Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:16]>Cl.CO.O1CCCC1>[ClH:16].[NH:5]1[CH2:6][CH2:7][S:2](=[O:15])(=[O:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCNCC1
Temperature: 25 °C

Procedure:
tert-Butyl 1,1-dioxothiomorpholine-4-carboxylate (2.03 g, 8.63 mmol) was dissolved in a mixture of hydrochloric acid-methanol 10 (20 ml) and tetrahydrofuran (20 ml); hydrochloric acid (4.0 ml) was added thereto during stirring at room temperature; and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated; methanol (20 ml), tetrahydrofuran (20 ml) and hydrochloric acid (4.0 ml) were added to the obtained crystals. Furthermore, water (10 ml) was added to this solution to perfectly dissolve the crystals; and this solution was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure; and the obtained crystals were suspended in methanol, filtered off, washed with methanol, and dried under aeration to yield the title compound as colorless crystals (1.49 g, 8.65 mmol, quantitative).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])(=O)=O.[CH3:22][NH2:23]>CO>[CH3:13][O:12][C:9]([CH3:11])([CH3:10])[CH2:8][C@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][NH:23][CH3:22]
Reactant: COC(C)(C)C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CN
Solvent: CO
Product: CNC[C@H](CC(C)(C)OC)NC(=O)OC(C)(C)C
Temperature: 120 °C

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-4-methoxy-4-methylpentyl methane-sulfonate (1.08 g, 2.99 mmol) in MeOH was added methylamine in methanol (33 wt %, 4.0 mL). The resulting solution was heated in CEM microwave reactor at 120° C. for 5 min. Reaction completion was confirmed by LC-MS. Solvent was removed under vacuum to give a crude (S)-tert-butyl 4-methoxy-4-methyl-1-(methylamino)pentan-2-ylcarbamate, which was used for the next step without purification. MS m/z 261 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:2]2[C:3]([C:8]3([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)C1(c2nccnc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
To a vial with 1-tert-butyl 4-methyl 4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (58 mg, 0.163 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (39.5 mg, 0.163 mmol), and cesium carbonate (106 mg, 0.326 mmol) under N2 is added DMSO (1.0 mL). The reaction is heated to 100° C. in an oil bath 3 h. The reaction was cooled to rt, added to H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by RPHPLC to give 1-tert-butyl 4-methyl 4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate (36 mg, 0.064 mmol, 39.3% yield) as a white solid. [M+1]=562.1. IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[NH:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[N:14]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:21][CH2:20][CH2:19][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:8])[NH:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: NCCN1CCCC1
Reactant: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1[nH]c(C(=O)NCCN2CCCC2)cc1Cl
Yield: 69 %

Procedure:
A solution of methyl 3-chloro-5-(chlorocarbonyl)-1H-pyrrole-2-carboxylate (0.100 g, 0.387 mmol) in 4 mL of DCM was treated with [2-(1-pyrrolidinyl)ethyl]amine (0.110 g, 0.967 mmol). After 1 hour saturated NaHCO3 was added and the mixture shaken. The DCM layer was separated, dried over MgSO4 and evaporated onto silica gel. Purification was accomplished on silica with 0 to 10% MeOH in EtOAc to afford the title compound (0.080 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (t, 1H), 6.80 (d, 1H), 3.78 (s, 3H), 3.32 (q, 2H), 2.52 (t, 2H), 2.45 (br. s., 4H), 1.65 (br. s., 4H). LCMS: m/z 298.2 (M−1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:29]\[C@H:30]3[CH2:50][CH2:49][C:32]4(O[C@H](C5C=CC=CC=5)[C@@H](C5C=CC=CC=5)[O:33]4)[CH2:31]3)/[C:17]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[ClH:51].Cl.C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[ClH:51].[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:29]\[C@H:30]3[CH2:50][CH2:49][C:32](=[O:33])[CH2:31]3)/[C:17]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)O)cn1)/C(=C/[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@H](/C=C(/C(=O)Nc2ccc(C(=O)O)cn2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 6-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]prop-2-enoyl}amino)nicotinic acid (194 mg) in 1,4-dioxane (4 mL) was added 4 M hydrochloric acid (4 mL), followed by stirring at 50° C. for 2 hours. After leaving it to be cooled to room temperature, saturated brine was added thereto. After extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was dissolved in ethyl acetate (4 mL), and 4 M hydrogen chloride/ethyl acetate (1 mL) was added thereto. It was stirred at room temperature for 30 minutes and concentrated. The obtained oily substance was solidified with diisopropyl ether and collected by filtration to obtain 6-({(2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-oxocyclopentyl]prop-2-enoyl}amino)nicotinic acid monohydrochloride (87 mg) as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[H-].[Na+].[Br-].C(O[C@@H:46]1[C@@H:52](OC(=O)C)[C@@H:51](OC(=O)C)[C@@H:50]([CH2:61]OC(=O)C)O[C@@H:47]1O)(=O)C>>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:7][C@@H:8]1[O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]1[CH:27]=[C:26]([C:47]2[CH:46]=[CH:52][CH:51]=[CH:50][CH:61]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(=C/c1cccc(-c2ccccc2)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 26 %

Procedure:
The title compound was prepared as described for C4 using methyl 3-(3-arylphenyl)-2-oxopropanoate B12 (100 mg, 0.373 mmol), sodium hydride (9.0 mg, 0.373 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (153 mg, 0.373 mmol). The compound was isolated in the form of white solid in 26% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].CCN(CC)CC.[C:18](OCl)([CH3:20])=[O:19]>ClCCl.O>[C:18]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])(=[O:19])[CH3:20]
Reactant: CC(=O)OCl
Reactant: Cc1ccc(CO)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of (2-chloro-4-methylphenyl)methanol (365 mg, 2.331 mmol) and Et3N (0.390 mL, 2.80 mmol) in Dichloromethane (DCM) (10 mL) at 0° C. AcOCl (0.331 mL, 4.66 mmol) was slowly added and the mixture was left under stirring at 0° C. for 1 hour then at room temperature overnight. Next morning HPLC showed no starting material remaining volatiles were removed under vacuum and resulting crude was dissolved in DCM washed several times with water. Organic layers were dried over Na2SO4 and volatiles removed to afford 453 mg of the final compound as a brown oil.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:20])[C:12]([Cl:19])=[C:13]([Cl:18])[C:14](=[O:17])[C:15]=1[Cl:16].Cl.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[C:11]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([OH:20])[C:12]([Cl:19])=[C:13]([Cl:18])[C:14](=[O:17])[C:15]=1[Cl:16]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.82 g (3.33 mmol) of 2,3,5,6-tetrachloro-1,4-benzoquinone in 26 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.04 g of the desired product (yield 94%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17](OC)(=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCC.O1CCCC1>[O:27]=[C:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCCCCCCC(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g. (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml. of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 36.3 g. (0.20 mole) methyl decanoate is added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, to give dimethyl 2-oxo-undecylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]2.O.O.[Sn](Cl)[Cl:31]>C(O)C>[ClH:1].[ClH:31].[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[C:7]3[C:3]([CH:4]=[C:5]([C:21]([N:23]=[C:24]([NH2:27])[NH:25][CH3:26])=[O:22])[NH:6]3)=[C:2]([Cl:1])[CH:10]=2)=[CH:17][CH:16]=1
Reactant: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccc([N+](=O)[O-])cc3)cc2[nH]1
Reactant: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccc(N)cc3)cc2[nH]1
Product: Cl
Yield: 66.7 %

Procedure:
The reaction was carried out in a manner similar to Example 186 c) except for using 0.24 g (0.62 mmol) of 4-chloro-1-methyl-6-(4-nitrophenoxy)-2-indoloylguanidine, 0.72 g (3.20 mmol) of tin (II) chloride dihydrate and 15 ml of ethanol. Thus, 0.089 g of 6-(4-aminophenoxy)-4-chloro-1-methyl-2-indoloylguanidine dihydrochloride was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:41])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH2:43][CH:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)=[O:41])[CH2:38][CH2:39]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CN1CCC(COC(=O)C2CCNCC2)CC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(COC(=O)C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added (1-methylpiperidin-4-yl)methyl piperidine-4-carboxylate hydrochloride (178 mg, 0.64 mmol), DIEA (126 mg, 0.97 mmol), HATU (160 mg, 0.42 mmol). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting solution was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (32.0% MeCN up to 50.0% in 8 min); Detector, 254/220. This resulted in 37 mg (16%) of the formic acid salt of (1-methylpiperidin-4-yl)methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as an off-white solid. LCMS (Method 25) [M+H]+=685.2, RT=1.05 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.2, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.36-5.18 (m, 2H), 4.28-4.21 (m, 1H), 3.96-3.88 (m, 3H), 3.25-3.12 (m, 1H), 2.86-2.74 (m, 3H), 2.73-2.66 (m, 1H), 2.15 (s, 3H), 1.92-1.83 (m, 4H), 1.65-1.52 (m, 4H), 1.48-1.38 (m, 1H), 1.29-1.16 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[O:7][C:8]2[C:14]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])=[C:13]([F:28])[CH:12]=[C:11]([Cl:29])[C:9]=2[N:10]=1)(=[O:4])=[O:3].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:30][N:5]([C:6]1[O:7][C:8]2[C:14]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[N:17]([CH3:26])[C:16]3=[O:27])=[C:13]([F:28])[CH:12]=[C:11]([Cl:29])[C:9]=2[N:10]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(NS(C)(=O)=O)oc23)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)S(C)(=O)=O

Procedure:
This compound is prepared in the manner of Step F, Example 1, with 4.3 grams (10 mmole) of 3-(2-methylsulfonylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, 1.5 grams (11 mmole) of potassium carbonate, 1.7 grams (12 mmole) of methyl iodide, and 25 mL of acetone as reagents.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]([C:15]([OH:17])=[O:16])[OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CS(O)(=O)=O.[CH2:29](O)[CH3:30]>>[CH2:29]([O:16][C:15](=[O:17])[CH:13]([OH:14])[CH:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:30]
Reactant: O=C(NC(c1ccccc1)C(O)C(=O)O)OCc1ccccc1
Reactant: CCO
Agent: CS(=O)(=O)O
Product: CCOC(=O)C(O)C(NC(=O)OCc1ccccc1)c1ccccc1

Procedure:
The racemic N-CBZ-3-phenylisoserine of Formula 6 was then esterified by refluxing in ethanol with methane sulfonic acid to provide the (±)-N-CBZ-3-phenylisoserine ethyl ester (Formula 7) ready for chiral chromatographic separation:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1cccs1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, part B), 2-thiophenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed, and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [Na].[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[I-].[Na+].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Cl)[CH3:26]>C(O)C.O>[CH2:25]([O:27][C:28](=[O:31])[CH2:29][C:12]1([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:11][CH:10]=2)[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH3:26]
Reactant: CC(=O)Nc1ccc(C2C(=O)c3ccccc3C2=O)cc1
Reactant: CCOC(=O)CCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A solution of sodium (0.412 g) in absolute ethanol ((200 mL) was treated with 2-(4-acetylaminophenyl)-indan-1,3-dione (5 g, Reference Example 14) then with sodium iodide (2.69 g) and chloroacetic acid ethyl ester (3.6 mL). The mixture was heated at 100° C. for 20 minutes then poured into water (500 mL) and then extracted with ethyl acetate (500 mL). The organic extract was dried over magnesium sulfate and then evaporated to give the title compound (5.25 g) as a pale coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26](=O)[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>C(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCC(=O)c1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 96 h
Yield: 51.5 %

Procedure:
To a solution of ethyl 4-{7-[5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-3-yl}-4-oxobutanoate (D52) (300 mg) and TFA (5 mL) in ethanol (15 mL) and DCM (15 mL) was added sodium cyanoborohydride (235 mg) in portions. The reaction mixture was stirred at 20° C. for 4 days. The mixture was diluted with DCM (30 mL) and washed with water. The organic phase was separated and dried over anhydrous sulphate. After filtration, the solvent was evaporated to give the crude product, which was purified by preparative TLC separation to afford ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]butanoate (D53) as a white solid (150 mg). MS (ES): C25H26ClN3O4 requires 467; found 468.2 (M+H+).