Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)c1cc(SCCCO)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio] propanol (2.0 g, prepared as described in U.S. Pat. No. 4,857,558) was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10°-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: BrCc1cccs1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3cccs3)c3ccc(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 9.1 g (30 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 87, part B) and 50 mL (50 mmol) of a freshly prepared 1M solution in ethyl ether of 2-bromomethyl-thiophene. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 7.7 g (65% of yield) of 4-(5-methoxy-1-thiophen-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C)CCN(C)C.C([Li])CCC.[C:30](=[O:32])=[O:31].[Cl-].[NH4+]>C(OCC)C>[C:12]([O:11][C:10]([NH:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=1[C:30]([OH:32])=[O:31])=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1ncccc1NC(=O)OC(C)(C)C
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1nccc(C(=O)O)c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
T-butyl (2-methoxypyridin-3-yl)carbamate (8.0 g, 35.7 mmol) and tetramethylethylenediamine (8.3 g, 71.4 mmol) were dissolved in diethyl ether (100 mL). The reaction solution was stirred at −78° C., to which n-butyllithium (2.44 M in hexane, 36.6 mL) was dropwise added at that temperature. The reaction solution was stirred at −78° C. for 1 hour, then gradually heated up to 0° C., and CO2 (solid) was added to it at 0° C. This was stirred at that temperature, and then aqueous saturated ammonium chloride solution was added thereto. The aqueous layer was separated, controlled to have a pH of 1 with 1 N hydrochloric acid added thereto, and extracted with chloroform. All the organic layers were combined, and dried with magnesium sulfate. The solvent was evaporated off under reduced pressure to obtain the intended compound (6.74 g, 70.4%) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:17])[C:14]([CH3:16])=[CH2:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[ClH:18].O>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:17])[C:14]([Cl:18])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: Cl
Reactant: C=C(C)C(C)Oc1cc(OCC#CC)ncn1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC#CCOc1cc(OC(C)C(C)(C)Cl)ncn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 3 ml of carbon tetrachloride were dissolved 0.23 g of 4-(2-butynyloxy)-6-(1,2-dimethylallyloxy)pyrimidine and 0.01 g of trioctylmethylammonium chloride, to which 1 ml of concentrated hydrochloric acid was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.05 g of 4-(2-butynyloxy)-6-(2-chloro-1,2-dimethylpropyloxy)pyrimidine (the present compound (34)).
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH2:20]([S:32]([CH2:35][C:36]#[N:37])(=[O:34])=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C(O)C>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][C:7](=[C:35]([S:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[C:36]#[N:37])[CH2:12]1
Reactant: CCCCCCCCCCCCS(=O)(=O)CC#N
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCS(=O)(=O)C(C#N)=C1C=C(N2CCCC2)CC(C)(C)C1

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (3.2 g.), dodecylsulfonylacetonitrile (2.7 g.) and triethylamine (3.1 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 5 minutes. After chilling, the solid is collected on a filter, washed with methanol and dried. Obtaining pure dye by recrystallization from methanol proved difficult. The product is eluted from basic alumina, using a 10% methanol-90% chloroform solvent mixture, and then recrystallized from methanol. The yield of purified dye is 0.5 g. (11%), m.p. 114°-115°C. This dye compound shows good ultraviolet absorption characteristics as indicated in the data in Table 1 below.
Reaction SMILES: FC(F)(F)[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C@H:8]2[CH2:12][O:11][S:10](=[O:14])(=[O:13])[N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.[Cl:26]C1C=CC(C[C@H](NC(OC(C)(C)C)=O)C(O)=O)=CC=1.C(OC(N[C@@H](CC1C=CC(C(F)(F)F)=CC=1)C(O)=O)=O)(C)(C)C>>[Cl:26][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C@H:8]2[CH2:12][O:11][S:10](=[O:14])(=[O:13])[N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O

Procedure:
To a solution of allyl 3-(isoquinolin-6-yl)isoxazol-5-ylcarbamate (0.055 g, 0.19 mmol) in 3 mL of DMF was added cesium carbonate (0.12 g, 0.37 mmol). The mixture was heated to 50° C. (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.097 g, 0.28 mmol) was added slowly in 0.75 mL of THF. After 30 minutes, the reaction was cooled to room temperature and diluted with 10 mL of EtOAc. 10 mL of 10% HCl was then carefully added. After 30 minutes, the reaction was diluted with 15 mL of 5% aq. NaOH. The biphasic mixture was partitioned and the aqueous portion was extracted twice with 20 mL of EtOAc. The combined organic extracts were washed with twice with 10 mL of water and 15 mL of brine and then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc/hexanes) afforded the desired adduct (0.095 g, 91% yield) as a yellow solid. (S)-tert-Butyl 4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared in a similar manner as that described for (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide in Scheme 1, using (S)-3-(4-chlorophenyl)-2-(tert-butoxycarbonylamino)propanoic acid commercially available from 3B Scientific Corporation Product List (Order Number 3B3-011434) instead of (S)-2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].CN(C)C=O.[CH3:12][C:13]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:26][O:27][CH3:28])[C:24]#[N:25]>C(OCC)(=O)C>[CH3:28][O:27][N:26]=[C:23]([C:24]1[NH:25][N:3]=[N:2][N:1]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:14]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:13]=1[CH3:12]
Reactant: [N-]=[N+]=[N-]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(c1nnn[nH]1)c1ccccc1COc1cc(C)ccc1C
Temperature: 115 °C
Reaction time: 9 h
Yield: 87.4 %

Procedure:
Sodium azide (1.30 g, 20 mmol), ammonium chloride (1.07 g, 20 mmol) and dimethylformamide (10 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.59 g, 2 mmol), and the mixture was stirred at 115° C. for 9 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1H-tetrazol-5-yl ketone O-methyloxime (0.59 g, 87.4%) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CS(C)=O>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1cnccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.150 g, 0.50 mmol), 2-chloropyrazine (0.57 g, 1.67 mmol), triethylamine (0.1 ml, 0.72 mmol), and DMSO (50 ml) was stirred for three hours at 100° C. The crude reaction mixture was purified directly by reverse phase HPLC to give the product as a purple solid (0.014 g, 0.7%) MP=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.41 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.81 (m, 3H), 7.76-7.70 (m, 1H), 7.58-7.52 (m, 1H), 4.28-4.22 (m, 2H), 3.39-3.28 (m, 2H), 3.12 (s, 2H), 2.11-2.04 (m, 2H), 1.88-1.79 (m, 2H); LCMS: 380 [M+H].
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:33][CH2:34][CH3:35]>CN(C)C=O>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:33][CH2:34][CH3:35])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCI
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one ( 2 g, 5.1 mmol) in anhydrous dimethylformamide (15 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.22 g of a 55-60% dispersion in mineral oil, 5.1 mmol) in one portion, at 0° C. After 45 min at 0° C., 1-iodopropane (0.55ml, 5.6 mmol) was added in one portion and the solution allowed to reach ambient temperature and stirred overnight. After this time the solvent was removed under reduced pressure, and the crude residue partitioned between water (25 ml) and dichloromethane (25 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (3×25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.74 g, 79%) as a colourless solid. mp 160°-163° C. 1H NMR (360 MHz, CDCl3) δ 0.82 (3H, t, J=10.5 Hz), 0.94-1.48 (5H, m), 1.50-1.76 (5H, m), 1.79-1.90 (1H, m), 1.96-2.08 (1H, m), 2,70-2.84 (1H, m), 3.46-3.59 (1H, m), 4.22-4.35 (1H, m), 5.06-5.16 (3H, m), 5.07 (1H, d, J=12.0 Hz), 7.21-7.40 (7H, m), 7.44-7.59 (2H, m).
Reaction SMILES: Cl.COC1C=CC(C[S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([NH:30][C@@H:31]3[CH2:35][CH2:34]N[CH2:32]3)=[O:29])[CH2:11]2)=CC=1.[N+:38]([C:41]1[CH:54]=[CH:53][C:44]([CH2:45][O:46][C:47]([NH:49][C:50](=[NH:52])[CH3:51])=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39]>>[SH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:52]([C:50](=[N:49][C:47]([O:46][CH2:45][C:44]3[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:54][CH:53]=3)=[O:48])[CH3:51])[CH2:32]2)=[O:29])[CH2:11]1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N[C@@H]3CCNC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 53.1 %

Procedure:
Following a procedure similar to that described in Preparation 23(iii) and 23(iv), but using 0.76 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-[(3R)-pyrrolidin-3-ylaminocarbonyl]pyrrolidine hydrochloride and 0.33 g of N-(4-nitrobenzyloxycarbonyl)acetamidine, 0.45 g of the title compound was obtained as a powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH2:4][N:5]=[C:30]=[O:31]
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: O=C(Cl)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=NCc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-fluoro-5-trifluoromethyl benzyl amine(5.23 mmol) at 0° C. was added solid Proton sponge (5.23 mmol) then a 20% solution of phosgene in toluene (5.23 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated to provide the title compound. 1H-NMR (CDCl3): 7.7 ppm (t, 1H); 7.60 ppm (m, 1H); 7.2 ppm (m, 1H); 4.64 ppm (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH:3]1[CH2:7][N:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]([C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)=O)[CH2:4]1.[H-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:28])[CH:3]1[CH2:7][N:6]2[C:8](=[O:17])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=3)[N:5]2[CH2:4]1
Reactant: CSc1nccc(C(=O)N2CC(N(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(N(C)C)C3)n1
Temperature: 0 °C

Procedure:
1-[4-Dimethylamino-2-(2-methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-1-yl]-2-(4-fluorophenyl)-ethanone, 23, (4.0 g, 10 mmol) is dissolved in THF (75 mL). This solution is then added dropwise via cannula to a suspension of NaH (0.440 g of a 60% dispersion in mineral oil, 11 mmol) at −30° C. The reaction is allowed to gradually warm to 0° C. over 3 hours. The reaction is quenched with NH4Cl (sat. aq.) (15 mL). The mixture is stirred at room temperature, then concentrated in vacuo. The residue is diluted with tetrahydrofuran (250 mL) and the mixture filtered through Celite. The filtrate is concentrated in vacuo to give an oil. The crude product is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford the desired product.
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:6](=[O:29])[C@H:5]1[CH2:30][C:31]12[CH2:32][CH:33]3[CH2:34][CH:35]([CH2:36][CH:37]([CH2:39]3)[CH2:38]1)[CH2:40]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccc(C)cc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccc(C)cc2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)O

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(4-methylbenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:13]([O:16][NH2:17])([CH3:15])[CH3:14].[OH-].[Na+].[N+](=C)=[N-]>O.C(O)C>[CH:13]([O:16][N:17]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:10])=[O:9])([CH3:15])[CH3:14]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CC(C)ON
Agent: C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)ON=C(C(=O)O)c1ccccc1
Yield: 97.6 %

Procedure:
A mixture of phenylglyoxylic acid (3.0 g.), isopropoxyamine hydrochloride (2.5 g.), ethanol (100 ml) and water (50 ml) was stirred and adjusted to pH 4.5 to 5 with sodium hydroxide solution (2N). The solution was stirred for 5 hr. maintaining the pH at 4.5-5 with further additions of sodium hydroxide solution. The ethanol was removed by evaporation, the aqueous residue acidified and the product collected by extraction with ethyl acetate. Evaporation of the ethyl acetate gave a brown oil (4.2 g.). that was esterified conventionally with diazomethane to give a mixture of the syn and anti methyl esters of the title compound as an oil (4.04 g.).
Reaction SMILES: [CH2:1]1N2CCN(CC2)C1.[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:41])=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+].Cl>CN(C=O)C.C(=O)(OC)OC.C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][C:28]([F:41])=[C:29]4[C:33]=3[N:32]([CH3:1])[CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Reactant: C1CN2CCN1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 94 °C
Reaction time: 72 h
Yield: 25.2 %

Procedure:
DABCO (121 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D46) (340 mg) in DMF (2 mL) and dimethyl carbonate (2 mL). The reaction mixture was stirred at 94° C. for 3 days. Then the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated to afford the crude product as a yellow solid. This solid was dissolved in THF (3 mL) and water (3 mL). Sodium hydroxide (40 mg) was then added to the mixture. The reaction mixture was stirred at 90° C. for 1 h. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E20) (83 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.59 (2H, t), 3.03 (2H, t), 3.62 (3H, s), 4.88 (1H, m), 6.95 (1H, dd), 7.22 (1H, s), 7.42 (2H, m), 8.12 (1H, dd), 8.19 (1H, d), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −120.6. MS (ES): C23H21ClFN3O4 requires 457; found 458.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:14][C@H:13]([CH:15]1[CH2:16][CH2:17]1)[C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Cc1c(F)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CC2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c(Cl)cccc1O[C@H](C1CC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was dissolved in DMF (15 mL, 200 mmol). Washed and dried sodium hydride (298 mg, 12.4 mmol) was added carefully in three separate portions and the resulting mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorotoluene (749 μL, 6.2 mmol) was added, and the mixture was stirred overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated and concentrated. The crude material was then treated with 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred overnight at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg, 99.4% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12. found 266.0.