Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51](O)=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C(N(C(C)C)C(C)C)C.[CH3:64][NH:65][CH2:66][CH2:67][OH:68]>CN(C=O)C>[F:30][C:28]1[CH:27]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51]([N:65]([CH2:66][CH2:67][OH:68])[CH3:64])=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: CNCCO
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
TBTU (108 mg, 0.34 mmol) was added in one portion to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.103 mL, 0.59 mmol) and 2-(methylamino)ethanol (0.027 mL, 0.34 mmol) in DMF (1 mL). The resulting solution was stirred at RT for 2 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 64%) as a off-white solid. Mass Spectrum: M+H+ 502. NMR Spectrum (DMSOd6 at 323° K): 1.58 (d, 3H), 2.65 (s, 3H), 3.01 (s, 3H), 3.23-3.40 (m, 5H), 3.4-3.71 (m, 7H), 4.74 (bs, 1H), 5.52 (s, 1H), 5.57 (q, 1H), 6.38 (t, 1H), 6.53 (d, 2H), 7.74 (bs, 1H), 7.93 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].CN.[CH2:36]([N:38](CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:38][CH3:36])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 3 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (30 mg, 61 μmol) was dissolved in absolute THF (2 ml), a 2 M solution of methylamine in THF (91 μl, 182 μmol; 3 eq.) and triethylamine (6.1 mg, 61 μmol; 1 eq.) were added at room temperature and the mixture was stirred for 3 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (25 mg, 83% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.C1COCC1.C(N(CC)CC)C.[NH:23]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:24]([C:34](ON1C(=O)CCC1=O)=[O:35])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[NH:23]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:24]([C:34]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:35])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)C[C@H](N)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
In 80 ml of H2O was suspended 4.50 g of H-Asn-OH.H2O, followed by addition of 80 ml of a THF solution containing 4.20 ml of triethylamine and 14.13 g of Boc-Ser(Bzl)-OSu under ice-cooling. The mixture was stirred at room temperature for 20 hours, after which the THF was distilled off. The residual aqueous solution was adjusted to pH 3 with 1M citric acid under ice-cooling and the resulting oily product was extracted with 200 ml of ethyl acetate. The extract was washed with 50 ml of saturated aqueous sodium chloride solution twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was treated with ether/petroleum ether (2:1) for solidification and the resultant powder was reprecipitated from methanol-isopropyl ether to give 8.74 g of Boc-Ser(Bzl)-Asn-OH (yield 71.2%). mp: 138°-139° C. [α]D22 : 10.2° (c=1, DMF) Rf: 0.54 (chloroform:methanol:acetic acid=7:2:1) Amino acid analysis: Asp 1.14 (1), Ser 0.86 (1)
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:19]=[CH:18][C:10]2[C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][O:13][C:9]=2[C:8]=1[CH2:20][CH2:21][CH3:22].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.CCOCC>[CH2:20]([C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]=2[CH:18]=[CH:19][C:7]=1[O:6][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:21][CH3:22]
Reactant: BrCCCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCBr)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF solution (50 mL) of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole as prepared in Example 4 step 2 (6.5 gram, 26.5 mmol) was added 1,4-dibromobutane (16 mL, 133 mmol), followed by cesium carbonate (9.1 grams, 27.8 mmol). The mixture was stirred at room temperature overnight. After aqueous/ether work-up and silica gel chromatography (hexanes: 2.5% ethyl acetate), the title compound was obtained.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=[S:23])[CH2:9][CH2:10][C:11]1[S:12][C:13]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:14]=2[N:15]=1)[CH3:7])C.[OH-].[Na+]>O.O1CCOCC1>[F:22][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]([N:6]([CH3:7])[CH2:5][C:4]([OH:24])=[O:3])=[S:23])[S:12][C:13]=2[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: CCOC(=O)CN(C)C(=S)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(=O)O)C(=S)CCc1nc2c(F)c(F)cc(F)c2s1
Yield: 89 %

Procedure:
To a solution of N-[3-(4,5,7-trifluorobenzothiazol-2-yl)-1-thioxopropyl]-N-methylglycine ethyl ester (190 mg, 0.5 mmol) in a mixture of water (3 ml) and dioxane (6 ml) was added dropwise 2N sodium hydroxide (0.6 mmol) with stirring under ice-cooling and the mixture was stirred for 1 hour at room temperature, then diluted with water and washed with ether. The aqueous phase was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and then evaporated to yield a residue, which was crystallized from isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)-1-thioxopropyl]-N-methylglycine (155 mg, 88%) as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.CN(C)P(N(C)C)(N(C)C)=O.C(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([Cl:23])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: Cc1ncsc1C(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: Cc1ncsc1C(=O)Cl
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 7.2 g (0.05 mole) of 4-methylthiazole-5-carboxylic acid were suspended in 100 ml of toluene, followed by the addition of 0.02 g of hexamethylphosphoramide Under heating and reflux, phosgene was blown at a rate of 1.2 l/hr for 2.5 hours (0.13 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 8.0 g of 4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 99.2% an d99.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.88(3H,s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A solution of p-bromomethylphenylacetic acid (3.64 g, 15.9 mmol) in acetone (100 ml) was treated with a solution of sodium azide (1.04 g, 16.0 mmol) in H2O (15 ml). The mixture was stirred at room temperature overnight (ca. 20 h). After evaporation of the acetone, the residual solution was cooled in an ice-bath. The white gelatinous precipitate that formed was collected, washed with cold water and dried yielding 2.175 g (11.4 mmol, 71.5%) of p-azidomethylphenylacetic acid as a white solid: 1Hmr (DMSO-d6) δ: 3.59 (2H, s, --CH2CO2), 4.42 (2H, s, --CH2N3) and 7.32 ppm (4H, s, aromatic Hs); ir (nujol) νmax : 2500-3400 (b, --CO2H), 2070 (s, --N3) and 1690 cm-1 (s, C=O).
Reaction SMILES: [B:1](Cl)(Cl)[Cl:2].[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl-:2].[Cl-:2].[CH3:5][N:6]([BH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNc1ccccc1
Reactant: ClB(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: BN(C)c1ccccc1
Product: [Cl-]
Yield: 87.7 %

Procedure:
To a solution of boron trichloride (14.77 g) in toluene (60 ml), a solution of methylaniline (13.5 g) in toluene (30 ml) is added dropwise at -20° C. with stirring. A solution of triethylamine (12.8 g) in toluene (20 ml) is added to the above mixture, which is stirred at room temperature overnight. The precipitate is filtered under nitrogen atmosphere and washed with toluene. The filtrate and washings are combined, evaporated under reduced pressure to remove the toluene, and the residue is distilled to give N-methylanilinoborane dichloride (10.5 g) as an oil distilling at 60° to 65° C./3 mm Hg. [Niedenzu, J. Am. Chem. Soc., 81, 5553 (1959)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: COc1ccccc1N
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: COc1ccccc1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-methoxyaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-methoxyphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (68%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.56-8.43 (m, 2H), 7.87 (d, J=7.9 Hz, 2H), 7.45 (d, J=7.9 Hz, 2H), 7.23-7.15 (m, 2H), 7.11-6.96 (m, 3H), 6.90 (d, J=7.9 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.48 (s, 1H), 6.42 (s, 1H), 5.01 (ABq, 2H), 4.85 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.90 (s, 3H), 3.07-2.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.0, 164.7, 161.9, 161.4, 148.1, 141.8, 139.7, 134.9, 132.7, 128.8, 127.8, 127.7, 127.6, 124.1, 124.0, 123.7, 121.2, 120.1, 120.0, 119.8, 118.9, 109.9, 109.1, 93.4, 93.3, 80.7, 72.4, 57.8, 55.8, 43.9, 29.1; MS (ES+) m/z 519.1 (M+1).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[N:17]=[CH:18][C:19]([CH:22]=O)=[N:20][CH:21]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[N:20][C:19]([CH2:22][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:18][N:17]=1
Reactant: O=Cc1cnc(Cl)cn1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(Cc2cnc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium triacetoxyborohydride (870 mg) was added to a solution of 5-chloropyrazine-2-carbaldehyde (390 mg) and 1-methylpiperazine (0.335 mL) in acetonitrile (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (285 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[ClH:11].[CH3:12][NH:13][CH3:14].[CH2:15]=O.Cl>CC(C)=O.C(O)C>[ClH:11].[CH3:12][N:13]([CH3:15])[CH2:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(C(=O)CCN(C)C)cc1
Reaction time: 4 h

Procedure:
53.6 Grams (g) (0.4 mole) of p-methylacetophenone, 42.4 g (0.52 mole) dimethylamine hydrochloride, 15.6 g (0.52 mole) paraformaldehyde and 64 milliliters (ml) ethanol were placed in a round-bottom flask equipped with a condenser and the mixture was heated to reflux with stirring. Next, 0.8 ml of concentrated hydrochloric acid was added to the mixture and refluxing was continued for 4 hours. The mixture was cooled and 600 ml of acetone was added. The desired product precipitated and was filtered and dried. m.p. 162°-163°. Yield: 70 g (76.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[CH3:26][S:27]([O-:29])=[O:28].[Na+].Cl>CS(C)=O.C(OCC)(=O)C.O.[Cu]I>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([OH:25])=[O:24])=[CH:3][C:2]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=2
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc2c1C(=O)O
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc2c1C(=O)O
Temperature: 120 °C
Reaction time: 22 h
Yield: 45.3 %

Procedure:
To a suspension of 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (10 g, 21.94 mmol) in dimethyl sulfoxide (146 mL) was added copper(I) iodide (8.36 g, 43.9 mmol) and sodium methanesulfinate (5.27 g, 43.9 mmol). The reaction mixture was alternately evacuated and purged with nitrogen three times and heated to 120° C. for 18 h. Additional copper(I) iodide (8.36 g, 43.9 mmol) and sodium methanesulfinate (5.27 g, 43.9 mmol) was added, and the mixture was stirred for an additional 22 h. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The mixture was acidified to pH 2-3 with 2N HCl, filtered through Celite®, and rinsed with ethyl acetate. The organic layer was separated, washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.07 g, 30% yield) as an orange solid. MS (m/z) 410.0 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18](C(O)=O)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:23])[CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].O.C(=O)([O-])[O-].[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH3:23][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)[CH:19]=[CH:18]2
Reactant: Cc1ccc2nc(-c3ccc(C(=O)O)cc3)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cc1ccc2nc(-c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 170 °C
Yield: 70 %

Procedure:
In 5 ml of quinoline was dissolved 0.1 g of the 2-(4-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 16 and solution was heated at 170° C. for 0.5 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with dichloromethane, 0.06 g of 4-(6-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.5-8.3 (m,9H); 2.56 (s,3H).
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:1]([S:13]([C:16]1[CH:21]=[C:20]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CCNC1
Reactant: CCCCCCCCCCCCS(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCS(=O)(=O)c1cc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
A mixture of 27.5 g of 2-dodecylsulfonyl-4-chloronitrobenzene, 5.5 g of pyrrolidine, 138 g of potassium carbonate and 70 ml of dimethylacetamide was stirred for 3 hours at 90° C. To this reaction mixture was added 210 ml of water, and the precipitated crystal was collected by filtration and recrystallized with acetonitrile to obtain 12.7 g of 2-decylsulfonyl-4-pyrrolidinonitrobenzene.
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:25][C:3]1[C:2]([S:35][CH:32]2[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]2)=[CH:24][C:6]2[C:7]3[N:11]([CH:10]=[C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)[N:8]=3)[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(F)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 8 (300 mg, 0.738 mmol), 1-isopropylpiperidine-4-thiol (176 mg, 1.107 mmol), Pd2(dba)3 (34 mg, 5 mol %), XantPhos (43 mg, 10 mol %) and DIPEA (0.52 mL, 2.95 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The crude reaction mixture was diluted with DCM (100 mL) and purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by C18, gradient 20-55% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 209 as a white solid (217 mg, 61%). LCMS: RT 3.12 min [M+H]+ 485.1. 1H NMR (DMSO, 400 MHz): δ 8.49 (1H, d, J=8.69 Hz), 7.89 (1H, s), 7.01 (1H, d, J=10.14 Hz), 5.78-5.66 (1H, m), 4.57-4.46 (4H, m), 3.10-3.00 (1H, m), 2.78-2.69 (2H, m), 2.67-2.57 (1H, m), 2.24 (3H, s), 2.15 (2H, bt, J=10.98 Hz), 1.89 (2H, bd, J=12.50 Hz), 1.52-1.39 (8H, m), 0.90 (6H, d, J=6.56 Hz)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])[CH:20]=2)[O:15]1>C(OCC)(=O)C>[CH3:13][C:14]1([CH3:50])[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])[CH:20]=2)[O:15]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C=CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C=CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-{[1-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.42 g, 74%) as a colorless solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].C(N(CC)CC)C>C(O)C>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: Sc1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a suspension of 33.35 g (0.30 mol) of 4-mercaptopyridine and 51.44 g (0.30 mol) of 1-bromo-4-chlorobutane in 500 ml of ethanol, 41.9 ml (0.30 mol) of triethylamine was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and chloroform was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent:ethyl acetate/n-hexane=1:1) to give 54.27 g of the desired compound (89.7% yield, colorless oil).