Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: CCCCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 74 mg of the title compound. 1H NMR (CDCl3) δ 0.95 (t, 3H, J=7.31 Hz), 1.50 (m, 2H), 1.80 (m, 2H), 4.05 (t, 2H, J=6.48 Hz), 5.15 (s, 2H), 6.95 (d, 2H, J=9.04 Hz), 7.65 (d, 1H, J=8.22), 7.80 (d, 2H, J=9.04 Hz), 7.90 (dd, 1h, J=1.88, 7.91), 8.45 (d, 1H, J=1.88). MS (m/z): 368 (M+1). CHN Calc C, 55.51; H, 4.93; N, 3.81. Found C, 55.47; H, 4.84; N, 3.63.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:20]=O)[CH:16]=[N:15]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:16]=[N:15]1
Reactant: Cc1c(C=O)cnn1C
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1c(C=C2N=C(c3cccs3)OC2=O)cnn1C
Temperature: 90 °C
Yield: 42.7 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,5-dimethyl-1H-pyrazol-4-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 35 mg of the above-captioned compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[N:25]=[CH:26][N:22]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)[N:23]=2)[CH:28]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: c1cncc(-c2nc[nH]n2)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccnc4)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and 3-(1H-[1,2,4]-triazol-3-yl)-pyridine [CAS-No. 23195-63-3] (0.075 g, 0.51 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.095 g, 44%). MS (ISP) 437.3 [(M+H)+]; mp 190° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.[N-:17]=[N+:18]=[N-:19]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([N:17]=[N+:18]=[N-:19])=[O:9]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cnccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)c1cnccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of Pyrazine-2-carboxylic acid (295 mg, 2.1 mmol, 1 eq) and triethylamine (765 ul, 5.4 mmol, 2.6 eq) in THF (6 ml) at 0° C. was added dropwise diphenylphophoryl azide (1.4 ml, 2.8 mmol, 1.3 eq). The mixture was stirred under nitrogen at 0° C. for 30 minutes, then warmed to RT and stirring continued for a further 2 hours. The reaction mixture was concentrated under vacuum and purified by flash chromatography (90/10-60/40 Iso-hexane/EtOAc) to afford the title compound as white solid (265 mg, yield=78%). 1H NMR (400 MHz, CDCl3) δ 9.14 (d, 1H, J=1.2); 8.50 (dt, 1H, J=1.2, 0.4), 2.62 (s, 3H, broad).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:38][OH:39])CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:38][OH:39])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1cccnc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1cccnc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:32])=O>ClCCl>[CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([Cl:32])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To 8.00 g of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 100 ml of dichloromethane 0.1 ml of DMF and 4 ml of oxalyl chloride were added. The reaction was stirred at rt for 16 h, then concentrated and co-distilled with toluene to obtain 8.47 g (100%) of the crude product as a brown solid, which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>O>[C:1]1([CH:7]2[N:11]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:10][CH2:9][S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: c1ccc(C2NCCS2)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C(C(Cl)Cl)N1CCSC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Five (5) grams of 2-phenyl thiazolidine was dissolved in 50 ml. of acetone, 3.1 g. of thiethylamine was added and the mixture stirred in a room temperature water bath, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes and then poured into water, extracted with methylene chloride, separated, dried over magnesium sulfate, and the solvent stripped under vacuum. There was obtained a yield of 7.3 g. of an oil, the title compound, ND30 =1.5836.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([O-:49])=[O:48])=[CH:26][N:27]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22]2=[N:21][CH:20]=1)(C(C)(C)C)(C)C.[CH3:50]CCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[C:19]1[N:24]=[C:23]2[C:25]([C:47]([O:49][CH3:50])=[O:48])=[CH:26][N:27]([C:28]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:22]2=[N:21][CH:20]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)[O-])cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(C)c4ccc(O)cc34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.5 %

Procedure:
To a solution of 2-(5-(tert-butyldimethylsilyloxy)-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (3.4 g, 4.9 mmol) in THF (25 mL) was added TBAF (6.42 mL, 12.85 mmol) at 0° C., after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 0.5 hour, then H2O (25 mL) was added to the mixture extracted with EtOAc (100 mL), the organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 2-(5-hydroxy-1-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (3.2 g, >100%) as a yellow solid. LCMS: (M+H)+=566; (M+Na)+=588.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[S:33][C:32]=1[C:46](=O)[CH3:47]>C1(C)C=CC=CC=1.C1COCC1>[CH3:2][O:3][CH:4]=[C:46]([C:32]1[S:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[CH:35][C:31]=1[CH3:30])[CH3:47]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)triphenyl phosphonium chloride (3.96 g, 10.76 mmole) in toluene/THF (2:1, 60 mL), is added potassium t-butoxide (1.21 g, 10.76 mmole) in one portion and stirred for 30 minutes. To the resulting ylide, is injected into a solution of 1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone (1.53 g, 5.38 mmole). The reaction is stirred for 2 hours, and then concentrated on rota vapor. The residue is purified on a silica gel column, eluting with 0-10% ethyl acetate in hexane and concentrated to provide 2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thiophene as brown oil. The generated vinyl ether is treated with concentrated HCl(aq) (2 mL) in THF(60 mL) at 60° C. for 2 hours. The solvents are removed on rota vapor, and the residue is purified on a silica gel column, eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(O[CH:44]([CH2:47][OH:48])[CH2:45][OH:46])N=1.C(O)CCO.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:46][CH2:45][CH2:44][CH2:47][OH:48])[CH:7]=1
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: OCCCO
Product: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step 3 g) and propane-1,3-diol (1.1 g) in THF (50 ml) was added NaH (390 mg) slowly and the reaction was then allowed to stir at room temperature for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow oil. Yield 2.9 g
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:13]3[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=3)[NH:7][N:6]=2)[CH2:4][CH2:3]1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])[CH3:22].O>CN(C=O)C>[Si:24]([O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH:2]3[CH2:4][CH2:3]3)=[N:6][NH:7]2)=[CH:12][CH:11]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2c(C3CC3)n[nH]c2c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c(C3CC3)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Cyclopropylindazol-6-ol hydrochloride (5.18 g) which can be prepared according to the method described in Reference example 4, etc. and imidazole (4.21 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) were dissolved in dehydrated DMF (122 mL; manufactured by Kanto Chemical Co., Inc.). Then, TBDPSCl (15.67 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at 20° C. To the reaction solution, imidazole (1.8 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (6.27 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) were added and the mixture was stirred for 2 hours at 20° C. To the reaction solution, water was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (4.71 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc(N2CCN(Cc3ccc[nH]3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (310 mg) in 1,2-dichloroethane (20 mL) was added 1H-pyrrole-2-carboxaldehyde (95 mg) and acetic acid (67 mg). The solution was cooled at 0° C. and sodium triacetoxy borohydride (317 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (95/5) and the solid obtained was recrystallized from EtOH to give the title compound (180 mg) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](OC4C=CC=CC=4)=[O:27])[CH2:22][C@@H:21]3[C:35]([NH:37][O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)=[O:36])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>CN(C=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([NH:1][CH2:2][CH2:3][OH:4])=[O:27])[CH2:22][C@@H:21]3[C:35]([NH:37][O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)=[O:36])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Oc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Reactant: NCCO
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)NCCO)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
2-Aminoethanol (129 mg) was added to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-phenoxycarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (250 mg) in DMF (2 ml). The reaction mixture was stirred at 80° C. overnight. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with MeOH in CHCl3=2%, then 4%, to give 138 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-[N-(2-hydroxyethyl)-aminocarbonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 2-(methylsulfonyl)ethanamine (10.28 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (9.2 mg, 0.017 mmol, 36.2% yield): LCMS=537.1 [M+H]+; 1H NMR (400 MHz, methanol-d4 and CDCl3) δ ppm 8.15 (2 H, d, J=8.28 Hz), 7.66 (4 H, t, J=7.78 Hz), 7.47-7.60 (3H, m), 5.13 (1 H, s), 3.73 (2 H, t, J=6.40 Hz), 3.23-3.31 (2 H, m), 2.94 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.4 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN(C)CCOc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cn(S(=O)(=O)c2ccc(Br)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 16.5 mmoles) was stirred with dimethyl formamide (ca 8 mL) in a ice-cooled, three necked round bottom flask. A solution of [2-(1H-indol-3-yloxy)ethyl]dimethylamine (15 mmole), in dimethyl formamide (ca 5 mL) was then added dropwise to this cooled suspention of sodium hydride. After the addtion was complete, the reaction mixture was allowed to attain the room temperature (25° C.). After about one hour of stirring at 25° C., a solution of 4-Bromobenzenesulfonyl chloride (18 mmole) was added dropwise to this solution. The reaction was further stirred at 25° C. for next 3-4 hours. After the completion of reaction (TLC), reaction mixture was poured on the ice cooled water and extracted by Ethyl acetate (3×20 mL). The combined organic extract was washed with water and brine, dried over sodium sulphate and the volatiles were evaporated under vacuume to get the product as a thick dark oil. The residue was purified by column chromatography, on silica gel; using hexane (100%) to triethylamine:ethyl acetate (2:98) gradual gradient as mobile phase, to obtain the compound of general formula (I) as thick oil, which was identified by IR, NMR and mass spectral analyses. The final desired compound of general formula (I) can be further purified by preparation of their acid addition salts. Melting range (° C.): Isolated as oil; Mass (m/z): 423, 425 (M+H)+; IR spectra (cm−1): 1150 (SO2); 1H-NMR (ppm): 2.40 (s, 6H); 2.83-2.88 (t, 2H, J=5.4 Hz); 4.11-4.16 (t, 2H, J=5.4 Hz); 6.87 (s, 1H); 7.19-7.38 (m, 3H); 7.50-7.67 (m, 4H); 7.95-7.99 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=O)[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1C=CC=C(F)[C:23]=1C(O)=O.C(O)(=O)C1C(=CC=CC=1)N>>[F:1][C:2]1[C:10]2[C:6]3[C:11]4[C:12](=[O:20])[CH2:13][C:14]([CH3:18])([CH3:19])[CH2:15][C:16]=4[N:21]=[C:22]([CH3:23])[C:7]=3[NH:8][C:9]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Agent: Nc1ccccc1C(=O)O
Product: Cc1nc2c(c3c1[nH]c1cccc(F)c13)C(=O)CC(C)(C)C2

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(4-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-6-fluorobenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 246-247° C.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]([O:9]CC)=[O:8])=[N:4][C:3]=1[CH3:12].[OH-].[Na+].Cl>CO.O>[I:1][C:2]1[NH:6][C:5]([C:7]([OH:9])=[O:8])=[N:4][C:3]=1[CH3:12]
Reactant: CCOC(=O)c1nc(C)c(I)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)O)[nH]c1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 5-iodo-4-methyl-1H-imidazole-2-carboxylate (compound 239.2, 200 mg, 0.71 mmol) in methanol (4 mL). A solution of sodium hydroxide (114 mg, 2.85 mmol) in water (2 mL) was added to the reaction. The reaction mixture was stirred for 2 h at 60° C. The pH of the solution was adjusted to 1-2 with hydrogen chloride (1 M). The resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added to the residue. The salt was filtered off and the filtrate was concentrated under reduced pressure to give 290 mg (crude) of the title compound as a white solid.