Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=CC([N:15]([C:23]3[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=CC=2)O1.Br[C:32]1[CH:33]=[CH:34][C:35]2[C:39](C3C=CC(C)=CC=3)=[C:38](C3C=CC(C)=CC=3)[S:37][C:36]=2[CH:54]=1>>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([NH:15][C:24]2[C:23]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:28][CH:27]=[CH:26][C:25]=2[C:38]2[S:37][C:36]3[CH:54]=[CH:32][CH:33]=[CH:34][C:35]=3[CH:39]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Product: Cc1ccc(Nc2cccc(-c3cc4ccccc4s3)c2Nc2ccc(C)cc2)cc1

Procedure:
2,3-di-p-tolylaminophenyl-benzo[b]thiophene was synthesized in the same manner as in Synthesis Example 1, except that [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-phenyl]-di-p-tolylamine was used instead of p-tolylboronic acid used to synthesize Intermediate B in Synthesis Example 1.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:55])[CH2:13][CH2:14][NH:15][CH2:16][C@:17]23[CH2:51][CH2:50][C@@H:49]([C:52]([CH3:54])=[CH2:53])[C@@H:18]2[C@@H:19]2[C@@:32]([CH3:35])([CH2:33][CH2:34]3)[C@@:31]3([CH3:36])[C@@H:22]([C@:23]4([CH3:48])[C@@H:28]([CH2:29][CH2:30]3)[C:27]([CH3:38])([CH3:37])[C:26]([C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:25][CH2:24]4)[CH2:21][CH2:20]2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>O1CCOCC1.CO>[C:43]([C:42]1[CH:46]=[CH:47][C:39]([C:26]2[C:27]([CH3:38])([CH3:37])[C@H:28]3[C@:23]([CH3:48])([CH2:24][CH:25]=2)[C@@H:22]2[C@:31]([CH3:36])([C@@:32]4([CH3:35])[C@H:19]([CH2:20][CH2:21]2)[C@H:18]2[C@H:49]([C:52]([CH3:54])=[CH2:53])[CH2:50][CH2:51][C@:17]2([CH2:16][NH:15][CH2:14][CH2:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[O:55])[CH2:34][CH2:33]4)[CH2:30][CH2:29]3)=[CH:40][CH:41]=1)([OH:45])=[O:44]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCC(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 240 h
Yield: 52.4 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(4-(ethoxycarbonyl)piperidin-1-yl)-3-oxopropylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (16 mg, 0.021 mmol) in dioxane (1 ml) and methanol (2 ml) was added 1N sodium hydroxide (0.3 ml, 0.1 mmol) and H2O (0.5 ml). The resulting mixture was stirred at rt for 10 days. The reaction mixture was neutralized with 1N HCl and concentrated in vacuo. The crude product was purified by prep. HPLC to afford the title compound (8 mg). MS: m/e 727.6 (MH+), 1.69 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.95 (s, 3H) 0.97 (s, 3H) 1.04 (s, 3H) 1.08 (s, 3H) 1.17 (d, J=2.76 Hz, 3H) 1.73 (s, 3H) 0.87-1.86 (m, 23H) 1.92-2.10 (m, 3H) 2.15 (dd, J=17.32, 6.53 Hz, 1H) 2.47-2.56 (m, 1H) 2.57-2.67 (m, J=7.34, 7.12, 7.12, 3.76 Hz, 1H) 2.83-2.94 (m, 4H) 3.16-3.41 (m, 4H) 3.82-3.91 (m, 1H) 4.35-4.44 (m, 1H) 4.64 (s, 1H) 4.76 (d, J=1.51 Hz, 1H) 5.30 (d, J=5.27 Hz, 1H) 7.22 (d, J=8.28 Hz, 2H) 7.91 (d, J=8.28 Hz, 2H).
Reaction SMILES: C[C:2]([O-:5])(C)C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][N:31]([CH3:46])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>C1COCC1>[CH3:30][N:31]([CH3:46])[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[CH2:37][CH2:36][CH:35]([CH:2]=[O:5])[CH2:34][CH2:33]1
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
KOtBu (2.15 g, 19.2 mmol) dissolved in abs. THF (25 mL) was added in drops to a solution of (methoxymethyl)triphenylphosphonium chloride (6.58 g, 19.2 mmol) in abs. THF (25 mL) at 0° C. in argon. The resulting red solution was mixed after 30 min at 0° C. with a solution of 4-dimethylamino-4-(3-fluorophenyl)cyclohexanone (3.0 g, 12.76 mmol) in abs. THF (25 mL) and stirred overnight at RT. The solvent was removed in a vacuum, the residue mixed with 1M sulphuric acid (50 mL) and stirred for 2 h. The precipitate precipitated out during this was separated and the filtrate (pH 1) washed with ether (6×30 mL). The aqueous solution was adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[C:8]2([CH3:16])[CH3:15])([OH:4])(=[O:3])=[O:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[OH-].[Na+]>C(O)C(O)C.O>[Br-:17].[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N+:10]1[C:11]2[C:7](=[CH:6][C:5]([S:1]([OH:4])(=[O:2])=[O:3])=[CH:13][CH:12]=2)[C:8]([CH3:16])([CH3:15])[C:9]=1[CH3:14])([OH:25])=[O:24]
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)C
Reactant: O=C(O)CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Solvent: O
Product: CC1=[N+](CCCCCC(=O)O)c2ccc(S(=O)(=O)O)cc2C1(C)C
Product: [Br-]
Temperature: 80 °C
Yield: 30.7 %

Procedure:
To 5-sulpho-2,3,3-trimethylindole (potassium salt) (5.0 g, 18 mmol) was added 6-bromohexanoic acid (10.56 g, 53.8 mmol) in 1,2-propanediol (15 ml) and heated at 80° C. for 72 hours. The mixture was cooled and diluted with water (60 ml) and a solution of NaOH (10% in water, 60 ml) with stirring. The product was purified using preparative HPLC (Dynamax, C18 column, gradient of TFA/H2O to TFA/MeCN) to yield a grey/pink solid (2.4 g, 28%).
Reaction SMILES: [C:1]1([CH3:11])C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[OH:13].[Na+].[CH3:17][O:18][C:19]([O:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21]>>[CH2:20]([C:19]1([CH2:22][CH3:23])[O:24][C@@H:25]([CH2:11][CH2:1][OH:13])[CH2:17][O:18]1)[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(CC)(OC)OC
Reactant: O=C([O-])O
Agent: [Na+]
Product: CCC1(CC)OC[C@H](CCO)O1
Reaction time: 16 h

Procedure:
In 150 ml of 3,3-dimethoxypentane was dissolved 25 g of (S)(-)-butanetriol, and 0.1 g of p-toluenesulfonic acid was added to the solution. The solution was stirred for 16 hr to conduct a reaction. The resultant reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, the reaction product was extracted with an ether, and the extract was washed with a saturated saline solution. The solvent was distilled off from the extract as washed, and the resultant residue was purified by a silica gel column chromatography through the use of hexane-ethyl acetate as a developing solvent to obtain 26.5 g of (S)-2,2-diethyl-4-(2-hydroxyethyl)-1,3-dioxolane. The whole quantity of the product was dissolved in 500 ml of benzene, and 24 g of imidazole, 100 g of triphenylphosphine and 40 g of iodine were added to the solution. The mixture was stirred for 2 hr and then poured into ice water. The reaction product was extracted with an ether, and the extract was well washed with a 10% aqueous solution of sodium thiosulfate and dried over magnesium sulfate. The solvent was removed from the dried reaction product by distillation, and the resultant residue was purified by a silica gel column chromatography through the use of hexane-ethyl acetate as a developing solvent to obtain 31 g of (S)-2,2-diethyl-4-(2-iodoethyl)-1,3-dioxolane.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2>C(#N)C.O>[Br:1][C:19]1[CH:18]=[C:17]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[CH2:14][CH2:15][CH2:16]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Br)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
N-bromosuccinimide (1.26 g, 7.1 mmol) was added to a solution of 5-methoxyindan 124 (1.0 g, 6.7 mmol) in acetonitrile (34 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-10% ethyl acetate in hexane) provided 125 (1.53 g, 100%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([OH:23])=O.Cl.CON.C[N:37]1CCO[CH2:39][CH2:38]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:20]=1[C:21]([NH:37][CH2:38][CH3:39])=[O:23]
Reactant: CN1CCOCC1
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)O)c1
Agent: CON
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(OC)cc(OC)c1-c1nc2ncccn2c1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
400 mg of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzoic acid, 73 mg of O-methylhydroxylamine hydrochloride, 200 mg of DAPECI and 88 mg of 4-methylmorpholine are dissolved in 1 ml of DMF and stirred at RT for 1 hour. The solvent is removed, and the residue is purified by column chromatography (heptane/ethyl acetate), giving 90 mg (21%) of 2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]pyrimidin-2-yl]-N-ethyl-3,5-dimethoxybenzamide (A17) as solid; MS-FAB (M+H+) 489.7; Rf (polar method): 1.61 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]2[CH2:11][O:12]C(C3C=CC=CC=3)[O:14][C:8]2=[CH:7][CH:6]=1)[OH:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:1][CH2:2][CH:3]([C:5]1[N:10]=[C:9]([CH2:11][OH:12])[C:8]([OH:14])=[CH:7][CH:6]=1)[OH:4]
Reactant: Clc1cccc(Cl)c1COCCOCCCCCCBr
Reactant: NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCc1nc(C(O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)ccc1O
Temperature: 70 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 2-amino-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (EP220054A2) (93 mg) and 2-({2-[(6-bromohexyl)oxy]ethoxy}methyl)-1,3-dichlorobenzene (98 mg) in dimethylformamide (1 ml) and diisopropylethylamine (0.2 ml) was heated to 70° C. for 4 h and then at 20° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried and evaporated to dryness. The residue was dissolved in ethanol and applied to an SCX-2 cartridge (10 g) eluting with ethanol, followed by 10% aqueous ammonia in ethanol. The ammoniacal fractions were concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 ml) and water (2 ml) and the mixture was heated to 70° C. for 40 min. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with 10% aqueous ammonia in ethanol-dichloromethane (1:9 to 1:3). Appropriate fractions were combined and concentrated and the residue dissolved in acetic acid and re-evaporated to dryness to give the title compound (124 mg). LCMS RT=2.46 min, ES+ve m/z 487/489/491 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH:22]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][PH3+].C1CCN2C(=NCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH:22]=[CH:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [PH3+]Cc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CC=O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CC=Cc2cccs2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In tetrahydrofuran (50 ml) was dissolved 1,4-bis(tert-butoxycarbonyl)-2-formylmethylpiperazine (1.01 g). Under ice cooling, a solution of [(thien-2-yl)methyl]phosphonium (1.62 g) in chloroform (100 ml) was added to the resulting solution, followed by the dropwise addition of 1,8-diazabicyclo[5.4.0]-7-undecene (620 μl). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was distilled under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1 to 2:1), whereby the title compound (1.13 g) was obtained as a pale yellow oil.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:21])[O:20][C:6]2=[C:7]([CH3:19])[C:8]3[CH2:9][C:10]([CH3:18])([CH3:17])[N:11](C=O)[C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.C(=O)([O-])O.[Na+].O.C(OCC)(=O)C>CO>[I:1][CH2:2][C:3]1([CH3:21])[O:20][C:6]2=[C:7]([CH3:19])[C:8]3[CH2:9][C:10]([CH3:17])([CH3:18])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1
Reactant: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)C(C)(C)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Yield: 97.8 %

Procedure:
To a solution of 2,3,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-5H-furo[2,3-f]indole-5-carbaldehyde (2.42 g, 6.06 mmol) in methanol (10 ml) was added concentrated hydrochloric acid (3 ml), and heated under reflux for 2.5 hours under nitrogen atmosphere. The reaction mixture was added dropwise to a mixture of sodium hydrogen carbonate (3.7 g, 44 mmol) with water-ethyl acetate, neutralized and extracted three times with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 2.20 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:51][NH2:52].CN1CCOCC1>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:51][NH2:52])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 43.7 %

Procedure:
A solution of 4.8 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleric acid in 50 ml of dimethylformamide was cooled to 0° C. and treated with 2.80 g of pentafluorophenol and 2.65 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred at 0° C. for 2.5 hours and then treated with 4.73 g of hydrazine monohydrochloride and 6.97 g of 4-methyl morpholine. The mixture was stirred for a further 18 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed sequentially with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:1) as the eluant to give 2.18 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in the form of a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1B(O)O.C(O)(O)=O>C(#N)C.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>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:20]1[CH:19]=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[Cl:14])[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 1.0000 g, 4.693 mmol), 2-chloro-5-fluorophenylboronic acid (0.9002 g, 5.163 mmol), tetrakis(triphenylphosphine)palladium (0.2712 g, 0.2347 mmol), and sodium carbonate anhydrous (2.487 g, 23.47 mmol) in acetonitrile-water (3:1) (47.00 mL) was stirred at 100° C. After 3 hs, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)-2-methylquinoxaline as a red syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=8.4, 1.4 Hz), 8.03 (1 H, dd, J=7.6, 1.4 Hz), 7.88 (1 H, dd, J=8.4, 7.6 Hz), 7.75 (1 H, dd, J=9.0, 5.1 Hz), 7.61 (1 H, dd, J=8.6, 3.1 Hz), 7.46-7.53 (1 H, m), 2.54 (3 H, s); LC-MS (ESI) m/z 307.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C(=O)O)c2)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C(=O)NS(C)(=O)=O)c2)c1

Procedure:
A cloudy solution of 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylic acid (100 mg, 0.222 mmol), methanesulfonamide (24.3 mg, 0.256 mmol), DMAP (5.4 mg, 0.044 mmol), EDC (59.7 mg, 0.311 mmol), and triethylamine (0.043 mL, 0.31 mmol) in DMF (4 mL) was stirred for 14 hours at room temperature. The reaction mixture was purified directly via reverse phase HPLC (CH3CN:H2O with 0.1% TFA) to give 3′-methyl-N-(methylsulfonyl)-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxamide. MS ESI calc'd. for C20H18F3N4O3S [M+H]+ 451, found 451. 1H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.26 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.26 (d, J=5.0 Hz, 1H), 7.24 (s, 1H), 3.39 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:12][C:13]1C=CC(C(O)=O)=C[CH:14]=1.C(OC1C=CC(C(Cl)=O)=CC=1)(=O)CCCCCCCCC>>[C:13]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[CH:2][CH:10]=1)(=[O:12])[CH3:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CCCCCCCCCC(=O)Oc1ccc(C(=O)Cl)cc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
p-Acetoxybenzoic acid was prepared in the same manner as in Example 1(2) except that the 2-fluoro-4-hydroxybenzoic acid was replaced with p-hydroxybenzoic acid. The p-hydroxybenzoic acid was chlorinated in the same manner as in the above (2), to obtain an acid chloride. 1.8 Grams of the acid chloride and 2 g of the (R)-(+)-2-fluoro-4-hydroxy-1-(1-trifluoromethyl-6-ethoxyhexyloxycarbonyl)benzene obtained in Example 1 were dissolved in 50 ml of toluene, 6 ml of pyridine was added, and the mixture was stirred for 1 day. The reaction mixture was poured into water, consecutively washed with a hydrochloric acid aqueous solution, with a sodium hydroxide aqueous solution and with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off to give a crude product. The crude product was purified by silica gel column chromatography(eluting solvent: ethyl acetate/hexane=15/85), to give 2.8 g of an end product.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:8])[CH:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:3]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:26]([O:25][C:23]([CH:4]1[CH2:3][C:2](=[O:1])[O:6][CH:5]1[C:7]([OH:9])=[O:8])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Yield: 76.8 %

Procedure:
148 mg of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5-oxotetrahydrofuran-2,3-dicarboxylate in 4 ml of ethyl acetate was catalytically reduced with 15 mg of a 10% palladium-carbon catalyst at room temperature at atmospheric pressure of hydrogen for 15 hours. The catalyst was filtered off, and the solvent was evaporated in vacuo. The residue was washed with benzene to give 66 mg of the title compound as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([NH:18][C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[O:17])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc(-c2nc(C)c(C(=O)O)s2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C)c(C(=O)Nc3nnn[nH]3)s2)cc1
Yield: 64.4 %

Procedure:
A solution of 300 mg (1.20 mmol) of 2-(4-methoxyphenyl)-4-methyl-5-thiazolecarboxylic acid and 292.7 mg (1.81 mmol) of N,N'-carbonyldiimidazole (CDI) in dry dimethylformamide (8 ml) was stirred at room temperature for 1 hour. Under the same conditions, a solution of 5-aminotetrazole (122.8 mg, 1.44 mmol) in dry dimethylformamide (1 ml) was added thereto and allowed to react at 70° C. for 3 hours. After the solvent was distilled off from the reaction mixture, the residue was treated with water under ice-cooling and acidified with 2N-HCl to pH 2. The produced solids were filtered with suction, suspended in 100 ml of water and made alkaline with 1N potassium hydroxide (pH=11). After the impurities were removed from the alkaline solution by extracting with ethyl acetate, the aqueous phase was acidified with 2N-HCl to pH 2 and the deposited solids were filtered with suction, washed with water and recrystallized from methanol-THF-water to give 244.4 mg (yield 64 %) of 2-(4-methoxyphenyl)-4-methyl-N-(1H-tetrazole-5-yl)-5-thiazolecarboxamide as white crystals, m.p. 275°-278° C.