Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:11]([CH3:13])[CH2:12][N:6]12.C(Cl)(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>O.O1CCCC1>[CH3:1][NH:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[C:11]([CH3:13])=[CH:12][N:6]12
Reactant: CNC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(=O)C=C1CSc2c(C(=O)OC(C)C)c(C)cn21
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
15.3 g of N-methyl-(7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)acetamide was dissolved in a solvent mixture comprising 300 ml of chloroform and 120 ml of tetrahydrofuran. Then 11.7 g of 2,3-dichloro-5,6-dicyano-parabenzoquinone was added thereto under stirring and cooling with cold water. After 0.5 hour, a saturated aqueous solution of sodium hydrogencarbonate was added thereto. After stirring, the insoluble matters were filtered off with the use of celite and the filtrate was extracted with chloroform. The chloroform phase was washed with water and a saturated aqueous solution of sodium chloride and dried. After distilling off the solvent, the obtained crude crystals were recrystallized from ethanol. Thus 12.5 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH3:23][N:24]([CH3:28])[C:25](=[O:26])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(N)ccc2n1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2cc(NC(=O)N(C)C)ccc2n1
Temperature: 0 °C
Yield: 24.5 %

Procedure:
Ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (0.975 mmol, 0.2 g) was dissolved in THF (10 ml). Triethylamine (2.92 mmol, 0.296 g) was added and the reaction mixture was cooled to 0° C. Dimethylcarbamyl chloride (1.462 mmol, 0.135 ml) was added carefully and the mixture was allowed to warm to ambient temperature with stirring. More of dimethylcarbamyl chloride (1.462 mmol, 0.135 ml) was added and the stirring continued for another hour. The solvent was evaporated, DCM was added and the resulting mixture was washed with NaHCO3 solution and water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.066 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H), 2.95 (s, 6H), 4.29 (q, 2H), 7.39-7.44 (m, 1H), 7.50-7.54 (m, 1H), 8.41 (s, 1H), 8.54 (s, 1H), 8.89-8.93 (m, 1H).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[N:5]=[CH:4]1.O=S(Cl)[Cl:17].[CH3:19]O>>[ClH:17].[ClH:1].[CH3:19][O:13][C:12]([CH:7]1[C:6]2[N:5]=[CH:4][NH:3][C:11]=2[CH2:10][CH2:9][NH:8]1)=[O:14]
Reactant: O=C(O)C1NCCc2[nH]cnc21
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)C1NCCc2[nH]cnc21

Procedure:
32.3 g (0.134 moles) of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylic acid dihydrochloride in 500 ml of methanol were treated below -5° C. with 16 ml (0.220 moles) of SOCl2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])(=O)[CH3:2].I[C:16]1[CH:21]=CC=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C)([O-])=O.[Cu]>[NH:4]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])[C:1]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:2]=1
Reactant: COC(=O)c1cccc(NC(C)=O)c1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1cccc(Nc2ccccc2)c1

Procedure:
In accordance with the method described in Zhur. Obshchei Khim 30, 2693 (1960), methyl 3-acetylaminobenzoate was reacted with iodo benzene in nitromethane in the presence of potassium carbonate and active copper powder to yield 3-anilinobenzoic acid and the intended product was obtained by the following steps. ##STR254##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]([CH2:15][CH2:16][O:17][CH3:18])[CH3:14])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1COCC1.ClCCl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]([CH2:15][CH2:16][O:17][CH3:18])[CH3:14])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccc(CCl)cc3)sc12
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To a stirred solution of 300 mg (1.12 mmol) 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine and 1.12 ml (6.56 mmol) N-ethyldiisopropylamine in 10 ml THF at room temperature was added dropwise a solution of 257 mg (1.36 mmol) 4-(chloromethyl)-benzoyl chloride in 3 ml dichloromethane and stirring continued at room temperature for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether and hexane afforded 200 mg (42%) 4-chloromethyl-N-{4-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-benzothiazol-2-yl}-benzamide as a light yellow crystalline solid. ES-MS m/e (%): 422 (M{37Cl}+H+, 32), 420 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([N:32]([C:37]2[C:55]([CH:56]3[CH2:58][CH2:57]3)=[CH:54][C:40]3[C:41]([C:51](O)=[O:52])=[C:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[O:43][C:39]=3[CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:25][C:26]1[CH:27]=[C:28]([N:32]([C:37]2[C:55]([CH:56]3[CH2:58][CH2:57]3)=[CH:54][C:40]3[C:41]([C:51]([NH:2][CH3:1])=[O:52])=[C:42]([C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[O:43][C:39]=3[CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)N(c1cccc(Br)c1)c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1C1CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 1 h
Yield: 79.3 %

Procedure:
HATU (237 mg, 0.624 mmol) was added to a solution of 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylic acid (283 mg, 0.520 mmol), methylamine hydrochloride (70.2 mg, 1.040 mmol) and DIEA (0.318 mL, 1.819 mmol) in DMF (2 mL) at room temperature. The mixture was stirred for one hour. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate) to give 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (230 mg, 79%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 1H) 8.12 (s, 1H) 7.96 (dd, J=8.98, 5.47 Hz, 2H) 7.60 (t, J=2.05 Hz, 1H) 7.27-7.54 (m, 5H) 7.18 (s, 1H) 3.41 (s, 3H) 2.82 (d, J=4.69 Hz, 3H) 2.07-2.22 (m, 1H) 0.65-1.09 (m, 3H) 0.41 (m, 1H). LCMS (m/z, ES+)=557, 559 (M+H, M+2).
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:17](C1NC=CN=1)(C1NC=CN=1)=O.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>O1CCCC1>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:17]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(=O)NCCCN(C)C

Procedure:
1.37 gm (6 meq) of myristic acid and 972 mg (6 meq) of carbonyl diimidazole are combined in a minimum volume of tetrahydrofuran and reacted at room temperature for 1 hour. 0.8 Ml (6 meq+10%) of 3-dimethylaminopropylamine is added and reacted overnight at room temperature. The reaction mixture is evaporated under reduced pressure, dried in vacuo and the desired product purified by silica gel chromatography in the system CH2Cl2 :CH3OH:NH4OH (65:25:4). Fractions 53-65 are combined, evaporated and dried in vacuo to yield 325 mg of title compound having a m.p. of 46°-48° C. after recrystallization from acetone/water.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14]1)[CH:7]=[CH:6]2)#[N:2].Cl.[OH:26][NH2:27].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.ClCCl>[OH:26][NH:27][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:14]1)[CH:7]=[CH:6]2
Reactant: NO
Reactant: CC(C)(C)C(=O)NC1CCN(c2ccc3cc(C#N)ccc3n2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)NC1CCN(c2ccc3cc(C(=N)NO)ccc3n2)C1
Temperature: 90 °C

Procedure:
A mixture of the product of Step D (60 mg; 0.1863 mmol), hydroxyl amine hydrochloride (3 eq.), sodium carbonate (4 eq.) in 1.5 mL water and 2.5 mL ethanol was heated to 90° C. for 6 h. The mixture was diluted with dichloromethane, washed twice with brine, dried over sodium sulfate, filtered through a fritted funnel and the volatiles were removed under vacuum. This provided the product, MS: m/z 356, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:38]=[CH:37][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][CH:21]=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[CH:40](C)C(=O)C.C([O-])([O-])=O.[Ca+2].CN1C(=O)CCC1>C(#N)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:36])[N:15]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:16]([CH3:25])=[C:17]([C:19]3[O:20][C:21]([CH3:40])=[C:22]([CH3:24])[N:23]=3)[CH:18]=2)=[O:12])=[CH:37][CH:38]=1)(=[O:3])=[O:4]
Reactant: Cc1coc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)oc1C
Temperature: 140 °C
Yield: 12.8 %

Procedure:
6-Methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3,5-dicarboxylic acid 5-amide 4-methanesulfonyl-benzylamide (see Example 60, 0.05 g, 0.098 mmol), 3-bromo-2-butanone (0.020 g, 0.20 mmol), CaCO3 (0.015 g, 0.15 mmol), NMP (1.5 ml) and a magnetic stirrer bar were placed in a tube designed for microwave synthesis. The vial was sealed and the mixture was heated in a CEM Discover Microwave apparatus (100 W, 140° C.) for 2 h. The reaction was stopped and the crude mixture was dissolved in acetonitrile (2 ml) and water (2 ml) and was purified directly on preparative HPLC, giving the title compound (0.007 g, 13%) as a slightly brownish solid after freeze-drying the pure fractions.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:3]=1[CH2:4][N:5]1[CH2:9][CH:8]=[CH:7][N:6]1O.P(Br)(Br)([Br:18])=O>C(Cl)(Cl)Cl>[Br:18][C:9]1[N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:14][CH:13]=[CH:12][C:11]=2[F:15])[N:6]=[CH:7][CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: ON1C=CCN1Cc1c(F)cccc1F
Solvent: ClC(Cl)Cl
Product: Fc1cccc(F)c1Cn1nccc1Br
Temperature: 25 °C
Yield: 96.3 %

Procedure:
2-(2,6-Difluorobenzyl)-1-hydroxy-1H-pyrazole (81.2 mg, 0.386 mmol, 1.0 eq) and 5 ml of anhydrous CHCl3 were combined in a flame-dried 25 mL round-bottom flask under argon and cooled in an ice/water bath. A solution of POBr3 (398.1 mg, 1.39 mmol, 3.60 eq) in 3 mL of CHCl3 was added using a syringe in aliquots over an hour period with stirring. The reaction solution was warmed to room temperature and stirred for 16 hours. The CHCl3 was removed in vacuo and the resulting orange mixture was neutralized with saturated aqueous NaHCO3 and extracted with 3×30 mL of diethyl ether. The combined ether fractions were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 101.5 mg (96.7% yield) of 5-bromo-1-(2,6-difluorobenzyl)-1H-pyrazole as a hygroscopic orange-tan colored solid. 1H NMR (CDCl3 300 MHz) δ 7.51 (d, 1H), 7.34 (m, 1H), 6.94 (t, 2H), 6.29 (d, 1H), 5.50 (s, 2H). LC/MS (ES) M+1=273.1, 275.1
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[OH:13])=[O:5])[CH2:3][CH2:2]1.[IH:14]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:1][CH2:2][CH2:3][I:14])=[C:7]([OH:13])[CH:8]=1
Reactant: I
Reactant: O=C(c1ccc(F)cc1O)C1CC1
Product: O=C(CCCI)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
30.6 Parts of cyclopropyl (4-fluoro-2-hydroxyphenyl)methanone were added portionwise to 450 parts of hydroiodic acid solution 50%. The whole was heated to reflux and stirring was continued for 1.50 hours at reflux temperature. The reaction mixture was cooled to 0° C. The precipitated product was filtered off and dissolved in 300 parts of trichloromethane. The solution was dried, filtered and evaporated. The residue was dissolved in 210 parts of petroleum ether while heating. The solution was treated twice with activated charcoal and the latter was filtered off each time. The filtrate was evaporated and the residue was suspended in 35 parts of petroleumether. After cooling to 0° C., the product was filtered off and dried, yielding 36.4 parts (70%) of 1-(4-fluoro-2-hydroxyphenyl)-4-iodo-1-butanone; mp. 41.4° C. (intermediate 89).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:19]=[O:20])[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[Br:7].C1(C)C=CC=CC=1.[CH2:28](O)[CH2:29][OH:30]>C(OC(C)C)(C)C>[Br:1][C:2]1[N:3]=[C:4]([CH:19]2[O:30][CH2:29][CH2:28][O:20]2)[N:5]([CH2:8][C:9]2[C:17]([Cl:18])=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[C:6]=1[Br:7]
Reactant: OCCO
Reactant: O=Cc1nc(Br)c(Br)n1Cc1cc2c(cc1Cl)OCO2
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2

Procedure:
The product obtained in Stage 2 above is introduced into 200 ml of toluene, 20 ml of ethylene glycol is added and the reaction medium is taken to reflux overnight then evaporated to dryness. 200 ml of a saturated solution of sodium hydrogen carbonate is added which is extracted 3 times with 200 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride, then dried and evaporated to dryness. The residue obtained is impasted in isopropyl ether, filtered and dried. In this way 13.5 g of expected product (solid) is obtained. M.p.=188° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.[OH-].[Na+].Cl>CO>[C@@H:16]([NH:15][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[N:7]=1)[C:3]([OH:20])=[O:2])([CH2:18][CH3:19])[CH3:17]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(-c2nn[nH]n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(-c2nn[nH]n2)n1
Reaction time: 8 h

Procedure:
Treat a solution of (S)-2-sec-butylamino-6-(2H-tetrazol-5-yl)-isonicotinic acid methyl ester (250 mg, 0.91 mmol) in methanol (4 mL) at room temperature with 2 N NaOH (1.36 mL, 2.72 mmol). Stir overnight, acidify with 1 N HCl to about pH=3, concentrate and lyophilize to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[O:17][C:16]([F:28])([F:27])[F:15])=[O:21])=[CH:30]1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(c1ccccc1OC(F)(F)F)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-(2-trifluoromethoxy-phenyl)-methanone was prepared from phenanthridine, 2-(trifluoromethoxy)benzoyl chloride, and indole according to GP 2. Yield, 31%. 1H-NMR (DMSO-d6): δ=6.16 (s, br., 1H), 6.25 (d, J=7.9 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 7.00-7.12 (m, 4H), 7.23-7.29 (m, 1H), 7.36 (s, br., 1H), 7.37-7.59 (m, 6H), 7.85-7.95 (m, 2H), 8.05 (d, J=7.5 Hz, 1H), 10.68 (s, 1H); (+)-ESI-MS: m/z=485 [M+H]+, 368 [M-indole+H]+; (−)-ESI-MS: m/z=483 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(OCC)(=O)C>O1CCCC1>[CH2:34]([O:33][C:31]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:32])[CH3:35]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc2c(s1)CCN([C@H](C(=O)OC)c1ccccc1Cl)C2
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
(2S)-Methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (85 mg) was dissolved in 10 ml of anhydrous tetrahydrofuran, and 0.141 ml of triethylamine was added at room temperature and stirred for 10 min. Then, 0.167 ml of ethyl chloroformate was added dropwise at 0° C. After the addition, the reaction solution became a light yellow cloudy solution from a dark red clear solution. The ice bath was removed and the reaction was warmed to 10° C. for 1 hr. Then, 0.07 ml of triethylamine and 0.1 ml of ethyl chloroformate were additionally added in an ice bath at 0° C. The ice bath was removed and the reaction was warmed to 10° C. for 1 hr, at which the raw materials substantially disappeared. Water (20 ml) was added, the reaction solution was extracted with ethyl acetate (30 ml×3) and dried over anhydrous sodium sulfate, and the solvent was evaporated to give a crude product, which was subjected to flash column chromatography (petroleum ether:ethyl acetate=40:3) to obtain (S)-methyl 2-(2-(ethoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-14) (77 mg). Yield 75%, mp: 42-44° C., ee=97.3% (chiral HPLC analysis conditions were the same as those in Example 4), [α]D20=+40.00° (c 0.50, MeOH); 1H-NMR (300 MHz, CDCl3) δ 1.37 (t, 3H, J=7.2 Hz), 2.76-2.78 (m, 2H), 2.86-2.90 (m, 2H), 3.52 (d, 1H, J=14.2 Hz), 3.64 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.32 (q, 2H, J=7.1, 14.3 Hz), 4.90 (s, 1H), 6.30 (s, 1H), 7.24-7.68 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 14.4, 25.4, 48.4, 50.5, 52.4, 65.7, 68.1, 112.7, 126.2, 127.4, 129.7, 129.8, 130.1, 130.2, 134.0, 135.0, 152.9, 157.3, 171.5; ESI-MS m/z 410.1 [M+H]+, 432.1 [M+Na]+; HRMS Calcd for C19H21NO5SCl [M+H]+ m/z 410.0836. found 410.0829.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:23])=O>>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
13.9 g of p-n-decyloxybenzoic acid was heated with excess thionyl chloride for 1 hour under reflux. p-n-Decyloxybenzoic acid chloride was obtained after distilling unreacted thionyl chloride off. 10.6 g of the above prepared p-hydroxybenzoic acid 2-methylbutyl ester was dissolved in 40 ml of pyridine. When the solution was cooled, a toluene solution of said p-n-decyloxybenzoic acid chloride was admixed therewith under stirring to effect reaction at 80° C. for 2 hours. The solution was then acidified by the addition of ice and 6N hydrochloric acid. After the organic layers were washed with water, then with a 2N aqueous sodium hydroxide solution, and again with water, the solvent was distilled off. The residue was recrystallized twice from ethanol to obtain p-n-decyloxybenzoic acid p'-(2-methylbutoxycarbonyl)phenyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Yield: 63.7 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (5 g, 19.57 mmol)[prepared in Preparation 2], 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.28 g, 20.55 mmol)[prepared in Preparation 1], potassium carbonate (10.82 g, 78 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.500 g, 0.978 mmol) in 1,4-dioxane (82 ml) and water (16.31 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (3.2 g, 12.47 mmol, 63.7% yield) as a white solid: LCMS m/e ES 257, 259 (M, M+2)+.
Reaction SMILES: ClC1C=C([C@@H]2C3C(=CC=CC=3)[C@H](NC([C:22]3[CH:27]=[CH:26][N:25](C)[C:24](=[O:29])[C:23]=3[OH:30])=O)CC2)C=CC=1Cl.[B-](Cl)(Cl)(Cl)[S+](C)C>C(Cl)Cl.ClCCCl>[NH:25]1[CH2:26][CH2:27][CH2:22][C:24]1=[O:29].[NH:25]1[CH2:26][CH2:27][CH2:22][C:23](=[O:30])[C:24]1=[O:29]
Reactant: Cn1ccc(C(=O)N[C@@H]2CC[C@H](c3ccc(Cl)c(Cl)c3)c3ccccc32)c(O)c1=O
Agent: C[S+](C)[B-](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCCN1
Product: O=C1CCCNC1=O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of Example 8A (13 mg, 0.028 mmol) in DCM (0.5 mL) and DCE (0.5 mL) was added boron trichloride-methyl sulfide complex (30.6 mg, 0.171 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was quenched with ice and MeOH and example 8 isolated via prep HPLC (10 minute gradient from 5 to 100% B; Column: Phenomenex AXIA Luna 100×20 mm 5 μm; Solvent A: 10% ACN-90% H2O-0.1% TFA; Solvent B: 90% ACN-10% H2O-0.1% TFA). The desired fractions were evaporated to dryness to give Example 8 (5 mg, 0.01 mmol, 40% yield). LCMS RT=2.27 min, [M+1]=443.1 {(MeOH/H2O/TFA) Phenom. Luna C18; 50×4.6 mm; 4 min Grad}; HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=11.2 min, 95%}; Xbridge {RT=9.9 min, 96.3%}. 1H NMR (500 MHz, MeOD) δ ppm 2.01-2.06 (m, 3H) 2.19-2.25 (m, 1H) 3.59 (s, 3H) 4.20 (t, J=6.33 Hz, 1H) 5.33 (t, J=5.64 Hz, 1H) 6.74 (d, J=7.43 Hz, 1H) 6.86 (d, J=7.70 Hz, 1H) 7.10 (dd, J=8.25, 1.93 Hz, 1H) 7.14 (d, J=7.43 Hz, 1H) 7.18 (t, J=7.57 Hz, 1H) 7.24 (t, J=7.29 Hz, 1H) 7.34 (d, J=2.20 Hz, 1H) 7.39 (d, J=7.43 Hz, 1H) 7.43-7.46 (m, 1H).