Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[C:9](OC(C)=O)[C@@H:8]([O:16][C:17]([CH3:19])=[O:18])[C@@H:7]1[O:20][C:21]([CH3:23])=[O:22])=[O:3].N1C=CC=CC=1.Cl.C(Cl)(Cl)Cl.[OH:35][NH2:36]>>[C:17]([O:16][C@H:8]1[C@H:7]([O:20][C:21](=[O:22])[CH3:23])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][CH2:10][C:9]1=[N:36][OH:35])(=[O:18])[CH3:19]
Reactant: CC(=O)OC[C@H]1OC=C(OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OCC(=NO)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
[litt=F. W. Lichtenthaler and P. Jarglis. Tetrahedron Letters 21 (1980) 1425-1428] To a solution of 2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal (7.90 g, 23.9 mmol) in dry pyridine (40 mL, 496 mmol), HONH2, HCl (5.85 g, 84.2 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was concentrated and dissolved in CHCl3 (300 mL). The organic phase was washed with 1 M HCl (aq., 75 mL), sat. aq. NaHCO3 (75 mL) and H2O (75 mL), dried (MgSO4) and evaporated to a syrup of 2, (7.19 g, 99%). By addition of a small volume of EtOH the product crystallysed (4.43 g, 61%, mp 86-89° C.). Two recrystallisations from toluene afforded an analytical sample: mp 90-92° C.; [α]D−39.4° (c 1.3, CHCl3) [Lit. mp 89-90° C., [α]D−39.0 (c 0.4, CHCl3)].
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]([NH:8][C:9](N)=[O:10])=[O:7]>>[NH:1]1[C:9](=[O:10])[NH:8][C:6](=[O:7])[NH:4][C:2]1=[O:3]
Reactant: NC(=O)NC(N)=O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
Cyanuric acid can be produced by heating urea or biuret in a solvent medium. During the process, particles of cyanuric acid are formed as a slurry in the hot solvent. Previous processes have employed operations to cool the reaction slurry and to separate the cyanuric acid from the slurry in which cyanuric acid was deposited on the cooling surfaces and the resulting product was discolored.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[Na+].[I-:18].CNCCNC>O1CCOCC1.[Cu]I>[I:18][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: COc1ccc(Cc2cc(Br)sc2C)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cc2cc(I)sc2C)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of bromide 10 (1.5 g, 5.05 mmol) in 1.4-dioxane (10 mL) were added NaI (1.5 g, 10.1 mmol), CuI (0.1 g, 0.51 mmol) and N1,N2-dimethylethane-1,2-diamine (0.11 mL, 1.01 mmol) at room temperature. The reaction mixture was evacuated and backfilled with nitrogen. The mixture was stirred 120° C. for 18 hours. The mixture was cooled to room temperature and filtered off through celite. The filtrate was extracted with EtOAc/H2O (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 11 was dried under high vacuum and used without further purification (2.32 g, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:16][CH2:15][N:23]2[C:11](=[O:12])[C:6]3=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]3[C:8]2=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCc1ccccc1
Reaction time: 2.5 h
Yield: 88.6 %

Procedure:
A mixture of 4-nitrophthalic anhydride (18 g, 93.3 mmol) and phenethylamine (11.5 g, 95 mmol) in toluene (250 mL) was heated to reflux. After 2.5 h, the mixture was concentrated to solid residue, which was triturated and filtered to yield the title compound (24.5 g, 89%). Mp 142°-3° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[CH:26]2[CH2:30][CH2:31][CH2:32][CH2:33][CH:25]12.[Na]>CN(C)C=O>[C:24]1(=[O:34])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:27](=[O:29])[CH:26]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:25]3[C:24]2=[O:34])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:29])[CH:26]2[CH2:30][CH2:31][CH2:32][CH2:33][CH:25]12
Reactant: O=C1NC(=O)C2CCCCC12
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1C2CCCCC2C(=O)N1CCOC(OCCN1C(=O)C2CCCCC2C1=O)(C(=O)c1ccccc1)c1ccccc1
Yield: 91.2 %

Procedure:
Benzil-di-(β-bromoethyl)ketal (13.26 g) and 11.55 g of sodium hexahydrophthalimide were dissolved in 100 ml of N,N-dimethylformamide, and heated at 50° to 60° C. for 5 hours with stirring. The reaction mixture was worked up in the same way as in Example 4 to afford 16.05 g (yield 89.5%) of benzil-di-(β-hexahydrophthalimidoethyl)ketal. Recrystallization from a mixture of ethanol and chloroform afforded crystals having a melting point of 115°-116° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[N:4][N:3]=2)[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(OC)c2cnnc(Cl)c2c1
Product: COc1cc(OC)c2cnnc(NC3CCN(Cc4ccccc4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 2.4 by reacting 1-chloro-5,7-dimethoxyphthalazine with 4-amino-1-benzylpiperidine.
Reaction SMILES: C(N(CC)CCC1C=CC([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)=CC=1)C.Br[C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH:36][C:37](=[O:39])[CH3:38]>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([NH:36][C:37](=[O:39])[CH3:38])=[C:29]([C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:24](=[O:25])[NH:23][CH2:22][CH2:21][C:20]=2[C:19]=34)[CH:34]=1
Reactant: CC(=O)Nc1ccc(F)cc1Br
Reactant: CCN(CC)CCc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Product: CC(=O)Nc1ccc(F)cc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for 2-[4-(2-diethylamino-ethyl)-phenyl]-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (Example YY), the tricyclic bromide (300 mg, 1.13 mmol) and N-(2-bromo-4-fluoro-phenyl)-acetamide (276 mg, 1.19 mmol) were coupled to yield N-[4-fluoro-2-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-phenyl]-acetamide, 83 mg (22%) as a beige solid: m.p. 260-261° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ1.97 (s, 3H), 2.66 (m, 2H), 3.33 (m, 2H), 7.25 (m, 3H), 7.56 (dd, J=7.5, 0.6 Hz, 1H), 7.70 (dd, J=7.2, 0.6 Hz, 1H), 7.76 (m, 1H), 8.04 (br t, 1H), 11.50 (br s, 1 H). MS (FAB, MH+): 338. Anal. (C16H19FN3O2.0.16 H2O) C, H, N.
Reaction SMILES: [BH4-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CC(O)C>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc[nH]c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(c1ccccc1)n1cccc1

Procedure:
Papireddy, K. et al. have recently disclosed the antimalarial activity of prodiginines. In this paper, the authors disclosed the synthesis of 2-alkylated pyrroles and 3-alkylated pyrroles. The intermediates were subsequently used to generate synthetic analogs of prodiginines. In order to generate 2-alkylated pyrroles, pyrrole was acylated using zinc powder to afford 2-acylpyrroles. The 2-acylpyrroles were reduced to the corresponding 2-alkylated pyrroles using an excess of sodium borohydride in 2-propanol under reflux. In order to generate 3-alkylated pyrroles, pyrrole was treated with phenylsulfonyl chloride in the presence of sodium hydroxide to provide N-phenylsulfonylpyrrole. Use of aluminum trichloride permitted the regioselective acylation of the N-phenylsulfonylpyrrole at the 3 position with an acyl chloride to afford N-phenylsulfonyl-3-acylpyrroles. The N-phenylsulfonyl-3-acylpyrroles were hydrolyzed under basic conditions to afford 3-acylpyrroles. In the final step, 3-acylpyrroles were reduced to afford 3-alkylpyrroles using sodium borohydride under reflux. See, Papireddy, K. et al., “Antimalarial Activity of Natural and Synthetic Prodiginines”, J. Med. Chem., 54:5296-5306 (2011).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.[N:37]1C=CN=CC=1C(O)=O>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:37][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: O=C(O)c1cnccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(F)cc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccc(F)cc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2,4-difluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 229 and pyrazine-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:45][C:46]([CH3:50])=[CH:47][CH2:48]O>O1CCCC1>[CH3:45][C:46]([CH3:50])=[CH:47][CH2:48][O:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(C)=CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)=CCOC1=CC(=O)c2ccccc2C1=O
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
To a stirred solution of 2-hydroxynaphthalene-1,4-dione (10.0 g, 57.4 mmol) and triphenylphosphine (15.1 g, 57.4 mmol) in dry tetrahydrofuran (150 ml) at 0° C. under an atmosphere of nitrogen was added diethyl azodicarboxylate (10.0 g, 57.4 mmol). After stirring for a further 5 minutes, a solution of 3-methylbut-2-enol (7.42 g, 86.1 mmol) in dry tetrahydrofuran (10 ml) was added dropwise and stirring was continued for 2 hours. The precipitate was collected, air-dried and recrystallised from aqueous methanol to yield the title compound (8.3 g) as a yellow crystalline solid with a melting point of 138° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:27][C:28]1[O:32][C:31]([CH3:33])=[N:30][CH:29]=1>CN(C)C=O>[CH3:33][C:31]1[O:32][C:28]([CH2:27][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:29][N:30]=1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reactant: Cc1ncc(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 26 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole in 282 parts of N,N-dimethylformamide there were added 4.8 parts of a dispersion of sodium hydride in mineral oil (50%) under a nitrogen atmosphere. After stirring for 1 hour, there was added portionwise a solution of 15 parts of 5-(bromomethyl)-2-methyloxazole in 47 parts of N,N-dimethylformamide, while cooling in an ice-bath (<20° C.). The whole was stirred for 18 hours and allowed to warm to room temperature. The oily layer was separated and discarded. The N,N-dimethylformamide layer was poured into water and the whole was extracted with 4-methyl-2-pentanone (3×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was successively crystallized from 2,2'-oxybispropane and acetonitrile, yielding 14.31 parts (42.0%) of 1-[(2-methyl-5-oxazolyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 108.6° C. (comp. 1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)=[O:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:40][C:41]([CH3:43])=[O:42]>C(Cl)Cl>[C:15]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:41]([OH:42])([CH3:43])[CH3:40])[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 3,5-di-tert-butyl-4-hydroxyacetophenone (Apim Chemicals, Ltd.) (4 g) in dry methylene chloride (250 mL) is cooled to -78° C. and di-isopropyl ethylamine (7.3 mL) is added followed by trimethylsilyl trifluoromethanesulphonate (Aldrich Chemical Co.) (8.0 mL). The mixture is stirred at -78° C. for 10 minutes and is allowed to warm to ambient temperature over 1 hour. The mixture is cooled again to -78° C. and dry acetone (4.05 mL) is added dropwise. After stirring for 25 minutes, the mixture is washed with 1N aqueous hydrochloric acid and brine. The organic solution is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is dissolved in methanol-1N aqueous HCl mixture (10:1, v/v, 200 mL) and the homogenous solution is stirred for 1 hour at room temperature. Methanol is removed under reduced pressure; the mixture is washed with methylene chloride. The organic extracts are washed: with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The crude product is crystallized from hexane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-methyl-butan-1-one as orange crystals. Two additional crystallizations give product of analytical purity, mp 113°-14° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:19])[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:19][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@@](C)(OC)[C@H](O)COCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC[C@@](C)(OC)[C@@H](COCc1ccccc1)OC1CCCCO1

Procedure:
A solution of (2R,3R)l-benzyloxy-3-methoxy-3-methyl-6-heptene-2-ol (10) (37.1 mmol, 9.8 g), dihydropyran (55.7 mmol, 5.1 ml) and pyridinium paratoluene sulfonate (3.71 mmol, 0.93 g) in anhydrous dichloromethane (100 ml) is stirred under nitrogen atmosphere for 24 h. Ether (400 ml) is added, and the organic layer is washed with water, brine, saturated aqueous NaHCO3 and brine. After drying over anhydrous magnesium sulfate the solvent is flash evaporated. The product 11b is used as such in the next reaction.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1)=[O:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[S:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: O=Cc1cc(C(=O)O)cs1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(C=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g). 5-Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3-thiophenecarboxylic acid ethyl ester (0.71 g). 5-Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (0.7 g). 5-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (5 ml), and 1N aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].C(N(CC)CC)C.[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:17][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]3)[C:2]=2[CH3:1])=[O:34])=[CH:31][CH:30]=1)([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2ccc(OC(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
To a solution of 117 mg (0.500 mmol) of 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine, 0.26 mL (1.5 mmol) of triethylamine, and 4-isopropoxybenzoic acid in 2.5 mL of DMF was added HATU at RT. The reaction mixture was stirred at RT for 19 hours then partitioned between 50 mL of EtOAc and 50 mL of water. The organic layer was washed with 50 mL of saturated NaHCO3 solution, dried (MgSO4) and concentrated. Column chromatography (0->30% ethyl acetate/hexanes in 10 minutes) gave 175 mg (0.443 mmol, 88%) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1[C:26](OC)=[O:27].COC1C=CC(OC)=CC=1B(O)O>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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([O:27][CH3:26])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(OC)c(B(O)O)c1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Yield: 69 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2,5-Dimethoxyphenylboronic acid (2.42 g, 13.3 mmol) to afford 2.08 g (69%) of methyl (2', 5'-dimethoxy-4-nitro-2-biphenylcarboxylate) as a white solid. Data for methyl (2', 5'-dimethoxy-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.70 (d, J=2.4, 1H), 8.37 (dd, J=8.4, 2.5, 1H), 7.52 (d, J=8.5, 1H), 6.92 (dd, J=8.8, 3.0, 1H), 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [Li][C:2]1([Si](C)(C)C)[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl[C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[CH3:21][O:20][C:18]([CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCCc2cc(C)cnc21
Temperature: 25 °C

Procedure:
8-Lithio-5,6,7,8-tetrahydro-3-methyl-8-trimethylsilylquinoline, prepared as in Example 3, is treated with 1 equivalent of methyl chloroformate in THF at -20° C. under nitrogen. After the addition the mixture is allowed to warm to ambient temperature and the solvent removed by evaporation. The residue is dissolved in 2NHCl and washed with ether basified with Na2CO3 and extracted with chloroform. The extracts are dried and evaporated. Distillation of the residue gives the title compound as a pale yellow oil bp 120°/0.25 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]([CH3:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][C:11]([CH3:20])([C:16]([F:19])([F:17])[F:18])[C:12]([F:13])([F:14])[F:15])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)CC(C)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(CS(=O)c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To 1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene (4.13 g, 13.0 mmol) in carbon tetrachloride (50 mL) add NBS (2.31 g, 13.0 mmol), benzoyl peroxide (314 mg, 1.30 mmol) and stir overnight at reflux. Cool to ambient temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the title compound as colorless oil (2.3 g, 55%).