Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:35]([CH3:40])([CH3:39])[CH:36]([CH3:38])[CH3:37])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][OH:30])[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[CH3:41][Si:2]([CH3:1])([C:35]([CH3:39])([CH3:40])[CH:36]([CH3:37])[CH3:38])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][O:30][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](CO)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COS(C)(=O)=O)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Yield: 131.9 %

Procedure:
A solution of 31 mg of (4R,9S)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl -1,2,4-oxadiazol-5-yl)-6-thioxo-1,3,4,5,6,7,8,9, 10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one and 11.5 mg of methanesulfonyl chloride in 0.2 ml of pyridine was stirred at 20° C. for 3 h. The solution was partitioned between dichloromethane and 1M aqueous oxalic acid. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to yield 46 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl) -silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-9-(methyl -sulfonyloxymethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one as an amorphous solid.
Reaction SMILES: Br[CH:2]([C:14](=[O:21])[C:15]1[S:19][C:18]([Cl:20])=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[C:22]([O-:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>C(#N)C>[C:22]([S:29][CH:2]([C:14](=[O:21])[C:15]1[S:19][C:18]([Cl:20])=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(Cl)s1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=C(SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Cl)s1)c1ccccc1

Procedure:
As for Example 21, 0.01 mole of 1-[3-bromo-3-(5-chloro-2-thenoyl)propionyl]-L-proline is reacted with sodium thiobenzoate for 16 hours in acetonitrile to give the product of the Example as a glass.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.FC(F)(F)S(O[C:21]1[CH:22]=[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:24]=[CH:25][CH:26]=1)(=O)=O.C[Sn](C)C.C[Sn](C)C.[Cl-].[Li+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:25]2[CH:24]=[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21][CH:26]=2)[CH:8]=1
Reactant: O=S(=O)(Oc1cccnc1)C(F)(F)F
Reactant: CCOC(=O)Cc1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: [Cl-]
Product: CCOC(=O)Cc1cccc(-c2cccnc2)c1

Procedure:
3-(Trifluoromethylsulfonyloxy)-pyridine is condensed with ethyl m-(trifluoromethanesulfonyloxy)-phenylacetate in the presence of hexamethylditin, lithium chloride and tetrakis-(triphenylphosphine)-palladium to obtain ethyl m-(3-pyridyl)-phenylacetate. The product is alkylated with 1-bromo-4-chlorobutane to obtain the alpha-(4-chlorobutyl)substituted phenylacetic acid ester. The ester is then reduced to the aldehyde which is condensed with e.g. methyl(triphenylphosphoranylidene)-acetate. The resulting alpha,beta-unsaturated ester is saturated to methyl 8-chloro-4-[m-(3-pyridyl)phenyl]-octanoate which is converted to methyl 8-amino-4-[m-(3-pyridyl)-phenyl]octanoate according to methodology described herein.
Reaction SMILES: C1C(O)=C(O)C(SCC(N)C(O)=O)=CC=1CC(N)C(O)=O.[NH2:22][C@H:23]([C:25]([C:27]1[CH:39]=[C:38]([OH:40])[C:30]2[N:31]=[C:32](C(O)=O)[CH2:33][S:34][C:29]=2[CH:28]=1)=[O:26])[CH3:24]>>[NH2:22][C@H:23]([C:25]([C:27]1[CH:39]=[C:38]([OH:40])[C:30]2[N:31]=[CH:32][CH2:33][S:34][C:29]=2[CH:28]=1)=[O:26])[CH3:24]
Reactant: C[C@H](N)C(=O)c1cc(O)c2c(c1)SCC(C(=O)O)=N2
Agent: NC(CSc1cc(CC(N)C(=O)O)cc(O)c1O)C(=O)O
Product: C[C@H](N)C(=O)c1cc(O)c2c(c1)SCC=N2

Procedure:
The other pathway from dopaquinone to melanin involves the addition of cysteine to dopaquinone to produce 5-S-cysteinyldopa, followed by the oxidation of 5-S-cysteinyldopa to 5-S-cysteinyldopaquinone. A ring closure of the 5-S-cysteinyldopaquinone then yields 7-alanyl-5-hydroxy-3-carboxy-2H-1,4-benzothiazine which is subsequently decarboxylated to yield 7-alanyl-5-hydroxy-2H-1,4-benzothiazine. At this point, the 7-alanyl-5-hydroxy-2H-1,4-benzothiazine is converted to melanin and pheomelanin. Tyrosinase does not play any additional role in this melanin production pathway.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([C:46]([F:49])([F:48])[F:47])[CH:40]=3)=[O:37])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:36]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([NH:25][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]6[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]6)=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)[S:27][C:28]=3[CH:34]=2)=[O:37])=[CH:40][C:41]=1[C:46]([F:48])([F:47])[F:49]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Product: COc1cc2c(Nc3nc4ccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)cc4s3)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-(2-{6-methoxy-7-[3-(4-methylpiperazin-1-yl)-propoxy]quinazolin-4-ylamino}benzothiazol-6-yl)urea was prepared from 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)-propoxy]quinazoline (Intermediate 6, 38.6 mg, 0.11 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-tri-fluoromethylphenyl)urea (Intermediate 3, 42.5 mg, 0.11 mmol) according to GP 1. The crude product was isolated by centrifugation and washed thoroughly with dioxane, methanol, water, and finally methanol. After drying, tetrahydrofuran was added (0.5 mL) and the mixture was filtered through glass wool to obtain pure product (pale yellow solid, 36 mg, 52 μmol, 47%). LC/ESI-MS: m/z=701 [M(35Cl)+H]+; m/z=699 [M(35Cl)−H]−; Rt=2.88 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([C:15]1[CH2:16][C:17]2[C:22]([C:23]=1[N:24]1CCCC1)=[CH:21][CH:20]=[CH:19][CH:18]=2)=O.Cl.[NH2:30]N.O>CCO>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:30][N:24]=[C:23]2[C:22]3[C:17]([CH2:16][C:15]=12)=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: Cc1onc(-c2ccccc2)c1C(=O)C1=C(N2CCCC2)c2ccccc2C1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1[nH]nc2c1Cc1ccccc1-2
Temperature: 80 °C

Procedure:
The compound from step b) was dissolved in EtOH (30 ml) and treated with hydrazine monohydrochloride (1.0 g, 13.3 mmol). The reaction vessel was fitted with an air-cooled condenser and heated to 80° C. for 36 h. The reaction mixture was cooled, water (10 ml) added, and the ethanol removed in vacuo. The residue was partitioned between EtOAc and water and the organic layer washed with water (2×). The organic layer was dried over MgSO4, evaporated, and the residue purified on alumina (Grade III), eluting with 0.5% EtOH/CH2Cl2 to obtain the title compound as a white solid (20.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.72 (brs, 1H), 7.52 (d, J=7.6 Hz, 2H), 7.43–7.34 (m, 5H), 7.28 (t, J=9.6 Hz, 2H), 3.3 (brs, 2H), 2.56 (s, 3H), m/z (ES+) 314 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([N:19]=[C:20]=[S:21])[CH3:18]>CCOCC>[CH2:17]([NH:19][C:20]([N:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:12][CH2:13]1)=[S:21])[CH3:18]
Reactant: CCN=C=S
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Solvent: CCOCC
Product: CCNC(=S)N1CCN(c2ccc3ccccc3n2)CC1
Reaction time: 1 h

Procedure:
To a slurry of 4.26 g. of 1-(2-quinolinyl)piperazine in 30 ml. of anhydrousether is added dropwise a solution of 1.74 g. of ethyl isothiocyanate in 30ml. of anhydrous ether. The mixture is stirred for one hour and the resulting solid is collected and recrystallized from 150 ml. of ethanol, giving 4.43 g. of the desired product as a white crystalline solid, m.p. 193°-195° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17](Cl)[O:18][CH:19]=1)=[O:14])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.CCCCCC>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:18][CH:19]=1)=[O:14])[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1coc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccccc2)n1
Yield: 83 %

Procedure:
A mixture of phenylboronic acid (729 mg, 5.98 mmol), 2-chloro-oxazole-4-carboxylic acid ethyl ester (prepared according to the procedures described in Org. Lett. 2002, 4 (17), 2905 and J. Med. Chem. 1971, 14, 1075) (1.0 g, 5.70 mmol), Pd[PPh3]4 (329 mg, 0.285 mmol), and sodium carbonate (2M, 2 mL) in ethylene glycol dimethyl ether (10 mL) were heated at 90 degrees overnight. After cooling the reaction, solvent was removed to give the crude residue. Flash chromatography (Merck silica gel 60, 230-400 mesh, 5-45% ethyl acetate in hexane for 35 min) gave 2-phenyl-oxazole-4-carboxylic acid ethyl ester (1.03 g, 83%) as colorless oil. LCMS calcd for C12H11NO3 (m/e) 217, obsd 218 (M+H).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(I)[I:19]>CC#N>[I:19][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: ICI
Solvent: CC#N
Product: CCOC(=O)c1sc(I)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Ethyl 2-amino-4-phenyl-1,3-thiazole-5-carboxylate (6.1 g, 25 mmol), prepared according to known procedure (Yamaguchi K. et al. Biorg. Med. Chem. Lett. 1999, 9(7), 957-960), was dissolved in MeCN (240 ml) and treated with CH2I2 (7 ml, 150 mmol) isoamylnitrite (12 ml, 112.5 mmol). The reaction was stirred at room temperature for 1 hour. The solvents were removed under high vacuum and the mixture was submitted to flash chromatography by eluting with light petroleum/ethyl acetate (9:1) to give the title compound as a solid. Yield: 57%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[CH3:9].C(OC(=O)[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[C:40]([CH:42]=O)[NH:39][N:38]=2)=[CH:33][CH:32]=1)(C)(C)C>CN(C=O)C>[CH2:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]3[NH:22][C:42]([C:40]4[NH:39][N:38]=[C:37]([C:34]5[CH:35]=[CH:36][C:31]([NH2:30])=[CH:32][CH:33]=5)[CH:41]=4)=[N:23][C:18]=3[CH:17]=2)[CH2:14][CH2:15]1)[CH3:9]
Reactant: CCN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(C=O)[nH]n2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc3[nH]c(-c4cc(-c5ccc(N)cc5)n[nH]4)nc3c2)CC1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Triethylamine (509 μL, 3.62 mmol) was added to a solution of 4-(4-ethylpiperazin-1-yl)-benzene-1,2-diamine as the tetra-hydrochloride salt in anhydrous DMF (4 mL). After five minutes, a solution of [4-(5-formyl-1H-pyrazol-3-yl)phenyl]carbamic acid tert-butyl ester in anhydrous DMF (2 mL) was added to the diamine. The reaction flask was left open to the air and heated to 65° C. After twelve hours the reaction was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the product (87 mg, 99% yield) as a light purple solid. Note that the BOC group was removed under the purification conditions: 1H NMR (400 MHz, CDCl3): δ 7.90 (m, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.46 (m, 2H), 7.42 (dd, J=9.2, 2.0 Hz, 1H), 7.41 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 4.01 (bd, J=12.0 Hz, 2H), 3.74 (bd, J=10.4 Hz, 2H), 3.35-3.27 (m, 4H), 3.23 (m, 2H), 1.44 (t, J=7.2 Hz, 3H); MS (EI) for C22H25N7: 388.2 (MH+).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)OCC3C=CC=CC=3)=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1.[C:22]([O:25][C@H:26]([CH2:32]Cl)[CH2:27][NH:28][C:29](=[O:31])[CH3:30])(=[O:24])C.O(C(C)(C)C)[Li]>CN(C=O)C.CO.CC(O)=O>[CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:32][C@H:26]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:25][C:22]3=[O:24])=[CH:10][C:5]=2[CH2:4][CH2:3][S:2]1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Reactant: O=C(Nc1ccc2c(c1)CCSC2)OCc1ccccc1
Agent: [Li]OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCSC3)C(=O)O1
Temperature: 25 °C
Reaction time: 32 h
Yield: 72.8 %

Procedure:
A solution of phenylmethyl (3,4-dihydro-1H-2-benzothiopyran-6-yl)carbamate (Step 3, 2.55 g, 8.52 mmol), (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate (Tet. Lett. 1996 37 (44) 7737-7740; 3.30 g, 17.03 mmol) and MeOH (0.690 mL, 17.03 mmol) in dry DMF (5.6 mL) under N2 is treated with LiOtBu (1M in hexanes, 25.5 mL, 25.5 mmol) dropwise over 2 hrs, and the resulting biphasic mixture is stirred at ambient temperature for 32 hrs. The mixture is then cooled in an ice bath and treated with glacial HOAc (975 μL), and MeOH (10 mL) is added and the layers are separated. The hexane layer is reextracted with 20% H2O/MeOH (20 mL), and the combined MeOH/H2O phase is diluted with H2O (40 mL) and extracted with EtOAc (3×40 mL). The combined EtOAc phase is then washed with H2O (2×50 mL) and brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (0.5/99.5-3/97). Those fractions with an Rf=0.27 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the product triturated with EtOAc/Et2O to give 1.90 g (73%) of the title compound as an off-white solid, mp 112-114° C. (decomp.). MS (ESI+) for C15H18N2O3S m/z 307 (M+H)+; [α]25D=−24° (c 0.80, DMSO).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-4-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-4-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3=CCCCC3)c2s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution (0.1 M) of methyl 6-cyclohex-1-en-1-yl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in TFA at 0° C. was treated with triethylsilane (1.5 eq.). The reaction mixture was stirred at 0° C. for 1 h then solvent was evaporated to give the title compound (95%) as a solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[CH3:16][C:17]12[CH2:27][CH:21]3[CH2:22][C:23]([CH3:26])([CH2:25][C:19]([CH2:28][C:29](O)=[O:30])([CH2:20]3)[CH2:18]1)[CH2:24]2>>[CH3:26][C:23]12[CH2:22][CH:21]3[CH2:27][C:17]([CH3:16])([CH2:18][C:19]([CH2:28][C:29]([NH:1][N:2]4[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:3]4=[O:15])=[O:30])([CH2:20]3)[CH2:25]1)[CH2:24]2
Reactant: CC12CC3CC(C)(C1)CC(CC(=O)O)(C3)C2
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Product: CC(C)c1nn(NC(=O)CC23CC4CC(C)(CC(C)(C4)C2)C3)c(=O)c2ccccc12

Procedure:
The product from Example 1B and 2-(3,5-dimethyl-1-adamantyl)acetic acid were processed using the method described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.81 (s, 6H) 0.98-1.20 (m, 2H) 1.20-1.42 (m, 14H) 1.52 (s, 2H) 1.98-2.14 (m, 3H) 3.49-3.73 (m, 1H) 7.89 (t, J=7.48 Hz, 1H) 7.95-8.04 (m, 1H) 8.11 (d, J=8.24 Hz, 1H) 8.34 (d, J=6.71 Hz, 1H) 11.12 (s, 1H); MS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36](F)=[C:35](F)[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2].C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C(N3CC[C:80]([F:84])([F:83])[CH2:79]3)=O)C=C(Br)C=2)C=1CCC(OCC)=O)C.C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=[C:26]([C:28]([N:29]3[CH2:30][CH2:79][C:80]([F:84])([F:83])[CH2:31]3)=[O:32])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N3CCC(F)(F)C3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Yield: 58 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (135 mg, 0.194 mmol), phenylboronic acid (48.27 mg, 0.388 mmol), PdCl2(dppf) (21.24 mg, 0.03 mmol) and cesium carbonate (127.3 mg, 0.388 mmol) in 1,2-dimethoxyethane (5.0 mL) to obtain 4-[3-{6-[5-(3,3-difluoro-pyrrolidine-1-carbonyl)-biphenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (78 mg, 58%) as a colorless oil.
Reaction SMILES: C(OC(=O)C=C[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:32][CH2:31]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)C.[CH3:36][O:37][C:38](=[O:67])[C:39](C1C=CC(C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=CC=1)([CH3:41])[CH3:40].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:36][O:37][C:38](=[O:67])[C:39]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[C:22]3[CH:21]([N:28]([CH:30]4[CH2:31][CH2:32]4)[CH3:29])[CH2:20][CH2:19][C:18]([CH3:34])([CH3:33])[C:17]=3[CH:16]=2)=[CH:11][CH:12]=1)([CH3:41])[CH3:40]
Reactant: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-5-(cyclopropyl-methyl-amino)-2-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 164, 0.11 g, 0.37 mmol), methyl-2-(4-iodo phenyl)-2-methyl-propionate (Reagent 2, 0.118 g, 0.39 mmol), triethyl amine (10 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by work up and flash column chromatography over silica gel (230-400 mesh) using 1%-4% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow amorphous solid (0.125 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=O)[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:27][OH:28].N1C=CC=CC=1.O>C(O)C>[Cl:1][C:2]1[C:3]([C:12](=[N:27][OH:28])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
To a solution of 0.47 g of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-oxoethyl]phthalimide and 0.54 g of hydroxylamine hydrochloride in 5 ml of ethanol, 0.94 g of pyridine was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 1:3 to 2:2) as the eluent to obtain 325 mg of the desired product as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].C1C(C(O)=O)=CC=C(N)C=1.Cl[C:23]([O:25][CH2:26][CH3:27])=O.ClC([O-])=O>>[CH2:26]([O:25][C:23]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:27]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CCOC(=O)Cl
Agent: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])Cl
Product: CCOc1nc2cccc(C)c2c(=O)o1

Procedure:
By following the procedure of Part A, but replacing 2-amino-6-methyl benzoic acid with the appropriate aminobenzoic acid prepared in Preparation I, and/or replacing ethyl chloroformate with the appropriate chloroformate prepared in Preparation II, the following compounds of Formula (1) are prepared: