Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22]#[N:23])=[N:6][N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:8]=1[NH2:9])(=O)[CH3:2].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[NH2:9][C:8]1[N:7]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:6]=[C:5]([C:22]#[N:23])[C:4]=1[C:1](=[N:25][OH:26])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4-acetyl-5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.25g) in pyridine (5 ml) was added hydroxylamine hydrochloride (0.05 g). After stirring at room temperature for 6 hours the mixture was heated at 50° C. for 3 hours, after which it was evaporated. The residue was taken up in ether and washed with aqueous citric acid solution (1M), water, then dried and evaporated. The residue was crystallised from propan-2-ol/hexane and further purified by column chromatography on silica gel eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a tan solid, m.p. 105-110° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:18][C:19]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(CC(=O)O)C(=O)c1ccc(Br)cc1
Product: CC(CC(=O)O)C(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To 300 ml of fuming nitric acid was added by small portions 51 g of 3-(4-bromobenzoyl)butyric acid with stirring over 2 hours, during which the internal temperature of the reaction mixture was maintained at 10° to 20° C. The resulting mixture was poured into 1 liter of ice water and then extracted with chloroform. The chloroform layer was washed with water and concentrated. The residue was crystallized from water to give 46 g (77%) of 3-(4-bromo-3-nitrobenzoyl)butyric acid [Compound a; Compound (IV) wherein R3 =CH3 ].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7) was reacted with 4-fluoro-3-methoxyphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=486.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][O:13][CH3:14].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a cooled mixture of 6-fluoro picolinic acid (1.19 g, 8.43 mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL, 23.52 mmol) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), evaporated to dryness, and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (1.19 g) in 73% yield. ESMS m/z (relative intensity): 185 (M+H)+ (100).
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C@@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11]>CO>[CH3:11][C:10]1([CH3:12])[S:13][CH:1]([C:2]2[O:6][CH:5]=[CH:4][CH:3]=2)[NH:8][C@H:9]1[C:14]([OH:16])=[O:15]
Reactant: O=Cc1ccco1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CC1(C)SC(c2ccco2)N[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
A solution containing 2.48 ml of furfural and 4.27 g of D-penicillamine in 90 ml of 30% methanol is stirred for 8 hours, then evaporated to dryness. The partly crystalline residue is rubbed with ether to give the title compound, m.p.: 141°-143° C., [α]D20 =+103° (c=0.602, dimethylsulphoxide).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5]
Reactant: C1=COCCC1
Reactant: CCCCCC(O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CC#N)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A mixture of 3-hydroxycaprylonitrile (5.2 g., 36.8 millimole), dihydropyran (3.8 g., 45 millimole) and p-toluenesulfonic acid. hydrate (catalytic amount) is stirred at 25° C. for 16 hours, then diluted with ether (100 ml.). The resulting solution is washed with 5% aqueous sodium hydroxide (25 ml.) and water (2 × 25 ml.), dried over magnesium sulfate and filtered. Evaporation of the filtrate in vacuo affords the title compound as a pale yellow oil (7.9 g., 95%), pmr (CDCl 3) δ 0.93 (3H, t), 2.54 (2H, q) and 4.68 (H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:36](OCC)=[O:37])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[N:28]=3)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=O)C.[NH2:41][C:42]([NH2:44])=[O:43].[H-].[Na+]>CS(C)=O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:28]=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:14]4[N:13]=[CH:12][C:11]([N:7]5[C:6]6([C:4](=[O:3])[NH:44][C:42](=[O:43])[NH:41][C:36]6=[O:37])[CH2:10][CH2:9][CH2:8]5)=[CH:16][CH:15]=4)=[CH:23][CH:22]=3)[O:25][CH:26]=2)=[CH:34][CH:33]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(-c3nc(-c4ccc(F)cc4)co3)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc(-c4nc(-c5ccc(F)cc5)co4)cc3)nc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
1-(6-{4-[4-(4-Fluoro-phenyl)-oxazol-2-yl]-phenoxy}-pyridin-3-yl)-pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.0 grams, 9.16 mmol) and recrystallized urea (2.75 grams, 45.82 mmol) were dissolved in anhydrous dimethylsulfoxide (110 mL), and the solution was placed in a cold water bath. Sodium hydride (770 mg of a 60% dispersion in mineral oil, 19.23 mmol) was added in two portions. The cold water bath was removed after an addition of the second portion, and the resulting solution was stirred for 1 hour at room temperature. The reaction was then poured into 550 mL water and stirred for 20 minutes until cool. The aqueous layer was extracted three times with diethyl ether, and the combined organic layers were set aside. The pH of the aqueous layer was adjusted to 5 with 1 M hydrochloric acid, and the aqueous layer was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and a solution of saturated sodium chloride, dried over sodium sulfate, and concentrated to give 4.8 grams of crude product as a white foam. This material was chromatographed on silica gel (ISCO MPLC purification, 50 minutes, 0-100% ethyl acetate gradient, Biotage flash 40 m column) to provide 3.44 grams (73%) of the title compound as a white solid. MS m/z: ESI+ 514.0 (M+H)+; ESI− 512.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.[BrH:11].[NH+]1C=CC=CC=1>Br.C(O)(=O)C>[BrH:11].[NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH2:9][Br:11])=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)c1sc(N)nc1C
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: Cc1nc(N)sc1C(=O)CBr
Reaction time: 5 h

Procedure:
To a suspension of 2-amino-4-methyl-5-acetylthiazole (15.6 g) in 30% of hydrogen bromide in acetic acid (120 ml) was added pyridinium hydrobromide perbromide (36 g) at ambient temperature and the mixture was stirred at the same temperature for 5 hours. The precipitate was collected by filtration, washed with diisopropyl ether, and dried over calcium chloride to give 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (26.8 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15](Cl)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([NH2:28])[CH:20]([OH:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.Cl.[OH-].[K+]>C(O)C.O>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15]([NH:28][CH:19]([CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[OH:27])[CH3:18])=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(N)C(O)c1ccccc1
Reactant: Clc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Nc1nc(Cl)nc2c1cnn2-c1ccccc1)C(O)c1ccccc1
Reaction time: 4 h
Yield: 90 %

Procedure:
390 mg of 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 15 ml 95% ethanol. 828 mg norephedrine HCl was dissolved in 100 ml H2O, made basic with 10% KOH, and the free base extracted with 100 ml ether. The organic was dried over MgSO4, filtered, and concentrated to yield an oil which was added to the stirred reaction. After 4 hours the solution became clear and the solvent was removed under vacuum. The crude oil was then purified by radial chromatography (5-10-20% isopropyl alcohol/hexane, 4 mm plate) to yield 535 mg of [R-(S*,R*)]-α-[1-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]ethyl]benzenemethanol (90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH:21]C(=O)C)[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][CH2:9]1.O.NN.CS(C)=O>[Cl-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[CH2:19][CH:18]([CH2:20][NH2:21])[O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[O:14])[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Temperature: 130 °C
Yield: 104.4 %

Procedure:
423 mg (1.0 mmole) of N-({3-[3-fluoro-4-(1-oxo-1lambda4,4-thiazinan-4-yl)phenyl}-4,5-dihydro-5-isoxazolyl}methyl)acetamide is combined with 1.5 ml hydrazine hydrate and 1.5 ml dimethylsulfoxide in a 15 ml screw cap pressure tube. The reaction is heated to 130° C. for 24 hours. The mixture is cooled to room temperature, is diluted with 25 ml 50% saturated sodium chloride, and is extracted with 5×20 ml 5% methanol/chloroform. The organics are dried over potassium carbonate and are concentrated in vacuo to give 325 mg (87%) of N-({3-[3-fluoro-4-(1-oxo-1lambda4,4-thiazinan-4-yl)phenyl}-4,5-dihydro-5-isoxazolyl}methyl)amine. The crude solid, 315 mg (1.01 mmole) is dissolved in 10 ml 1:1 dichloromethane/tetrahydrofuran in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution is treated with triethylamine (0.28 ml, 2.02 mmole) followed by ethyl dithioacetate (0.23 ml, 2.02 mmole) and the reaction is stirred 1 hour at room temperature. The suspension is brought to homogeneity with chloroform, is treated with 4 g silica gel (230-400 mesh), and is concentrated to dryness. The plug is chromatographed over 30 g silica gel (230-400 mesh) eluting with 2% methanol/dichloromethane for a 350 ml forerun followed by 3% methanol/dichloromethane while collecting 50 ml fractions. Fractions 2-5 are combined and concentrated to provide 277 mg (75%) of the title compouns as solid. mP=199° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:30]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:36]Cl)([O-:32])=[O:31]>CN(C)C=O>[C:1]([O:5][C:6](=[O:23])[C@H:7]([N:11]([CH2:36][C:35]1[CH:38]=[CH:39][C:40]([CH3:41])=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C)c([N+](=O)[O-])c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (0.15 g, 0.44 mmol) and potassium carbonate (0.32 g, 2.32 mmol) in dry dimethylformamide (15 mL) was added 3-nitro-4-methylbenzyl chloride (81.1 mg. 0.44 mmol). The reaction mixture was stirred overnight and then concentrated on the rotoevaporator. The residue was dissolved in a 1:1 ethyl acetate and brine (50 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated to give 2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid tert-butyl ester (0.196 g) as a yellow viscous oil which was converted to 2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid by following the procedure described in Example 10, Step 8 below. 2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)-amino]-3-methylbutyric acid is then converted to N-hydroxy-2(R)-[(3-nitro-4-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide by following Example 1, Steps 6 and 7 above.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([C@@H:27]1[O:29][C@H:28]1[CH2:30]O)[CH2:24][CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:23]([C@@H:27]1[O:29][C@H:28]1[CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCOc1cnc(-c2cccc(O)c2)nc1
Reactant: CCCC[C@@H]1O[C@H]1CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2cccc(OC[C@@H]3O[C@H]3CCCC)c2)nc1

Procedure:
The synthesis is carried out analogously to Example 11 from 2-(3-hydroxyphenyl)-5-octyloxypyrimidine and (2S,3S)-3-butyloxiran-2-ylmethanol. ##STR45## [α]D20 (CHCl3)=-14.74
Reaction SMILES: [P:1]([O:44]C(C)(C)C)([O:39]C(C)(C)C)([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@@H:29]3[CH2:34][CH2:33][C@@H:32]([OH:35])[C@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2].Cl.O1CCOCC1>CO>[P:1]([OH:39])([OH:44])([O:3][CH2:4][C@@H:5]([NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([NH2:28])=[N:26][CH:25]=[C:24]([C@@H:29]3[CH2:34][CH2:33][C@@H:32]([OH:35])[C@H:31]([F:36])[CH2:30]3)[N:23]=2)=[CH:18][C:17]=1[F:37])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([F:13])[CH:7]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)N[C@H](COP(=O)(O)O)c2cc(F)cc(I)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of (S)-2-(4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (315 mg, 0.392 mmol) was added HCl 4M in dioxane (5 mL, 20.00 mmol) and methanol (Volume: 0.5 mL). The reaction mixture was stirred at room temperature for 1 hour followed by LCMS. The solvent was concentrated off. The crude material was basified and dissolved with 3M NaOH solution with minimal MeOH added. The material was purified by 12 gram Grace Reveleris C18 reverse phase column eluted with 0-15% ACN/water over 18 minutes at a flow rate of 15 ml/minute, without buffers. The desired fractions were collected, acidified with 1 M HCl to pH of 1 and extracted with ethyl acetate (5×). The combined organic layer (800 ml) was washed with minimal water (3×25 ml) to remove salts. The solvent was concentrated off, dissolved in 1:1 ACN/water and lyophilized to give 207 mg of the desired product as HCL salt. (72% yield). LCMS (m/z): 693.2 (MH+), 0.64 min. 1H NMR (<cd3od>) d: 7.87 (s, 1H), 7.81-7.86 (m, 1H), 7.65-7.72 (m, 2H), 7.61 (dd, J=11.7, 1.6 Hz, 1H), 7.46 (ddd, J=8.0, 2.3, 1.4 Hz, 1H), 7.26 (dt, J=9.5, 1.9 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.29-4.49 (m, 1H), 4.18-4.29 (m, 2H), 3.64 (tdd, J=11.6, 8.6, 4.9 Hz, 1H), 2.76-2.92 (m, 1H), 2.27 (ddd, J=8.8, 5.9, 2.5 Hz, 1H), 2.01-2.13 (m, 1H), 1.76-1.94 (m, 2H), 1.58-1.71 (m, 1H), 1.39-1.55 (m, 1H). 31P NMR (<cd3od>) d: 0.16 (br. s., 1P).
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@H:62]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65].Cl.CCN(C(C)C)C(C)C>>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:29]([NH:61][C@H:62]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65])=[O:30])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Temperature: 40 °C
Yield: 91 %

Procedure:
A solution of 1-[6-(2-acetylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (100 mg, 226 μmol) in DMF (7.0 mL, 90 mmol) was added to HATU (85.9 mg, 226 μmol). The resulting mixture was stirred for 5 minutes before (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid.HCl (52.4 mg, 226 μmol) and DIPEA (315 μL, 1.8 mmol) were added. The resulting solution was heated at 40° C. overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (48 mg; 91% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H33N5O7S, 620.21; found 620.4.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ccc([N+](=O)[O-])c(Br)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a solution of N-(6-bromopyridin-2-yl)acetamide (9.0 g, 40 mmol) in H2SO4 (100 mL) was added HNO3 (69%, 5.5 g, 60 mmol) dropwise at 0° C. The mixture was stirred at this temperature for 4 hours, and was then poured into ice-water. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 6-bromo-5-nitropyridin-2-amine (7.5 g, 82%). 1H NMR (400 MHz, DMSO) δ 8.10 (d, J=8.8 Hz, 1H), 7.73 (brs, 2H), 6.46 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask containing a solution of 29 (0.21 g, 0.59 mmol), Et3N (0.18 g, 1.78 mmol) and DMAP (0.034 g, 0.28 mmol) in CH2Cl2 (5 mL) was added ethanesulfonyl chloride (0.19 g, 1.48 mmol), dropwise, at RT and the reaction allowed to stir overnight at RT.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:5][CH:6]=1.[CH2:16]1[O:18][CH2:17]1.O>C1COCC1.[Li+].CC([N-]C(C)C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:5][C:6]=1[CH2:16][CH2:17][OH:18]
Reactant: CCc1ccc(Cc2cc(Br)cs2)cc1
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(Br)c(CCO)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under a nitrogen stream, to 4-bromo-2-((4-ethylphenyl)methyl)thiophene (2.80 g, 10.0 mmol) in anhydrous THF (40 ml), LDA (2.0 M, 5.50 ml, 11.0 ml) was added dropwise at −78° C. over 5 minutes. After the reaction mixture was stirred at 0° C. for 30 minutes, a THF solution of ethylene oxide (10 ml) was added dropwise at −78° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. After addition of water, the reaction mixture was extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:9)) to give the titled compound (2.55 g, 78%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:8][C:9]1[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][C:12]([Cl:15])=[C:11]([C:16]([F:17])([F:18])[F:19])[CH:10]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
6.0 g (20.6 mmol) N-ethoxalyl-4-chloro-3-trifluoromethylaniline was dissolved in 30 ml 100% nitric acid and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was poured into 500 ml ice-water. The crude product was filtered off, washed with water and recrystalized (ethanol) to give 4.95 g (72%) of N-ethoxalyl-4-chloro-6-nitro-3-trifluoromethylaniline. M.p. 96.5°-97.5° C.