Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:5]([OH:15])[C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:1]1([CH:5]([OH:15])[C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(C(O)C2CCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C(O)C2CCC2)cc1
Reaction time: 1.5 h
Yield: 104.3 %

Procedure:
N,N-dimethylformamide (9.00 mL) was added to a vial containing 4-(cyclobutyl(hydroxy)methyl)benzoic acid (370 mg, 1.79 mmol), ethyl 3-aminopropanoate hydrochloride (551 mg, 3.59 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.36 g, 3.59 mmol). Diisopropylethylamine (1.56 mL, 8.97 mmol) was then added. The reaction was stirred for 1.5 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(cyclobutyl(hydroxy)methyl)benzamido)propanoate (570 mg, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 4.63 (d, J=7.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.72 (q, J=6.0 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.61-2.54 (m, 1H), 2.08-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.27 (t, J=7.1 Hz, 3H). MS (M+1): 306.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[OH:11][CH2:12][C:13]([CH2:15]O)=O.[Cl-].[NH4+]>[OH-].[NH4+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:15]=[C:13]([CH2:12][OH:11])[N:10]=1
Reactant: N=C(N)c1ccccc1Cl
Reactant: O=C(CO)CO
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Product: OCc1c[nH]c(-c2ccccc2Cl)n1
Temperature: 25 °C

Procedure:
According to literature reference (Huang, Y.; Luedtke, R. R.; Freeman, R. A.; Wu, L.; Mach, R. H. Bioorg. Med. Chem. 2001, 9, 3113–3122), to a mixture of 2-chlorobenzenecarboximidamide (5.4 g, 34.8 mmol), 1,3-dihydroxyacetone dimmer (6.2 g, 34.8 mmol) and ammonium chloride (7.5 g, 139 mmol) is added concentrated ammonium hydroxide (40 mL). The reaction mixture is then heated to reflux for 30 minutes after which time it is cooled to room temperature and poured into a ice/water mixture. This aqueous suspension is extracted with CH2Cl2 and the combined organic extracts are dried over sodium sulfate and concentrated to provide a crude solid. The crude product is recrystallized from ethyl acetate to afford 3.9 g of [2-(2-chlorophenyl)-1H-imidazol-4-yl]methanol.
Reaction SMILES: C([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[C@H:10]([OH:15])[CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:18]>C(O)C.[Pd]>[ClH:18].[CH3:13][C:11]1([CH3:14])[CH2:12][NH:8][CH2:9][C@H:10]1[OH:15]
Reactant: [H][H]
Reactant: CC1(C)CN(Cc2ccccc2)C[C@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CNC[C@H]1O
Yield: 99 %

Procedure:
To a solution of 6.34 g (41.7 mmol) of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol in 250 mL of ethanol and 50 mL of 1N hydrochloric acid was added 300 mg of 10% palladium on carbon. The reaction mixture was stirred under 40 psi of hydrogen gas for 18 h. To the reaction mixture was added 300 mg of 10% palladium on carbon and 2 mL of concentrated hydrochloric acid. The reaction mixture was stirred under 40 psi of hydrogen gas for 72 h. The catalyst was filtered off over celite, and the filtrate was concentrated. Several portions of toluene were distilled from the residue, which was then dried under high vacuum to afford 4.74 g (>99%) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride. 1H-NMR (300 MHz, DMSO-d6): δ 9.46 (d, J=40 Hz, 2H), 5.43 (br s, 1H), 3.75 (m, 1H), 3.36 (m, 1H), 2.88 (m, 3H), 0.96 (d, J=10 Hz, 6H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[C:17]([Cl:23])=[C:16]([NH:24][C:25]3[NH:29][N:28]=[C:27]([CH:30]4[CH2:32][CH2:31]4)[CH:26]=3)[N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:23][C:17]1[C:18]([CH:20]2[CH2:22][CH2:21]2)=[N:19][C:14]([C:11]2[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=2)=[N:15][C:16]=1[NH:24][C:25]1[NH:29][N:28]=[C:27]([CH:30]2[CH2:32][CH2:31]2)[CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)c(Cl)c(C3CC3)n2)s1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)c(Cl)c(C3CC3)n2)s1
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
The solution of N-tert-butyl-5-(5-chloro-4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (60 mg, 0.12 mmol) in trifluoroacetic acid (5 mL) was stirred at 60° C. After 0.5 h, the solution was evaporated to give the crude product, which was recrystallized from ether to afford 5-(5-chloro-4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2 sulfonamide (Compound 304) (25 mg, 48%). LC-MS (m/z)=436.9 [M+H]+; δ (400 MHz, DMSO-d6); 0.73-0.77 (m, 2H), 0.96-0.99 (m, 2H), 1.12-1.14 (m, 4H), 1.91 (m, 1H), 2.43-2.47 (m, 1H), 6.39 (s, 1H), 7.48 (s, 2H), 7.96 (d, J=1.6 Hz, 1H), 8.18 (d, J=1.2 Hz, 1H), 9.18 (s, 1H)
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][NH:4]1.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:26])[O:24][CH3:25].[NH4+].[Cl-]>ClCCl>[F:13][CH:2]([F:1])[CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][N:4]1[C:23]([O:24][CH3:25])=[O:26]
Reactant: COC(=O)C1CCNC(C(F)F)C1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(C(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
Methyl 2-(difluoromethyl)piperidine-4-carboxylate (1.85 g, 9.58 mmol) was dissolved in dichloromethane (50 mL), DIPEA (2.335 mL, 13.41 mmol) and methyl carbonochloridate (0.905 mL, 11.49 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M NH4Cl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Crude dimethyl 2-(difluoromethyl)piperidine-1,4-dicarboxylate (2.35 g, 98%) was isolated.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1Cl)(=[O:3])[CH3:2].[BH4-].[Na+].[OH:12]C(C1OC=CC=1Cl)C.BrBr>CO.O>[CH3:8][C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:12])[C:1]=1[OH:3]
Reactant: CC(O)c1occc1Cl
Reactant: CC(=O)c1occc1Cl
Agent: BrBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Acetyl-3-chloro-furan (1.0 g, 7 mmoles) in 30 ml methanol was cooled to 10° C. and 0.065 g, (1.7 mmoles) of NaBH4 added in one portion. After stirring for 30 minutes at 25° C., the solution was treated with 15 ml of water and cooled to 5° C. To the formed 2-(1-hydroxyethyl)-3-chloro-furan was then added 1.1 g (7 mmoles) of bromine, dropwise and with cooling. After the addition was complete the reaction was heated to 95° C. for 2 hours, distilling off a portion of the methanol. The reaction was then cooled and maltol isolated by the method of Example 1.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].[CH2:28]1COCC1>>[CH2:1]([CH:3]([O:6][C:7]1[C:16]2[N:15]([CH3:28])[C:14](=[O:17])[CH2:13][N:12]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[N:10]=[C:9]([CH3:27])[CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCC(CC)Oc1cc(C)nc2c1NC(=O)CN2c1c(C)cc(C)cc1C
Product: CCC(CC)Oc1cc(C)nc2c1N(C)C(=O)CN2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 8-(1-ethyl-propoxy)-6-methyl-4-(2,4,6-trimethyl-phenyl)-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg, 0.136 mmol) in 3 ml of dry THF was added 1.0M of LiN[Si(CH3)3]2 in THF (0.14 ml, 0.14 mmol) at −78° C. After stirring at that temperature for 20 min, the reaction mixture was warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and saturated ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated to give 51 mg of a golden oil. The oil was purified through silica gel column chromatography using 10% ethyl acetate in hexane as eluent to give 41 mg (79%) of the title compound as a golden oil. 1H NMR (CDCl3) δ 6.9(s,2H), 6.17(s,1H), 4.30(m,1H), 4.01(s,2H), 3.47(s,3H), 2.30(s,3H), 2.20(s,3H), 2.01(s,6H), 1.70(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[C:26]([F:27])=[C:25]([N+:28]([O-:30])=[O:29])[CH:24]=[CH:23][C:22]=1[F:31]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:26]1[C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=[C:22]([F:31])[C:21]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Temperature: 150 °C
Yield: 33.9 %

Procedure:
2-Tributylstannanylpyridine (4.24 g, 12 mmol), 2-bromo-1,3-difluoro-4-nitrobenzene (2.5 g, 10 mmol) and Pd(PPh3)4 (605 mg, 0.5 mmol) in dioxane (20 mL) were placed in a microwave vial. The sealed vial was evacuated and purged with argon (×3). The resulting mixture was heated, under microwave irradiation, at 150° C. for 1.5 h. The cooled mixture was evaporated, and the residue was suspended in DCM and the resulting mixture filtered to remove insoluble material. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a bright orange solid (0.8 g, 33%). 1H NMR (CDCl3, 400 MHz): δ 8.79 (1H, ddd, J=6.5, 2.4, 1.3 Hz), 8.18 (1H, ddd, J=12.4, 10.8, 7.4 Hz), 7.86 (1H, td, J=10.4, 2.4 Hz), 7.51 (1H, dquin, J=10.5, 1.6 Hz), 7.41 (1H, ddd, J=10.2, 6.5, 1.5 Hz), 7.16 (1H, ddd, J=13.3, 10.8, 2.5 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1CCNC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCCC4)c3)ccc2C)cc1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with pyrrolidine. There was thus obtained the title compound in 81% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 1.95-2.0 (m, 4H), 2.2 (s, 3H), 2.4-2.5 (m, 4H), 3.3 (m, 4H). 3.6 (s, 2H), 6.4-6.5 (m, 1H), 6.85-6.95 (m, 2H), 7.2 (d, 2H), 7.45 (d, 2H), 7.58 (m, 1H), 7.8 (m, 1H), 7.95 (d, 2H), 9.8 (s, 1H), 10.1 (broad s, 1H); Mass Spectrum: M+H+ 503.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:21]([CH2:20][CH3:19])=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C=C(CC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl 3-oxo-n-valerate and finely powdered Amberlyst®-15 (an organic polymeric resin featuring free sulphone groups) as catalyst there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-ethylvinyl]ureido}-benzoate, m.p. 123°-126° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[BH4-].[Na+].C[O-].[Na+].O>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[F:12]
Reactant: O=C(CCl)c1ccc(Br)c(F)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1cc(C2CO2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-chloro-1-(4-bromo-3-fluoro-phenyl)-ethanone (6.16 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (788 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (562 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-fluoro-phenyl)-oxirane (4.69 g) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][NH2:30]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCCc1ccccn1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCCc1ccccn1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-(2-pyridyl)propan-1-amine (20.0 mg, 0.12 mmol). The title compound was obtained as a solid (14.5 mg, 26% yield). MS m/z: 469.01, 471.01 [M+H]+.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:26])([F:25])[F:24])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccccc2)cc1
Yield: 60.4 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-4,5-dihydro-1H-imidazole (step 2) (5.43 g, 14.1 mmol) and p-toluenesulfonic acid monohydrate (1.63 g) in toluene (500 mL) was heated to reflux for 96 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate (65/35) to give pure 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole (3.12 g, 60%) as a white solid: mp (DSC) 233° C. Anal. Calc'd for C17H13N2F3SO2: C, 55.73; H, 3.58; N, 7.65; S, 8.75. Found: C, 55.49; H, 3.47; N,7.46; S, 8.95.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24]>ClCCl>[CH:1]1([CH2:4][C:5]([N:22]([O:23][CH3:24])[CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: CNOC
Reactant: O=C(O)CC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-cyclopropylacetic acid (C62) (30 g, 300 mmol) in dichloromethane (800 mL) was added 1,1′-carbonyldiimidazole (54 g, 333 mmol) portion-wise, not allowing the temperature to exceed 25° C. The mixture was stirred at room temperature for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (30 g, 308 mmol) was added in one portion and stirred at room temperature for 18 hours. The mixture was washed with water (2×200 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate and concentrated to give crude product as a yellow oil, which was directly used in the next step. Yield: 48 g, 336 mmol, 112%. 1H NMR (400 MHz, CDCl3) δ 3.62 (s, 3H), 3.12 (s, 3H), 2.30 (d, J=7.2 Hz, 2H), 1.03-1.06 (m, 1H), 0.48-0.52 (m, 2H), 0.11-0.13 (m, 2H).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]([F:37])([F:39])[F:38])=[C:29]([CH:33]=1)[C:30]([NH:2][CH2:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][CH:5]=1)=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCc1cccc(=O)[nH]1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NCc1cccc(=O)[nH]1)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of the crude product from Example 3, 20 ml of acetone and 4.7 g of sodium carbonate was added dropwise 2.8 g (8.21 mmole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 10 ml of acetone. The mixture was stirred at about 20° C. for about 16 hours. To the mixture was added 50 ml of acetone, and the resulting inorganic residue was separated by filtration and washed with acetone. The filtrate and washings were combined and evaporated. This residue was dissolved in benzene, and the solution was washed sequentially with 10% aqueous sodium carbonate solution, 2% acetic acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulfate, and then filtered and evaporated. The residue was boiled in carbon tetrachloride, and the mixture was cooled and the solid was separated by filtration. The solid was purified by chromatography on 30 g of silica gel. The column was eluted sequentially with 5% ethyl acetate in dichloromethane and 2% methanol in dichloromethane. The product was obtained as a white solid, 6-[5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>C(Cl)Cl.CO>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:5]4[O:4][C:3]([N:2]([CH3:1])[CH2:13][CH:14]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]5)=[N:7][C:6]=4[CH:8]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(C5CCCCC5)cc4)ccc3o2)C1
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.150 g, 0.576 mmol), 4-cyclohexyl-benzoic acid (0.177 g, 0.864 mmol), HATU (0.219 g, 0.576 mmol), polystyrene-bound diisopropylamine (1.44 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (20 mL). Shake the mixture overnight at room temperature. Add HATU (0.219 g, 0.576 mmol) and shake for 21 h at room temperature. Dilute with 1:1 CH2Cl2/MeOH, wash with 10M NaOH (equal volume), dry over Na2SO4, filter, and concentrate in vacuo. Subject the mixture to silica gel flash column chromatography (2×12 g columns, 5% 2M NH3 in MeOH/CH2Cl2, then ramping to 10% after 10 min) to yield the desired product as a colorless oil (0.103 g, 40%). Subject the product to chiral preparative chromatography [Chiralpak AD-H column, (8×32 cm), eluting with 70/30 3 Å ethanol/ACN w/0.2% dimethylethylamine; Flow rate=350 mL/min] to yield isomer 1 (0.039 g). mass spectrum (m/e): 447.3 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.80-7.76 (m, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.6, 1.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 3.61-3.46 (m, 2H), 3.19 (s, 3H), 2.77-2.51 (m, 6H), 2.42-2.37 (m, 1H), 2.37 (s, 3H), 2.07-1.97 (m, 1H), 1.91-1.80 (m, 4H), 1.76 (d, J=12.8 Hz, 1H), 1.61-1.52 (m, 1H), 1.48-1.22 (m, 4H).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[N:11][CH:10]([Cl:13])[N:9](Cl)[CH:8]=1.[H-].[Na+].[Cl-].[Na+].O.O>CN(C)C=O>[Br:6][C:7]1[C:8]([O:5][CH2:4][CH:2]2[CH2:1][O:3]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: ClC1N=CC(Br)=CN1Cl
Reactant: OCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(Br)c(OCC2CO2)n1
Yield: 96.2 %

Procedure:
A solution of glycidol (13.0 g, 0.175 mole) and 5-bromo-2,3-dichloropyrimidine (40.0 g, 0.175 mole) in dimethylformamide (350 mL) was added dropwise to a stirring nitrogen-flushed, chilled suspension of sodium hydride (from 10.1 g, 0.21 mole, of NaH washed free of mineral oil) in dimethylformamide (350 mL). Following the addition, the reaction mixture was poured into 1:1 brine-water (4.5 l) and extracted with ethyl acetate (5×750 mL). Combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo to give 44.7 g of an oil which solidified. Trituration of the crude product in isopropyl alcohol-isopropyl ether gave 21.9 g (47%) of product, m.p. 63°-73°.
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:19][OH:20])[C:13]=2[CH:12]=[CH:11]1.C1C(=O)N([Cl:29])C(=O)C1>CN(C=O)C>[CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH:19][OH:20])[C:13]=2[C:12]([Cl:29])=[CH:11]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(NO)ncnc21
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(Cl)c2c(NO)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Nucleoside 117 (0.1 mmol) is dissolved in DMF (0.5 mL) and cooled to 0° C. NCS (0.1 mmol) dissolved in DMF (0.5 mL) is then added dropwise and the reaction stirred for 30 minutes at 0° C. and 30 minutes at room temperature. The reaction is quenched with methanol (5 mL) and then concentrated. Column chromatography (SiO2) with MeOH/DCM affords 123.