Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=4)[N:16]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:15]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[C:43](=O)([O:52][C@H:53]1[CH2:57][CH2:56][O:55][CH2:54]1)[O:44]N1C(=O)CCC1=O>C1COCC1>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([C:9]3[N:8]=[C:7]([NH:6][CH:4]4[CH2:3][N:2]([C:43]([O:52][C@H:53]5[CH2:57][CH2:56][O:55][CH2:54]5)=[O:44])[CH2:5]4)[C:12]([F:13])=[CH:11][N:10]=3)=[CH:15][N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:17]2=[N:18][CH:19]=1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CN(C(=O)O[C@H]5CCOC5)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.06 g, 0.11 mmol) in THF (1 mL) was treated with iPr2NEt (0.30 mL, 1.70 mmol) then solid (S)-2,5-dioxopyrrolidin-1-yl tetrahydrofuran-3-yl carbonate (0.03 g, 0.11 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature and then quenched with 200 μL of morpholine and evaporated to dryness to afford (S)-tetrahydrofuran-3-yl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6d, which was used without purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:4]2[N:3]=[N:2][NH:1][CH:5]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2c[nH]nn2)cc1
Reactant: O=C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
5 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred with 2.9 g of cyclohexanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.6 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:45])[CH2:21][NH:22][C:23]([CH3:44])([CH3:43])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]2=[O:42])[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:45][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]([CH3:43])([CH3:44])[CH2:24][CH2:25][N:26]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([CH2:39][CH2:40][CH3:41])([CH2:36][CH2:37][CH3:38])[O:28][C:27]1=[O:42]
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c2ccccc21

Procedure:
A suspension of 270 mg (0.438 mmol) 1-{3-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one and 27 mg Pd/C (10%) in MeOH (8 mL) is hydrogenated at RT and 1 bar hydrogen pressure for 3 hours. The catalyst is filtered off through CELITE® filter aid and washed with MeOH (5 mL) and the filtrate is concentrated by evaporation in vacuo. The residue is dissolved in EtOAc/dichloromethane (1:1, 10 mL), acidified to pH 2 by the addition of HCl solution (saturated in EtOAc) and concentrated by evaporation in vacuo. The residue is triturated with ether, filtered and dried in vacuo. Yield: 80 mg (33%; hydrochloride), HPLC-MS: Rt=12.8 min. (method A), ESI-MS: [M+H]+=526.
Reaction SMILES: [NH:1]1[CH:9]2[CH:4]([N:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]2[NH:34][CH:35]=[CH:36][C:29]=12>CN1C(=O)CCC1>[NH:34]1[C:30]2=[N:31][CH:32]=[CH:33][C:28]([N:1]3[CH:9]4[CH:4]([N:5]([C:10]([O:12][CH2:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[O:11])[CH2:6][CH2:7][CH2:8]4)[CH2:3][CH2:2]3)=[C:29]2[CH:36]=[CH:35]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C(OCc1ccccc1)N1CCCC2NCCC21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC2C1CCN2c1ccnc2[nH]ccc12
Temperature: 160 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product of Example 1, Step 1 (136 mg, 0.524 mmol) in NMP (0.262 mL), in a microwave vial, was added Et3N (0.073 mL, 0.52 mmol) and 4-chloro-1H-pyrrolo[2,3-b]pyridine (16 mg, 0.11 mmol). The resulting solution was heated at 160° C. for 2 hours in a Biotage Initiator microwave. An additional 4 equivalents of 4-chloro-1H-pyrrolo[2,3-b]pyridine (64 mg, 0.42 mmol) was added to the reaction mixture and the resulting solution was stirred at 160° C. for another 2 hours in a Biotage Initiator microwave. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc (50 mL) and saturated sodium bicarbonate (50 mL). The layers were separated, and the organic layer was collected, dried over sodium sulfate and concentrated in vacuo to afford a crude oil that was purified by reverse phase HPLC. Lyophilization of the product fractions afforded the title compound (TFA salt) as a white solid. LRMS calc'd for C22H25N4O2 [M+H]+, 377; found 377. Jak1 activity: +.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([S-:10])=[N:2]1.[K+].Br[CH2:13][CH2:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O>[F:19][C:15](=[C:16]([F:18])[F:17])[CH2:14][CH2:13][S:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: [S-]c1nsc2ccccc12
Reactant: FC(F)=C(F)CCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)=C(F)CCSc1nsc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.05 g (0.01 mol) Potassium 1,2-benzoisothiazole-3-thiolate was suspended in 25 ml dimethylformamide. At a temperature of 20° C., a solution of 2.3 g (0.01 mol) 4-bromo-1,1,2-trifluorobut-1-ene in 10 ml dimethylformamide was added dropwise. The mixture was then stirred for 2 hours at room temperature. The mixture was added to 300 ml ice/water and extracted several times with ethyl acetate. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residual oil was purified by silica gel column chromatography (eluent: hexane/diethyl ether 9:1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:16]1)(=[O:14])=[O:13])=[CH:6]2.C(N(C(C)C)CC)(C)C.[C:50](=O)([O:58]C1C=CC([N+]([O-])=O)=CC=1)[O:51][CH:52]([O:54][C:55](=[O:57])[CH3:56])[CH3:53]>C(O)C>[C:55]([O:54][CH:52]([O:51][C:50]([CH:28]1[NH:27][CH2:26][C:25]2[S:24][C:23]([C:21]([N:18]3[CH2:19][CH2:20][N:15]([S:12]([C:7]4[NH:8][C:9]5[C:5]([CH:6]=4)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=5)(=[O:13])=[O:14])[CH2:16][CH:17]3[CH2:32][C:33]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[O:34])=[O:22])=[N:31][C:30]=2[CH2:29]1)=[O:58])[CH3:53])(=[O:57])[CH3:56]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(s1)CNCC2)N1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)OC(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In ethanol (6 ml) was dissolved 4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (200 mg), followed by the addition of diisopropylethylamine (83 μl) and 1-acetoxyethyl p-nitrophenyl carbonate (128 mg). The resulting mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure. Methylene chloride and an aqueous solution of sodium bicarbonate were added and the mixture was separated into layers. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (1-2% methanol-methylene chloride). The product was dissolved in ethyl acetate, followed by crystallization from diethyl ether, whereby the title compound (100 mg) was obtained as colorless powder.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:3][CH:2]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: Cc1ccc(Oc2cccc3[nH]c(C(=O)O)cc23)cc1
Agent: Cl
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to Example 1 from 4-p-tolyloxy-1H-indole-2-carboxylic acid 137 (preparation see below) and amine 5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:16][Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1.CI.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH:12]([CH3:16])[C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1csc2c1CCCC2=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1csc2c1CCC(C)C2=O
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (the compound of Preparation Example 3) (1.0 g) in tetrahydrofuran (9 mL) was added dropwise 1.0M lithium hexamethyldisilazide-tetrahydrofuran solution (4.9 mL). After stirring at −70° C. for 15 minutes, methyl iodide (0.34 mL) was added and the solution was warmed to room temperature and was stirred for 30 minutes. After an aqueous solution of saturated ammonium chloride was added and a further dilution with water, extraction was carried out with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (426 mg) was obtained as a colorless solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[O:10][C:11]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:12][C:13]=2[C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[CH2:18][CH2:17]3)[CH:6]=[CH:5][N:4]=1.O>[Ni].C(O)C>[N:25]1([CH2:24][C:11]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][N:8]=3)=[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[CH2:18][CH2:17]4)[CH:12]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CSc1nccc(-c2oc(CN3CCCCC3)cc2-c2ccc3c(c2)CCC3=O)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: O=C1CCc2cc(-c3cc(CN4CCCCC4)oc3-c3ccncn3)ccc21
Temperature: 25 °C
Yield: 104.9 %

Procedure:
A mixture of the product of Step 4 (0.135 g, 0.329 mmol) and Raney nickel (0.262 g of an aqueous suspension) in ethanol (15 ml) and water (5 ml) was heated at 100° C. for 20 hours. The mixture was then cooled to room temperature, filtered through celite and the filtrate reduced in vacuo. The residue was then purified by chromatography on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95), to furnish the title compound (0.016 g, 0.345 mmol); MS(ES+) m/e 374 [M+H]+.
Reaction SMILES: C(OCC)(OCC)OCC.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]1([N:24]=[CH:25]OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:12]1([NH:11][CH:25]=[N:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC=Nc1ccccc1
Reactant: Nc1ccccc1
Solvent: CCOC(OCC)OCC
Product: C(=Nc1ccccc1)Nc1ccccc1
Yield: 80 %

Procedure:
Thus, a mixture of triethyl orthoformate (1equ.) and aniline (2equ.) is heated at reflux for 2 hours. The ethanol evolved during the reaction is then distilled through a fractionating column. The reaction mixture is then allowed to cool, whereupon it solidifies. Recrystallisation of the solid from toluene yields N,N′-diphenyl formamidine in 80% yield.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:20][C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)Cl
Yield: 253 %

Procedure:
Oleyl alcohol (17.58 g, 65.40 mmol), and triphosgene (6.47 g, 21.80 mmol) were dissolved in 180 ml dichloromethane, stirred and cooled on an ice bath. Anhydrous pyridine (5.17 g of, 65.40 mmol) was added dropwise into the pre-cooled solution. The reaction mixture was stirred for an additional 2 h at room temperature, and then quickly extracted with ice water. The organic layer was combined, dried over Na2SO4 and evaporated to giving crude 18.25 g (84.3% yield) of oleyl chloroformate as liquid. 1H NMR in CDCl3: δ0.88 (t, 3H, J=6.3 Hz, CH3), 1.29 (d, 22H, J=7.7 Hz, CH2), 1.73 (t, 2H, J=6.6 Hz, βCH2), 2.02 (d, 4H, J=5.4 Hz, —CH2—CH═CH—CH2—), 4.31 (t, 2H, J=6.6 Hz, αCH2), 5.35 (m, 2H, —CH═CH—).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 50 °C
Yield: 34.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methane-sulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (200 mg) was dissolved in dimethylformamide (10 ml), to which 1H-1,2,4-triazole (83 mg) and potassium carbonate (168 mg) were added, and the mixture was heated at 50° C. for 20 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (15 ml), 1N-hydrochloric acid (15 ml×2) and a saturated aqueous solution of sodium chloride (15 ml). The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: ethyl acetate). The desired fraction was concentrated and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 44, 65 mg) as a colorless crystalline powder.
Reaction SMILES: COC1C=[C:5]([CH:10]=[C:11]([O:14][CH3:15])C=1O)[C:6](OC)=O.Br[CH2:17][CH2:18][CH2:19]C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:15]([O:14][CH2:11][CH2:10][CH2:5][CH3:6])[CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOCCCC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3,5-dimethoxy-4-hydroxybenzoate represented by Formula 87 (5 g, 23.56 mmol), 1-bromobutane (2.80 mL, 25.92 mmol), potassium carbonate (3.58 mg, 25.92 mmol) and potassium iodide (547.60 mg, 3.30 mmol) in DMF (50 mL) was agitated at 80° C. for 24 hours. After decreasing a temperature of the reaction mixture to room temperature, removing solids through filtration and adding ethyl acetate to the remaining filtrate, the filtrate was consecutively washed with water and a 5N-hydrochloric acid solution. After separating an organic layer and drying the same with magnesium sulfate, the solvent was removed under reduced pressure to form a concentrate mixture, which in turn, was subjected to separation and purification through column chromatography (ethyl acetate/hexane, 1:5) using silica gel (SiO2), resulting in an n-butylether compound represented by Formula 92 as a desired product (6.20 g, 94%). Analysis data of the product is provided as follows:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:20][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: Nc1ccnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
4-Amino-2-chloro-nicotinic acid (1 g, 5.795 mmol) was dissolved in DMF (30 mL) and dichloromethane (50 mL). Phenethylamine (0.87 mL, 6.954 mmol, 1.2 equiv.) was added followed by TEA (1.21 mL, 8.693 mmol, 1.5 equiv.) and HBTU (2.64 g, 6.954 mmol, 1.2 equiv.) and the reaction stirred at 20° C. for 12 hours. The reaction mixture was then diluted with dichloromethane and the aqueous layer was extracted with 20% isopropyl alcohol/dichloromethane. The combined organic portions were washed with 0.5N NaOH solution, NH4Cl solution, water, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography using 2:1 ethyl acetate:hexane to provide 1.23 g (77%) of product.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])C.C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>CN(C=O)C.C(OCC)(=O)C.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>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:4]([C:6]1[S:10][C:9]([C:38]2[S:37][CH:36]=[CH:40][CH:39]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:19]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1sc(-c2cccs2)nc1CN(CC(=O)OCC)Cc1ccc(OC)cc1OC

Procedure:
A solution of 2-Bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1 g, 2 mmol, example 96(b), 2-(tributylstannyl)thiophene (1.26 mL, 2 mmol), dichlorobis(triphenylphosphine)palladium II (140 mg, 0.2 mmol) in 13 mL anhydrous DMF was heated to 130° C. for 20 min. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 15-70% ethyl acetate in hexanes) to give 867 mg of a yellow oil. MS (ESI+): m/z 527.2 (M+23)
Reaction SMILES: C([O:4][C:5](=[O:75])[C@@H:6]([NH:25][C:26](=[O:74])[C:27]1[C:32]([F:33])=[CH:31][C:30]([CH2:34][NH:35][CH2:36][C:37]2[CH:42]=[C:41]([F:43])[C:40]([C:44](=[O:71])[NH:45][C@H:46]([C:65]([O:67]CCC)=[O:66])[CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]4[C:55](=[O:64])[N:56]([CH3:63])[C:57](=[O:62])[N:58]([CH3:61])[C:59]=4[CH3:60])=[CH:50][CH:49]=3)=[C:39]([F:72])[CH:38]=2)=[CH:29][C:28]=1[F:73])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)CC.C1COCC1.[Li+].[OH-]>O>[F:73][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([F:33])[C:27]=1[C:26](=[O:74])[NH:25][C@H:6]([C:5]([OH:75])=[O:4])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]([NH:45][C@@H:46]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[C:55](=[O:64])[N:56]([CH3:63])[C:57](=[O:62])[N:58]([CH3:61])[C:59]=3[CH3:60])=[CH:50][CH:49]=2)[C:65]([OH:67])=[O:66])=[O:71])=[C:39]([F:72])[CH:38]=1
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CNCc2cc(F)c(C(=O)N[C@@H](Cc3ccc(-c4c(C)n(C)c(=O)n(C)c4=O)cc3)C(=O)OCCC)c(F)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNCc4cc(F)c(C(=O)N[C@@H](Cc5ccc(-c6c(C)n(C)c(=O)n(C)c6=O)cc5)C(=O)O)c(F)c4)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a 200 mL flask containing (S)-2-[4-[[3,5-difluoro-4-[(S)-1-propoxycarbonyl-2-[4-[1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]phenyl]ethylcarbamoyl]benzylamino]methyl]-2,6-difluorobenzoylamino]-3-[4-[1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]phenyl]propionic acid propyl ester (1004 mmg, 0.97 mmol) was added THF (25 mL), water (25 mL) and LiOH (193 mg, 4.6 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated, dried from acetonitrile yielding a white solid that was mixed with DMSO (13 mL) and water (12 mL). This mixture was heated minimally, filtered and to the filtrate was added TFA (0.25 mL) resulting in a precipitate. The precipitate was diluted with water (50 mL), filtered, washed with water and hexanes and dried on high vacuum yielding the title compound as a white solid (696 mg, 75%). ES(+)-LRMS m/e calcd. for C48H45F4N7O10 (M+H)+ 956, obsd 956.