Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:36])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][CH2:30][C:31](OCC)=[O:32])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:38]=1.CO[BH-](OC)OC.[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:36])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:38]=1
Reactant: CCOC(=O)CCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Agent: CO[BH-](OC)OC
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCCCO
Yield: 48.6 %

Procedure:
To a solution of 7-chloro-1-{6-[2-(3-ethoxycarbonylpropoxy)benzoyl-amino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g)in ethylene glycol dimethyl ether (70 ml)is added sodium trimethoxyborohydride (3.78 g), and the mixture is refluxed for 3 hours. The reaction solution is gradually poured into diluted hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-1-{6-[2-(4-hydroxybutoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.12 g) as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([CH3:9])=[CH2:8])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])([CH3:9])[CH3:8])[CH3:2]
Reactant: COc1ccc(F)cc1
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
To a mixture of 5.9 g (26.1 mmol) of the above 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in 30 mL of 4-fluoroanisole was added 5.2 g (39.4 mmol) of aluminum chloride in several portions. The mixture became exothermic and turned black with the first addition and was cooled with an ice-water bath. The mixture was stirred for 3 days and was then poured into 200 mL of ice-cold 1 N aqueous HCl and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with 50 mL of 1 N aqueous hydrochloric acid, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with EtOAc-hexanes (1:9, then 2:8, then 3:7, then 4:6) to afford 6.6 g (71%) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2c1cccc(F)c1
Yield: 56.8 %

Procedure:
The title compound was synthesized from methyl 4-(3-fluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.145 g, 0.56 mmol) and lithium hydroxide (120 mg, 2.8 mmol in 1 mL water), according to General Procedure 7. In this example, methanol was used to solubilize the starting material. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound 78 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.17-2.27 (m, 1H) 2.70-2.98 (m, 3H) 4.20 (t, J=7.17 Hz, 1H) 6.54 (s, 1H) 6.85-6.92 (m, 2H) 7.01 (d, J=7.66 Hz, 1H) 7.22-7.31 (m, 1H). LCMS m/e 244 (M−H). 93% pure by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.Br[C:50]1[C:51]2[CH:67]=[CH:66][CH:65]=[CH:64][C:52]=2[S:53][C:54]=1[CH:55]([NH:57][S:58]([C:60]([CH3:63])([CH3:62])[CH3:61])=[O:59])[CH3:56]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:50]2[C:51]3[CH:67]=[CH:66][CH:65]=[CH:64][C:52]=3[S:53][C:54]=2[CH:55]([NH:57][S:58]([C:60]([CH3:62])([CH3:63])[CH3:61])=[O:59])[CH3:56])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(NS(=O)C(C)(C)C)c1sc2ccccc2c1Br
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(NS(=O)C(C)(C)C)c1sc2ccccc2c1-c1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
A mixture of 3,5-difluorophenylboronic acid (292 mg, 1.848 mmol), potassium phosphate (0.204 mL, 2.464 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (126 mg, 0.308 mmol), palladium (II) acetate (27.7 mg, 0.123 mmol) and N-(1-(3-bromobenzo[b]thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (444 mg, 1.232 mmol) in Toluene (10 mL) was purged with N2 for 2 min, then heated to 110° C. overnight. After 19 h, the reaction was partitioned between water and EtOAc. The organic layer was stirred over MgSO4, filtered and concentrated under reduced pressure to give amber oil. The product was purified by column chromatography on a silica gel column using 20 to 40% gradient of EtOAc in hexane as eluent to give N-(1-(3-(3,5-difluorophenyl)benzo[b]thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide as a colorless glassy solid: 1H NMR (400 MHz, DMSO-d6) δ 1.13 (s, 9H), 1.50 (d, J=6.7 Hz, 3H), 4.64-4.73 (m, 1H), 5.91 (d, J=4.7 Hz, 1H), 7.21 (dd, J=8.4, 2.3 Hz, 2H), 7.34-7.45 (m, 4H), 8.02 (ddd, J=7.5, 1.4, 1.1 Hz, 1H); LC-MS (ESI)] m/z 394.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])[NH:7][CH2:6][CH2:5]2>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])[NH:7][CH:6]=[CH:5]2
Reactant: NS(=O)(=O)c1cc2c(cc1F)CCN2
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc2[nH]ccc2cc1F
Yield: 37 %

Procedure:
A mixture of 3 grams of mangenese dioxide and 3 grams of 5-fluoro-2,3-dihydro-1H-indole-6-sulfonic acid amide in 30 ml of dioxane was heated at 50° overnight. The reaction was filtered and the filtrate was evaporated to afford crude product which was purified on silica gel eluting with methylene chloride/ethyl acetate to give 1.1 grams of the titled compound. mp: 181-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][NH:10][CH2:9][C@H:8]2[OH:12])=[CH:4][C:3]=1[F:15].C=O.[BH3-][C:19]#N.[Na+]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][N:10]([CH3:19])[CH2:9][C@H:8]2[OH:12])=[CH:4][C:3]=1[F:15]
Reactant: O[C@@H]1CNC[C@@H]1Oc1ccc(Cl)c(F)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](O)[C@@H](Oc2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 222.3 %

Procedure:
To a solution of 420 (0.35 g, 1.52 mmol) and MeOH (5 mL) was added HCHO (37% in water, 0.42 mL, 15.2 mmol). The mixture was stirred at RT for 2 h and then NaCNBH3 (1.43 g, 22.8 mmol) was added. The reaction was stirred at RT for 3 h. The reaction was quenched with aqueous NH4OH (50 mL) and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (3×50 mL), dried (Na2SO4) and concentrated in vacuo to afford 0.830 g of cis-(±)-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidin-3-ol as a brown oil (422) which used for next step without further purification: LC-MS (ESI) m/z 246 (M+H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[OH:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=[NH:12])[O:9]CC.O1CCCC1>C1(C)C=CC=CC=1>[C:13]1([CH:7]2[O:6][C:1](=[O:2])[NH:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2ccccc2)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 16 hours at room temperature was used following cold perfusion with phosgene, ethyl 1-hydroxy-1-phenylmethanecarboximidate hydrochloride (22 g., 0.102 mole) in 450 ml. of tetrahydrofuran was converted to toluene recrystallized 5-phenyloxazolidine-2,4-dione (10.5 g., m.p. 103°-105° C.).
Reaction SMILES: C(=O)(OC)O[C@@H:3]1[C@H:10]2[C@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C:5]([CH2:13][O:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4]1.[Cu]C#N.[CH:40]([Mg]Br)=[CH2:41]>C1COCC1>[CH3:11][C:8]1([CH3:12])[O:7][C@@H:6]2[C:5]([CH2:13][O:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4][C@@H:3]([CH:40]=[CH2:41])[C@@H:10]2[O:9]1
Reactant: C=C[Mg]Br
Reactant: COC(=O)O[C@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: C=C[C@@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methyl carbonate (1-2) (1.2 g, 2.19 mmol, 1 equiv) was dissolved in anhydrous THF (22 mL) and cooled to 0° C. To the resulting mixture was added copper(I) cyanide (65 mg, 0.72 mmol, 0.33 equiv) followed by 0.7 M vinylmagnesium bromide solution in THF (7.84 mL, 5.49 mmol, 2.5 equiv). After 1 h at 0° C., the reaction was quenched with NH4Cl (10 mL) and extracted with Et2O (3×25 mL). The combined organic extracts were washed with water, dried (MgSO4), and concentrated. Purification via flash chromatography on silica gel column (ethyl acetate/hexanes) gave (3aS,4R,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (1-3). 1H NMR (500 MHz, CDCl3) δ 7.25-7.55 (m, 15H), 5.94 (brd, 1H, J=0.5 Hz), 5.85 (ddd, 1H, J=7.5, 3, 17.5 Hz), 5.18 (dt, 1H, J=1.5, 17.5 Hz), 5.12 (dd, 1H, J=1, 10 Hz), 5.07 (d, 1H, J=5.5 Hz), 4.52 (d, 1H, J=6 Hz), 3.93 (d, 1H, J=14 Hz), 3.76 (d, 1H, J=14 Hz), 3.53 (d, 1H, J=7.5 Hz), 1.43 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([NH2:13])=O)[N:10]=2)[CH:7]=1>O=P(Cl)(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]#[N:13])[N:10]=2)[CH:7]=1
Reactant: Cc1c(C(N)=O)nc2ccc(I)cn12
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C#N)nc2ccc(I)cn12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxamide (600 mg) and POCl3 (40 ml) was heated at reflux for 3 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was poured into ice-cold saturated NaHCO3 solution, and extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (500 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1ccc(F)cc1F
Yield: 78 %

Procedure:
Prepared in 78% yield from 2-chloronicotinonitrile and 2,4-difluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 216.9 (M+H)+; 1H NMR (CDCl3) δ 6.97-7.09 (m, 2H), 7.45 (dd, J=8.0, 4.9 Hz, 1H), 7.57-7.64 (m, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 8.90 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][OH:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:15])([O-:3])=[O:2].NC1C=C([N+]([O-])=[O:24])C(C)=C([N+]([O-])=O)C=1>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:24])=[O:11])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:15])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])cc(NO)cc1[N+](=O)[O-]
Reactant: Cc1c([N+](=O)[O-])cc(N)cc1[N+](=O)[O-]
Product: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
An alternate method of pentanitroaniline synthesis, based on a recent patent (Reference 6), was examined (FIG. 4). 2,4,6-trinitrotoluene (TNT) (10) is dissolved in p-dioxane and H2S gas is bubbled through the solution holding the temperature below 50° C. The sulfur which precipitates is filtered off and the filtrate is poured over ice mixed with water to produce a mixture of the desired intermediate 4-amino-2,6-dinitrotoluene (11) and the partially reduced product 2,6-dinitro-4-hydroxylaminotoluene (12); the ratio of 11:12 usually is 3:2, but varies from 1:2 to 2:1. The crude mixture of 11 and 12 is suspended in hydrochloric acid and treated with potassium iodide. The hydrochloric acid and potassium iodide form hydroiodic acid (HI) which serves as the reducing agent to convert the hydroxylamine 12 into the amine 11. Cooling, filtration, and recrystallization provide the desired 11 in 45% overall yield from TNT. The amine 11 is nitrated using concentrated sulfuric acid/90% nitric acid with heating to 80° C. (Under these nitration conditions, the methyl group on the amine is oxidized, carbon dioxide is liberated, and subsequent nitration occurs at this position on the aromatic ring.) The nitrated mixture is allowed to cool to 60° C. and then extracted with dichloroethane. The extract is dried and concentrated to produce pentanitroaniline (9) in 22% yield (10% overall yield from TNT).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@@H:6]1[C@@H:19]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:18](O)[C@@H:17]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].CCN(S(F)(F)[F:42])CC>ClCCl>[Cl:1][CH2:2][C:3]([O:5][C@@H:6]1[C@@H:19]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:18]([F:42])[C@@H:17]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(=O)CCl)[C@@H](OC(=O)C(C)(C)C)[C@H]1O
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(=O)CCl)[C@@H](OC(=O)C(C)(C)C)[C@@H]1F
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
Compound (19) (300 mg, 0.583 mmol) was dissolved in dichloromethane (5.8 ml), and diethylaminosulfatrifluoride (DAST) was added to the solution with stirring under an argon stream at −15° C. The mixture was returned to room temperature 10 minutes after the addition of DAST and reacted for 1 hour. Disappearance of the material was confirmed by TLC, the DAST was quenched with methanol (3 ml), and the reaction mixture was concentrated in a vacuum. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:6), giving Compound (20) (in an amount of 211 mg, yield 70%).
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B(OC)(OC)OC.CSC.B.CO>C1COCC1>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Agent: B
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1ccc(C=O)c(F)c1I
Reaction time: 0.25 h

Procedure:
To a solution of 2-fluoro-3-iodo-4-methylbenzoic acid (2.00 g, 7.1 mmol) in anhydrous THF (10 mL) was added trimethyl borate (0.80 mL, 7.1 mmol) at RT. The resulting mixture was stirred for 15 min, then cooled in an ice bath and treated with borane-dimethyl sulfide (6.4 mL of 2.0 M solution in THF, 12.8 mmol) slowly. The reaction mixture was stirred for 4 h at RT. Methanol (0.5 mL) was added dropwise at RT. After stirring for 30 min, the reaction mixture was concentrated under vacuum. The residue was diluted with of ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate followed by brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give 2-fluoro-3-iodo-4-methylphenyl)methanol as an off-white amorphous solid, which was used without further purification.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.CC(C)=O.[C:18](=[O:20])=O.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[F:28]>C(OCC)C.C(OCC)(=O)C.CN(C)C=O.C(Cl)(Cl)(Cl)Cl.CC(C)=O>[F:21][C:22]1[C:23]([CH:18]=[O:20])=[N:24][CH:25]=[CH:26][C:27]=1[F:28]
Reactant: O=C=O
Reactant: Fc1ccncc1F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=Cc1nccc(F)c1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Butyllithium (ALDRICH, 1.529 mL, 3.82 mmol) was added dropwise over 10 min at −20° C. (CCl4/acetone) to a solution of N,N,N′,N′-tetramethylethylendiamine (ALDRICH, 0.521 mL, 3.48 mmol) in diethyl ether (anh) (15 mL). Reaction mixture was stirred at −20° C. for 1 h and cooled to −78° C. (acetone/CO2(s)). A solution of 3,4-difluoropyridine (CHEMCOLLECT, 400 mg, 3.48 mmol) in diethyl ether (1 mL) was added dropwise over 15 min at −78° C. Mixture was stirred at −78° C. temperature for 1 hour. N,N-Dimethylformamide (300 μl), previously dissolved in diethyl ether (1 mL), was added dropwise over 10 min at −78° C. Reaction mixture was stirred for 2 hours and was poured carefully onto a rapidly stirring ice/water mixture. Mixture was stirred for 20 min and diluted with ethyl acetate (15 mL). Aqueous layer was further extracted with DCM (4×15 ml). Organic layers were combined, dried over MgSO4(anh) and concentrated. Residue was purified by silica chromatography using Hexane-AcOEt (1:3) as eluents to yield the title compound (148 mg, 1.034 mmol, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.02-10.03 (m, 1H), 8.63-8.66 (m, 1H), 7.87-7.93 (m, 1H). [ES+MS] m/z 144 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:19])[C:14]([O:16]CC)=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[OH-].[Li+].Cl.[CH2:23]1COC[CH2:24]1>O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:14]([CH2:23][CH3:24])=[O:16])[CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC(=O)C(C)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of ethyl 2-[3-fluoro-4-(metylsulfonylamino)phenyl]propionate (1-26, 2 mmol) in H2O and THF (1:2, 30 mL) was treated with lithium hydroxide (6 mmol) and stirred for 4 h at room temperature. The mixture was diluted with H2O and CH2Cl2, acidified by 1 N HCl solution and extracted with CH2Cl2 several times. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized by diethyl ether and n-hexane to afford 2-[3-fluoro-4-(metylsulfonylamino)phenyl]propion acid compound (1-38, SU-660)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:21])=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)Nc3ccc(Cl)cn3)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C2CCNC2)cc1)Nc1ccc(Cl)cn1
Temperature: 60 °C
Yield: 187.7 %

Procedure:
To a stirred solution of (RS)-3-{4-[3-(5-chloro-pyridin-2-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg) in THF (4 ml) was added dropwise a solution of hydrogen chloride in dioxane (1.89 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to 0° C. and the ensuing crystals were collected by filtration, washing with ethyl acetate, and were dried in vacuo at 60° C. to afford (RS)-1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)-urea hydrochloride (167 mg, 94%) as a beige crystalline solid. MS (ISP): 319.1 ([{37Cl}M+H]+), 317.2 ([{35Cl}M+H]+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[N+:15]([O-:9])[CH:16]=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cncc(Br)c1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 33.1 %

Procedure:
A solution of mCPBA (70%, 4.46 g, 18.11 mmol) in DCM (100 ml) was added to a solution of methyl 5-bromonicotinate (3.11 g, 15.09 mmol) in DCM (100 ml). After stirring at room temperature for several hours, additional mCPBA (6.6 g, 26.77 mmol) was added (in portions) to drive the reaction to completion. After 4 days, the reaction mixture was sequentially washed with a saturated solution of sodium bicarbonate followed by water. The organic phase was dried over MgSO4, and concentrated to dryness. The crude material was purified by chromatography on silica gel using 50% EtOAc/hexanes to 100% EtOAc to give 1.16 g of the title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:18])=[O:11])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(-c2ccncc2)c1
Product: O=C(Cl)c1cccc(-c2ccncc2)c1

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-4-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g of crude 3-(pyridin-4-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 g, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added crude 3-(pyridin-4-yl)benzoyl chloride (1.5 g, 7 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-4-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH2:13][CH2:14][C:15]2[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[N:10][CH:11]=1)(=[O:4])=[O:3].[OH-].[Na+]>>[CH3:27][C:20]([O:19][C:18]1[CH:28]=[CH:29][C:15]([CH2:14][CH2:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][N:10]=2)[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=2)=[CH:16][CH:17]=1)([CH3:26])[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(NS(C)(=O)=O)cn2)cc1)C(=O)O
Yield: 64.2 %

Procedure:
Ethyl 2-[4-(2-{{5-[bis(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (39 mg) was reacted with NaOH (17 eq) as per general procedure H. Purification by radial chromatography (1–10% methanol-dichloromethane gradient), followed by crystallization from dichloromethane-hexane afforded the title compound as a white solid (21 mg; 66% yield).