c1)CCCS3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2nc3n(c2c1)CCCS3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottomed flask was loaded 1.1 grams of (3,4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol, 6 grams of manganese dioxide and 250 ml chloroform. The mixture was stirred for one hour at room temperature and then filtered through a pad of celite. This yielded 0.67 grams of product (61%). MS: 219.0 (M+H). H-NMR(CDCl3): δ 10.04(s, 1H), 7.67 (m, 3H), 4.25 (m, 2H), 3.27(m, 2H), 2.50 (m, 2H).
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8]([CH:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC)=[O:9])C.[CH3:22][C:23]([CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:24][CH2:25]O.Cl>CCCCCC.O.O1CCCC1>[CH3:21][C:11]([CH:12]=[CH:25][CH:24]=[C:23]([CH3:22])[CH:27]=[CH:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:10][C:8]([OH:7])=[O:9]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CC(C)=CCCC(C)=CC=CC(C)=CCO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC=CC(C)=CC=CC(C)=CC(=O)O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 30.3 g. of sodium ethoxide in 300 ml. of tetrahydrofuran was added 118 g. of diethyl 3-ethoxycarbonyl-2-methyl-2-propenylphosphonate. To the mixture was added 67 g. of 3,7,11-trimethyl-2,4,6,10-dodecatetraene-1-ol under stirring, chilling with ice and shielding from the light. After 1 hour, the reaction liquid was poured into 1 liter of water, and 1 liter of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml. portions of a mixture of methanoland water (2:1), and concentrated to give 99 g. ofa concentrate. To a refluxing solution of 8.2 g. of potassium hydroxide and 80 ml. of isopropyl alcohol was added 21 g. of the concentrate under shielding from the light. After 15 minutes, the reaction liquid was poured into 300 ml. of ice-water, made acidic by addition of hydrochloric acid, and extracted with 300 ml. of diethyl ether. The extract was washed with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was dissolved in 200 ml. of n-hexane and chilled to -20° C. to crystallize it. There was obtained 9.8 g. of the desired product as pale yellow crystals.
Reaction SMILES: [NH:1]([C:17]([O:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1)=[O:18])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)=[O:4].FC(F)(F)C(O)=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(#N)C>C(Cl)Cl>[N:2]([C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)=[O:4])=[N:1][C:17]([O:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:18]
Reactant: CN1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1C(C)(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 23.4 %

Procedure:
To a solution of 30.0 g bis(1,2,2,6,6-pentamethylpiperidin-4-yl) hydrazine-1,2-dicarboxylate in 60 mL of methylene chloride is added 16.0 g (10.8 mL), of trifiuoroacetic acid at 0°-5° C., followed the addition of 22.6 g of iodobenzene diacetate at room temperature. After stirring at room temperature for 2.5 hours, the reaction mixture is washed with saturated sodium bicarbonate solution and then with brine, and dried over anhydrous magnesium sulfate. The dried solution is evaporated to afford a pale yellow oil. Trituration with acetonitrile affords 7.0 g of the title compound as a pale yellow solid; mp 135°-137° C. NMR and IR analyses are consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH2:13].[CH3:15][C:16](=O)[C:17](=O)[CH3:18].CCOC(C)=O>CCO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:12])[C:5]=1[NH2:13])[N:11]=[C:17]([CH3:18])[C:16]([CH3:15])=[N:10]2)=[O:14]
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1N
Reactant: CC(=O)C(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc(C)c(C)nc2c(Cl)c1N
Yield: 60.6 %

Procedure:
To a solution of 1.5 g (6.96 mmol) of 2,4,5-triamino-3-chloro-benzoic acid methyl ester in 27 ml of EtOH, is added 0.81 ml (9.18 mmol) of 2,3-butanedione. The mixture is stirred under reflux during 1 hour. After cooling the mixture to ambient temperature EtOAc is added and the organic phase is washed with H2O (2 times). The organic phase is dried on Na2SO4, filtrated and evaporated. After purification by flash chromatography on silica gel, 1.18 g (4.22 mmol, 62%) of an orange-coloured solid were obtained. 1H-NMR (CDCl3, 300 MHz): ? ppm=2.67 (s, 3H), 2.75 (s, 3H), 3.97 (s, 3H), 6.47 (s br, 2H), 8.58 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(COC)OC.C([O-])([O-])=O.[Na+].[Na+]>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.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[CH3:8])=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)c1sccc1Br
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
Solvent: O
Product: COc1ccc(-c2ccsc2C(C)=O)cc1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
A flask was charged with 1-(3-bromothiophen-2-yl)ethanone (1.00 g, 4.88 mmol), 4-methoxyphenylboronic acid (0.740 g, 4.88 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), dimethoxyethane (50 mL), and 2 N aqueous Na2CO3 (7.3 mL) and then warmed to 80° C. for 7 h. At that time the reaction mixture was poured into H2O and extracted with EtOAc. The organic phase was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography, eluting with 5-15% EtOAc/hexanes to afford the product (0.50 g, 2.2 mmol). MS (M+H)+ 233.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:7](/[CH:19]=[C:20](\[CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)/[C:21]([O:23]CC)=[O:22])=[C:8]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:7](/[CH:19]=[C:20](\[CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)/[C:21]([OH:23])=[O:22])=[C:8]([CH2:10][O:11][Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(/C=C(\Cc2cccs2)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc(CO[Si](C)(C)C(C)(C)C)c(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-(t-butyldimethylsilyloxy)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate (0.287 mmol) in absolute ethanol (3 mL) is treated portionwise with one equivalent of 10% sodium hydroxide solution. After being stirred overnight at 25° C., the reaction is heated to 50° C. for 4 hours, then concentrated in vacuo. The residual product is taken up in water, acidified to pH 5-6 and extracted with methylene dichloride. The isolated, dried, concentrated product is triturated with methanol/ether to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16]CC)=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylate (20 mg, 0.07 mmol) in methanol (0.5 mL), an aqueous solution of 1N NaOH (140 μL, 0.14 mmol) was added. The mixture was left to stand at room temperature for 2 hours, the reaction mixture was acidified using a 1N HCl solution and methanol was removed in vacuo. The aqueous mixture was extracted with ethylacetate (3×3 mL), the organics combined, dried with MgSO4 and filtered before evaporation to dryness in vacuo to obtain 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid (18 mg, 0.07 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]4[C:18]([C:19]=3[CH:20]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.C(O[CH2:31][CH3:32])(=O)C>CCCCCC>[C:7]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:13]5[C:18]([C:19]=4[CH:20]=3)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:4][CH:3]=2)[C:31]2[C:32](=[CH:6][CH:5]=[CH:8][CH:20]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: Brc1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Solvent: CCCCCC
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc(-c5cccc6ccccc56)cc4)ccc32)cc1

Procedure:
The Rf values of the objective substance and 3-(4-bromophenyl)-9-phenyl-9H-carbazole were respectively 0.57 and 0.65, which were obtained by silica gel thin layer chromatography (TLC) (with a developing solvent containing ethyl acetate and hexane in a 1:10 ratio).
Reaction SMILES: [C:1]([C:4]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]([CH3:7])[O:5]1)([OH:3])=O.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:1]([C:4]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]([CH3:7])[O:5]2)=[O:3])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C1(C(=O)O)OC1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)OC1C
Yield: 46.7 %

Procedure:
Ethyl 2-carboxy-3-methyloxiranecarboxylate (5.09 grams, 0.03 mole), prepared in Part B, 4-bromo-2-methylaniline (5.44 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (6.03 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 4.72 grams (0.014 mole) of N-(4-bromo-2-methylphenyl)-2-ethoxycarbonyl-3-methyloxiranecarboxamide having a melting point of 57° C.-60° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(O)c1

Procedure:
To 3-hydroxyphenylacetic acid (5.07 g, 33.32 mmol) in MeOH (50 mL) was added thionyl chloride (4.85 mL, 66.65 mmol) dropwise over 30 minutes by addition funnel. Once no starting material was seen by analytical LCMS, the mixture was concentrated, and the residue was partitioned between EtOAc and 1N aqueous NaOH. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([C:21](=[N:23][OH:24])[CH3:22])=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25]I>C1COCC1>[CH3:25][O:24][N:23]=[C:21]([C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]=1)[CH3:22]
Reactant: CC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON=C(C)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
General Procedure Q. To a suspension of NaH (20 mg, 0.80 mmol) in THF (2 ml) at 0° C. was added a solution of 1-(5,6-diphenyl-pyridin-2-yl)-ethanone oxime (Compound 80, 46 mg, 0.16 mmol) in THF (1 ml). After the mixture was stirred at the same temperature for 1 hour, MeI (140 mg, 0.99 mmol) was added and the solution was stirred overnight at room temperature. The reaction was quenched with water, and the products were extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give title compound as an oil.