Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:13]3[C:8]4=[N:9][CH:10]=[CH:11][CH:12]=[C:7]4[N:6]=[C:5]3[C:3]([OH:4])=[O:2])[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
175.0 mg (0.46 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester were added to a solution of 19.6 mg (0.82 mmol) LiOH in 6 mL THF and 2 mL H2O. The reaction mixture was stirred for 2 h at 60° C., cooled to room temperature and acidified (pH=2) by the addition of a half concentrated HCl-solution. The precipitate was filtered off and washed with water to give pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b] pyridine-2-carboxylic acid as a brown crystalline solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:31])=[N:4][CH:5]=1)[CH2:21][CH:22]1[CH2:23][CH2:24]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (143 mg, 0.323 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (39 mg). MS found for C15H19N7O2S as (M+H)+ MS 362.2; UV 205.4, 275.6, 324.4 nm; t 0.418 min. 1H NMR: (CD3OD) δ 7.51 (s, 1H), 6.69 (s, 1H), 4.68-4.60 (m, 1H), 2.28 (s, 3H), 1.84-1.75 (m, 1H), 1.65-1.57 (m, 1H), 0.82-0.72 (m, 1H), 0.40-0.28 (m, 2H), 0.10-0.0 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(5-nitro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (927 mg, 3 mmol, prepared from 2-chloro-5-nitropyrimidine and N-Boc-piperazine) in tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon (240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-amino-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:14][CH3:15])[NH:5][C:6](=O)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Yield: 87 %

Procedure:
A round bottom flask was charged with ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylate (6 g) and phosphorus oxychloride (30 mL) and heated to reflux for 3 h. The phosphorus oxychloride was removed under vacuum. The residue was chromatographed (silica gel, eluting with methylene chloride) to afford the product (5.73 g, 87% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9]2)([O-])=O.[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>CO.O1CCCC1.[Pd].O.ClCCCl>[O:18]1[CH2:23][CH2:22][CH:21]([NH:1][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:12]=2[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: O=C1CCOCC1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCCl
Product: O=C(O)c1cc2cccc(NC3CCOCC3)c2[nH]1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Ethyl 7-nitroindole-2-carboxylate (2.5 g, 10.7 mmol) was dissolved in methanol (50 ml). 10% Pd/C (200 mg) was added, and the mixture was stirred for 1 h under hydrogen gas. The mixture was filtered though celite, and the filtrate was distilled under reduced pressure. The distillate was dissolved 1,2-dichloroethane (50 ml), and tetrahydro-4H-pyran-4-one (1.3 ml, 12.8 mmol) and sodium triacetoxyborohydride (3.4 g, 16.1 mmol) were added. The mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified by column chromatography. Thus obtained compound was dissolved in methanol (50 ml) and tetrahydrofuran (50 ml), 1N-sodium hydroxide (43 ml, 42.8 mmol) was added, and the mixture was stirred for 8 h at room temperature. 1N-hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to give the title compound (2.1 g, Yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:26]4[CH:31]=[C:30]([C:32](=[O:43])[NH:33][C:34]5([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[CH:29]=[CH:28][C:27]=4[CH3:44])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH2:46][CH2:47][OH:48])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:26]4[CH:31]=[C:30]([C:32](=[O:43])[NH:33][C:34]5([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)[CH2:35][CH2:36]5)[CH:29]=[CH:28][C:27]=4[CH3:44])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CCO)S(C)(=O)=O)c(-c3cc(C(=O)NC4(c5ccccc5)CC4)ccc3C)cc12

Procedure:
2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide was prepared from the alkylation of 2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-(methylsulfonamido)benzofuran-3-carboxamide using (2-bromoethoxy)(tert-butyl)dimethylsilane (K2CO3, DMF 55° C.) followed by deprotection using HCl in 1,4-dioxane at r.t. Purification was preformed by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.32-6.81 min. (UV detection at 220 nm). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=656.06, HPLC Rt=1.563 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.05 min; Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.38 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=11.42 min.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][S:11]([C:14]1[CH:43]=[CH:42][C:17]([O:18][C:19]2[C:20]([N:34]3[CH2:38][CH2:37][CH2:36][CH:35]3[CH:39](O)[CH3:40])=[CH:21][C:22]3[NH:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:24][C:23]=3[CH:33]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:7][CH:39]([CH:35]1[CH2:36][CH2:37][CH2:38][N:34]1[C:20]1[C:19]([O:18][C:17]2[CH:42]=[CH:43][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:33][C:23]2[NH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:26][C:22]=2[CH:21]=1)[CH3:40]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(F)C1CCCN1c1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.007 ml of diethylaminosulfur trifluoride was added to a chloroform (1 ml) solution of 21 mg of 1-(1-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-2-yl)-ethanol diastereomer A obtained in Example 354, at −78° C., and the reaction liquid was stirred at −78° C. for 1 hour. The reaction liquid was heated up to room temperature, and aqueous saturated sodium bicarbonate was added to the reaction liquid, and then extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:7](=[O:17])[CH2:8]P(=O)(OCC)OCC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[S:20]([N:30]1[C:34]2=[N:35][CH:36]=[C:37]([CH:39]=O)[N:38]=[C:33]2[CH:32]=[CH:31]1)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH:1]1([C:7](=[O:17])/[CH:8]=[CH:39]/[C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][N:30]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[C:34]3=[N:35][CH:36]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reactant: CCOP(=O)(CC(=O)C1CCCCC1)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/C(=O)C4CCCCC4)cnc32)cc1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of diethyl 2-cyclohexyl-2-oxoethylphosphonate (0.609 g, 2.32 mmol) in THF (10 mL) was added NaH (60% dispersion in mineral oil, 0.0664 g, 1.66 mmol). After about 30 min, a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.20 g, 0.64 mmol, Example#10, Step B) in THF (10 mL) was added. After about 2 h, EtOAc (50 mL) and saturated aqueous NH4Cl (50 mL) was added to the reaction mixture. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with IPA (20 mL) to provide (E)-1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)prop-2-en-1-one as a tan solid (0.20 g, 73%): LC/MS (Table 2, Method a) Rt=3.06 min; MS m/z: 410 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[O:11][N:10]=1)(C)(C)C.[Si](I)(C)(C)C.CO>C(Cl)(Cl)Cl>[NH2:7][CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[O:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NCc1noc(-c2ccnc(C#N)c2)n1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2nc(CN)no2)ccn1
Reaction time: 0.17 h

Procedure:
NEt3 (6.6 ml, 47.3 mmol) was added to a stirred solution of 2-cyanoisonicotinic acid (7.00 g, 47.3 mmol) in toluene (500 ml). The mixture was cooled to 0° C., before being treated with isobutyl chloroformate (6.1 ml, 47.3 mmol). Stirring was continued at 0° C. for 10 min, then the mixture was allowed to warm to rt over 1 h, before being treated with (N-hydroxycarbamimidoylmethyl)carbamic acid tert-butyl ester (7.44 g, 39.4 mmol) and dried 4 Å molecular sieves (40 g). The reaction was heated under reflux for 16 h. On cooling, the mixture was filtered through celite, washing with MeOH. The combined filtrates were concentrated in vacuo, then the residue was dissolved in EtOAc. The EtOAc solution was washed with saturated aqueous Na2CO3 and brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 7:3) furnished [5-(2-cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]carbamic acid tert-butyl ester m/z (ES+)=603.2 [2M+H]+. A stirred solution of this carbamate (1.95 g, 6.5 mmol) in CHCl3 (50 ml) was treated with TMS-I (2.2 ml, 15.6 mmol). After 10 min, the reaction was treated with MeOH (2.5 ml, 62.2 mmol), then stirring was continued for a further 10 min. The solvents were evaporated off under reduced pressure, then the residue was dissolved in MeOH and adsorbed onto SiO2. Column chromatography (EtOAc then EtOAc-MeOH, 9:1) afforded the title compound: m/z (ES+)=202.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[S:16][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 5.0 g of 2-fluoro-5-(trifluoromethyl)benzaldehyde, 3.3 g of methyl thioglycolate, 4.0 g of potassium carbonate and 50 ml of DMF was stirred at 60° C. for 2 hours, and then the reaction mixture was cooled to room temperature. To the reaction mixture was added water, and extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 6.3 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (the present compound 1).
Reaction SMILES: [OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@H:2]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([CH3:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: C1CCNC1
Reactant: C[C@H](Oc1ccc(-c2ccc(CC(=O)O)cc2)cc1)[C@H](O)CCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(-c2ccc(CC(=O)N3CCCC3)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
Prepared according to the method described in Example 66. (1S,2R)-[4′-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-biphenyl-4-yl]-acetic acid (Example 55, 0.07 g),pyrrolidine (0.014 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) were dissolved in dimethylformamide (2 ml) and stirred for 16 hours at room temperature. The dimethylformamide was removed by vacuum distillation, the residue was dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a glass (0.068 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:39]Br.OC1C=CC(C)=CC=1C1C2N=NNC=2C=CC=1OC(CC(C)(C)C)(C)C>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:39])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][C:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:20])=[CH:17][C:11]2=[N:10]1
Reactant: BrBr
Reactant: Cc1ccc(O)c(-n2nc3ccc(OC(C)(C)CC(C)(C)C)cc3n2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc(O)c(-c2c(OC(C)(C)CC(C)(C)C)ccc3[nH]nnc23)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(C)(C)Oc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 8.236 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-tert-octyloxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2 (2′hydroxy 5′methyphenyl)-5-tert-octyloxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-tert-octyloxybenzotriazole was 7.8 g (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([C:14](OC)=[O:15])=[CH:5]2.CC(C[AlH]CC(C)C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([CH2:14][OH:15])=[CH:5]2
Reactant: COC(=O)c1cc2cc(Cl)c(Cl)cc2nc1O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cc2cc(Cl)c(Cl)cc2nc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Methyl 6,7-dichloro-2-hydroxyquinoline-3-carboxylate (2.72 g, 10 mmol) was added in small portions to a stirred solution of DIBAL (1M in hexane, 25 ml, 25 mmol) in tetrahydrofuran (25 ml) under nitrogen at 25°-30° C. The mixture was stirred at ambient temperature for 0.5 h and then quenched with an excess of 20% HCl at 5°-10° C. The precipitate was collected and washed with water, tetrahydrofuran and ethyl ether to give 2.12 g of 6,7-dichloro-2-hydroxyquinoline-3-methanol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].CC([O-])(C)C.[K+].C1COCC1>CN(C=O)C>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][C:6]=2[O:10][CH3:11])[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COc1ccnc(Cl)c1C#N
Reactant: COC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2nccc(OC)c2c1N
Reaction time: 0.33 h

Procedure:
To 2-chloro-3-cyano-4-methoxypyridine (2.02 g) and methyl thioglycolate (1.1 mL) in DMF (24 mL) at 5° C. was added a 1.0M solution of KOtBu/THF (14.6 mL). The reaction was stirred 20 min at 5°, then 1 h at RT, quenched in saturated NH4Cl, the solid collected, washed with water and sucked dry. This was recrystallized from EtOAc to give 0.89 g of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33](=[O:50])[N:34]([CH2:38][C:39]2[CH:44]=[C:43]([CH2:45][CH2:46][O:47][CH3:48])[CH:42]=[CH:41][C:40]=2[Cl:49])[CH:35]2[CH2:37][CH2:36]2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:49][C:40]1[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][O:47][CH3:48])=[CH:44][C:39]=1[CH2:38][N:34]([CH:35]1[CH2:37][CH2:36]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:25]([Cl:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[Cl:30])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1)=[O:50]
Reactant: COCCc1ccc(Cl)c(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1ccc(Cl)c(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
Compound D5 (279 mg, 0.375 mmol) was dissolved in CH2Cl2 (3 mL). The sol. was cooled to 0° C., and HCl (4M in dioxane, 1.00 mL) was added. The mixture was stirred at 0° C. for 1 h. HCl (4M in dioxane, 1.00 mL) was added again, and the mixture was stirred for 2 h at rt. HCl (4M in dioxane, 1.00 mL) was added again, and the mixture was stirred for 3 h at rt. Aq. 1M NaOH was added until the mixture was slightly basic. The mixture was filtered over Isolute®. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (MeOH/CH2Cl2 1:19) yielded the title compound (120 mg, 50%). LC-MS: tR=0.96 min, ES+=645.49.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.[CH3:29][N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN>CN(C=O)C.C1COCC1>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:30][CH3:29])=[O:28])[CH:3]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.49 g, 1.2 mmol), HATU (0.70 g, 1.8 mmol), N-methyl morpholine (0.40 mL, 3.6 mmol), methylamine (2 M in THF, 3.0 mL, 6.0 mmol), THF (10 mL) and DMF (2.0 mL) were placed in a sealed tube. The mixture was stirred at room temperature for 18 h. The THF was evaporated and the residue was quenched with water. The resulting solid was collected by filtration. The crude product was purified by flash chromatography on silica gel (Hexanes/EtOAc, 1:1) to yield (1R,10R,11S,16S)-5-hydroxy-N,1,11,15,15-pentamethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (66) (0.25 g, 44%) as a white solid. 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.09 (s, 1H), 6.70 (s, 1H), 6.36 (m, 1H), 3.39 (m, 2H), 2.97 (d, 3H), 2.54 (m, 1H), 2.13 (m, 1H), 1.75-0.96 (m, 13H), 0.94 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H). MS m/z 420 (C23H33NO4S+H+).