Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 2-isopropylphenyl-isothiocyanate (17.7 g), N-methyl aminooxy acetic acid hydrochloride (14.2 g), triethylamine (20 g) and chloroform (300 mL) was stirred at ambient temperature for two hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×200 mL) then with water (100 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (21 g) of [[[[(2-isopropylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.0 (br s, 1H), 10.15 (s, 1H), 7.42-7.05 (m, 4H), 4.63 (s, 2H), 3.58 (s, 3H), 3.08 (m, 1H), and 1.15 ppm (d, 6H). The acid (20 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (14.7 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (700 mL) and washed with sodium bicarbonate saturated solution (3×400 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10-50% methylene chloride in hexane). The title compound (12.8 g) was obtained as a solid, m.p. 98-101° C. Mass spectrum (El, M.+) m/z 264. 1H-NMR (CDCl3; 400 MHz) δ7.37 (m, 2H), 7.22 (t, 1H), 7.06 (d, 1H), 5.12 (q, 2H), 3.69 (s, 3H), 2.69 (m, 1H), 1.15 (d, 3H), and 1.04 ppm (d, 3H).
Reaction SMILES: [N:1]#[C:2][NH2:3].N1C=CC=CC=1.OS(C(F)(F)F)(=O)=O.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[CH:20][CH:19]=1>C(#N)C>[C:2]([NH:3][S:25]([CH2:24][C:21]1[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=1)(=[O:27])=[O:26])#[N:1]
Reactant: O=S(=O)(Cl)Cc1ccncc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: N#CNS(=O)(=O)Cc1ccncc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
Anhydrous cyanamide (32 g, 0.76 mol) was dissolved in acetonitrile (600 ml) in a 2 l, 3-necked flask equipped with a mechanical stirrer, drying tube, and two dropping funnels. The solution was cooled in a 1:1 ethanol-water bath that was maintained at -20° C. by the addition of dry ice. Solutions of pyridine (57 g, 0.72 mol) in acetonitrile (70 ml) and of 4-pyridylmethanesulfonyl chloride triflate (130 g, 0.38 mol) in acetonitrile (200 ml) were added simultaneously at such a rate that the additions of both solutions were completed in 3 hrs. The resulting suspension was stirred at -10° C. for 1 hr and then filtered and the solids washed with cold acetonitrile (50 ml). The solid portion was recrystallized by adding it to ice-cold water (100 ml). The product was filtered off and washed with ice-water (100 ml) to give a light yellow solid (49.5 g). The mother liquors were refrigerated overnight to give additional product (5 g, 73% total yield).
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:15]=1[CH3:16].C(N(CC)CC)C.[H][H]>C(O)(C)C.[C].[Pd]>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]2[CH2:18][NH:19][CH2:20][CH2:21][CH:22]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(-c2cccnc2)nc1C
Reactant: [H][H]
Agent: [Pd]
Agent: BrCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=CCCNC2)nc1C
Temperature: 50 °C
Reaction time: 5 h
Yield: 19.6 %

Procedure:
Benzyl bromide in an amount of 1.06 g was added to a solution of 1 g of 5,6-dimethyl-2,3′-bipyridine in 15 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. to finish the reaction. To the reaction solution, 0.18 g of 10% palladium carbon and 0.59 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 400 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 1.70 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethylacetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 0.20 g of the entitled compound as light yellow crystals. Yield rate: 20%, EI-MS: (m/z) 188 (M+), melting point: 102-104° C.
Reaction SMILES: [NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31](OC)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[NH2:46][NH2:47]>C(O)C>[NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:46][NH2:47])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 24 h

Procedure:
Compound XII (1.50 g, 2.4 mmoles) is dissolved in ethanol (10 ml) and hydrazine hydrate (1.16 ml, 24 mmoles) is added. The mixture is allowed to stand at room temperature for 24 hours and then evaporated in vacuo. The resulting solid residue is dissolved in water-saturated ethyl acetate and the solution is washed with water two times and quickly dried over magnesium sulfate. The crystalline precipitates which separated upon standing at room temperature are filtered off, washed with ether and dried in vacuo. Recrystallization from ethyl acetate-ether affords the hydrazide XIII in pure form; yield 1.41 g (94%), mp. 121°-123° C, [α]D22.5 - 8.5°±0.5° (c 1.0, dimethylformamide), -18.2°±0.6° (c 1.0, methanol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[NH:9][CH:8]=1)=[O:25]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(C(F)(F)F)ccc23)C1(C)C
Yield: 9.8 %

Procedure:
A mixture of 6-(trifluoromethyl)indole (Lancaster, 1.0 g, 5.4 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.6 mL, 6.6 mmol), zinc chloride (1.0 M solution in Et2O, 6.6 mL, 6.6 mmol) and the product of Example 1A (8.1 mmol) in 40 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.17 g, 0.53 mmol, 10% yield). MS (DCI/NH3) m/z 310 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[N-:8]=[N+:9]=[N-:10].[Na+]>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH2:6][N:8]=[N+:9]=[N-:10])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCN=[N+]=[N-]
Temperature: 70 °C

Procedure:
A mixture of 2-bromoethyl acetate (500 μl, 4.54 mmol) in N,N-dimethylformamide (DMF) (2.0 mL) was treated with sodium azide (295 mg, 4.54 mmol) and then heated to 70° C. for 2 hours. The mixture was diluted with water and then extracted with ether. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) d=4.29-4.19 (m, 2 H), 3.53-3.44 (m, 2 H), 2.11 (s, 3 H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@H:12]1[C@H:17]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20][C:19]=2[O:28][CH3:29])[CH2:16][CH2:15][N:14]([CH3:30])[CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O.C(N(CC)CC)C>[CH3:30][N:14]1[CH2:15][CH2:16][CH:17]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20][C:19]=2[O:28][CH3:29])[C:12](=[O:11])[CH2:13]1
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(OC)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(OC)c(C2CCN(C)CC2=O)c(OC)c1
Temperature: -30 °C
Reaction time: 0.12 h
Yield: 76.4 %

Procedure:
Dimethyl sulfoxide (35 ml) is added dropwise under nitrogen to a solution, cooled to -60° C., of oxalyl chloride (20 ml) in dry methylene chloride (500 ml), and the mixture is stirred for 5-10 minutes. A solution of (±)-trans-3-hydroxy-4-(2,4,6-trimethoxyphenyl)-1-methylpiperidine (62 g) in methylene chloride (300 ml) is then added, while the temperature of the reaction mixture is held at -60° C. After the addition, the mixture is stirred for 15 minutes and triethylamine (155 ml) is added. The reaction mixture is then allowed to warm to a temperature of -30° C., diluted with water and rendered alkaline with sodium carbonate. The organic layer is separated off and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give a solid residue which, on crystallization from isopropanol, gives the desired product (47 g) of melting point 110°-112° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>O>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:9][CH2:10][CH2:11][C:12]2=[O:13])[CH2:3][CH2:4]1
Reactant: O=C1CCCO1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: O
Product: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Temperature: 190 °C

Procedure:
Add trans-4-aminocyclohexanol (230 g, 2.0 mol) to γ-butyrolactone (140 mL, 1.82 mol) in a 1 L round-bottom flask equipped with large magnetic stirrer, thermometer and condenser/nitrogen bubbler. Heat the mixture at 190° C. for 68 hours. Cool to ambient temperature and mix with water (1 L). Extract into dichloromethane (10×1.5 L). Dry the extracts over magnesium sulfate, filter and evaporate to a brown solid. Triturate with diethyl ether to afford 144.7 g (43%) of the title compound: MS (m/z): 184 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Na+].Cl>C(#N)C.O>[C:1]([C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(OC)c(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0.80 g portion of methyl 5-cyano-2,4-dimethoxybenzoate was dissolved in 8 ml of acetonitrile and 5 ml of water, and 7 ml of 2N sodium hydroxide aqueous solution was added, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction solution was poured into 2N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give 0.65 g of 5-cyano-2,4-dimethoxybenzoic acid.
Reaction SMILES: ONC(=O)C1C=CC=CC=1C#CC1C=CC=CC=1.[N+:19]([C:22]1[CH:27]=[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][C:23]=1[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([O-])=O>>[NH2:19][C:22]1[CH:27]=[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:24][C:23]=1[NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: O=C(NO)c1ccccc1C#Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Yield: 92 %

Procedure:
The procedure was followed as outlined in Scheme 3, Step 3 replacing compound 37 with compound 60 to afford tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate 61 (2.75 g, 92% yield) as a yellow solid. LRMS (ESI): (calc.) 290.11 (found) 235.1 (M(-tBu)Na)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:22]([CH3:25])([CH3:24])[CH3:23])/[CH:10]=[CH:11]/[P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])[C:5]([F:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:34]([S:46]([C:49]3[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[C:31]2=[N:32][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:26][C:5]1[C:6]([NH:8][C@@H:9]([C:22]([CH3:25])([CH3:24])[CH3:23])/[CH:10]=[CH:11]/[P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])=[N:7][C:2]([C:36]2[C:30]3[C:31](=[N:32][CH:33]=[C:28]([F:27])[CH:29]=3)[N:34]([S:46]([C:49]3[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=3)(=[O:47])=[O:48])[CH:35]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)OP(=O)(/C=C/[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C)OC(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](/C=C/P(=O)(OC(C)C)OC(C)C)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 100 °C

Procedure:
To a solution of (R,E)-diisopropyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate, 16a, (0.81 g, 1.99 mmol) and 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (1.24 g, 3.00 mmol) in 2-Me-THF (16 mL) was added K3PO4 (1.27 g, 3.00 mmol) and water (4 mL). The biphasic mixture was degassed under a stream of nitrogen for 15 minutes. Then, X-Phos (0.11 g, 0.24 mmol) and Pd2(dba)3 (0.06 g, 0.06 mmol) was added to the mixture. After degassing with nitrogen for an additional 5 minutes, the vessel was sealed and heated at 100° C. for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc, filtered through celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-50% EtOAc/CH2Cl2 gradient) to afford 1.123 g of the desired product: 1H NMR (400 MHz, d6-DMSO) δ 8.55-8.42 (m, 3H), 8.31 (d, J=3.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.9 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 6.80 (ddd, J=22.2, 17.1, 6.9 Hz, 1H), 5.99 (dd, J=20.3, 17.1 Hz, 1H), 4.95 (t, J=7.6 Hz, 1H), 4.51-4.32 (m, 2H), 2.35 (s, 3H), 1.19-1.14 (m, 6H), 1.11 (dd, J=6.0, 4.4 Hz, 6H), 1.02 (s, 9H).); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.06 minutes (M+H) 662.35.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.2 %

Procedure:
tert-Butyl ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)carbamate (300 mg, 0.6 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (20 mL). After being stirred at room temperature for 2 hrs, the solution was concentrated. The residue was treated with ether to give 250 mg of yellow solid. MS calculated for C18H24F3N3O: (M+H)+356; found 356.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:16]3[C:17]([CH3:33])=[C:18]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:12][N+:13]([O-])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O1CCCC1.C(OCC)(=O)C.[Zn]>[NH2:13][CH2:12][CH:11]([C:16]1[C:17]([CH3:33])=[C:18]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=[CH:20][CH:21]=1)[C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(Br)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.8 %

Procedure:
To a mixture of benzyl 3-(1-(6-bromo-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate (3.00 g, 5.90 mmol) and ammonium chloride (4.42 g, 83 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) at 0° C. was added zinc dust (5.40 g, 83 mmol) in one portion. The mixture was stirred at room temperature for 7 hr, then diluted with ethyl acetate (100 mL) and filtered through CELITE®. The filtrate was concentrated under vacuum. To the residue was added water (60 mL), and the mixture was extracted with ethyl acetate (4×80 mL). The combined extract was washed with brine (60 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (2.82 g, 5.89 mmol, 100% yield) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][NH:30][CH2:31][CH2:32][CH3:33]>CN1CCCC1=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([N:30]([CH3:29])[CH2:31][CH2:32][CH3:33])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CCCNC
Reactant: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(C)c1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 25° C., 6.83 g (0.02 mole) 4-chloro-3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, 4.1 g (0.03 mole) K2CO3, 3.1 mL (0.03 mole) N-methyl-N-propylamine and a catalytic amount of CuF2 were slurried in 50 mL 1-methyl-2-pyrrolidinone. The reaction mixture was stirred at 35° C. for 2 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was purified chromatographically using 15% ethyl acetate in hexane as the eluent to give 6.8 g (86%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluoro-N-methyl-2-nitro-N-propylbenzeneamine as an orange oil, nD25 1.5534.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([O:34]C)=[O:33])(=[O:30])=[O:29])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=[O:33])(=[O:29])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Prepared using General Procedure 17: To a stirred solution of (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (0.40 g, 0.8 mmol) in MeOH (4 mL) was added 6N NaOH (0.27 mL). After 24 h, the crude reaction was concentrated then partitioned between DCM/IPA and 1N HCl. The organic layer was dried over MgSO4 and concentrated to give 0.35 g (91%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 184. An analytically pure sample was prepared by preparative HPLC purification. LCMS-ESI (m/z) calculated for C23H22N4O6S: 482.1; found 505.1 [M+Na]+, tR=8.72 min (Method 2). (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid was synthesized in an analogous fashion from (S)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[CH2:29][OH:30].O.O1CCCC1>O.C(OCC)C>[CH2:11]([O:10][C:8]([NH:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[CH2:29][OH:30])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(C(F)(F)F)ccc1CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 98.9 %

Procedure:
1H-NMR (CDCl3): δ 1.65 (1H, brs), 4.35 (2H, brs), 4.71 (2H, s), 6.95 (1H, dd), 6.91 (1H, s), 7.16 (1H, d). (c) Sodium carbonate (2.5 g, 23.6 mmol) and benzyl chloroformate (3.3 ml, 23.1 mmol) were added to a solution of 2-amino-4-trifluoromethyl-1-hydroxymethylbenzene (4.08 g, 21.3 mmol), prepared in the step (b), in a water-tetrahydrofuran 1:1 solution (40 ml), and the mixture was stirred at room temperature for 21 hr. Diethyl ether and water were added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-benzyloxycarbonylamino-4-trifluoromethyl-1-hydroxymethylbenzene (6.85 g, 99%) as a white solid.
Reaction SMILES: C([Si]([O:11][CH2:12][C@@H:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(C(C)C)C(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][CH2:14][C@H:13]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)[CH2:12][OH:11])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(CO[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CO[C@H](CO)CNC(=O)OC(C)(C)C)cc1OC
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a 0° C. mixture of (2S)-3-(t-butoxycarbonylamino)-2-(3,4-dimethoxybenzyloxy)propyl triisopropylsilyl ether (1 g, 2.01 mmol) and THF (5 mL) was added 1 M TBAF/THF (2.11 mL, 2.11 mmol). The reaction was stirred for 1 h and satd citric acid (5 mL) and CH2Cl2 were added. The organic layer was partitioned, concentrated, and chromatographed (CH2Cl2 to 50% EtOAc/CH2Cl2) to give the title compound (545 mg, 80%).