Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.C[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCOCC1>[O:19]1[CH2:20][CH2:21][N:16]([C:2]2[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=2)[CH2:17][CH2:18]1
Reactant: CN1CCOCC1
Reactant: CCCc1nc(Cl)nc(NCCO)n1
Solvent: C1COCCO1
Product: CCCc1nc(NCCO)nc(N2CCOCC2)n1
Yield: 69.1 %

Procedure:
10.83 g (0.05 mole) of 2-[(4-chloro-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol and 15.15 g (0.15 mole) of N-methylmorpholine are mixed in 100 ml of dioxane. The mixture is heated under reflux for 20 hours; it is then cooled and the dioxane is removed under reduced pressure. The residue is dissolved in 200 ml of ethyl acetate. The solution is washed twice with 50 ml of water, dried over sodium sulfate and concentrated. The product crystallizes during the evaporation. 9.23 g of 2-[(4-morpholino-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol identical to the product obtained above are obtained.
Reaction SMILES: [CH3:1][S-:2].[Na+].O1CCCC1.[CH:9]([O:12][N:13]=[C:14]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)[C:15](=[N:21][O:22][CH:23]([CH3:25])[CH3:24])N1C=NC=N1)([CH3:11])[CH3:10]>O>[CH3:1][S:2][C:15](=[N:21][O:22][CH:23]([CH3:25])[CH3:24])[C:14]([N:26]1[CH:30]=[N:29][CH:28]=[N:27]1)=[N:13][O:12][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)ON=C(C(=NOC(C)C)n1cncn1)n1cncn1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(=NOC(C)C)C(=NOC(C)C)n1cncn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
Sodium thiomethoxide was added to 5 ml of a tetrahydrofuran solution (which was under heating and refluxing) containing 0.35 g (1.14 mmol) of the 1,2-diisopropoxyimino-1,2-bis(1H-1,2,4-triazol-1-yl)ethane produced in Example 6, with confirming a reaction by thin-layer chromatography. Then, stirring was conducted for 5 hours. The reaction mixture was cooled to room temperature and poured into water, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.17 g (yield: 52%) of a title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2cc(N)ncn2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
After suspending 6-(4-nitrophenoxy)pyrimidin-4-ylamine (306 mg, 1.32 mmol), iron powder (369 mg, 6.60 mmol) and ammonium chloride (706 mg, 13.2 mmol) in an ethanol (20 ml)—water (5 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was concentrated to obtain the title compound (266 mg, 1.32 mmol, 100%) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:21][S:22]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:24])=[O:23].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][S:22]([CH3:21])(=[O:23])=[O:24])[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 68.5 %

Procedure:
5-fluoro-4-methyl-2-nitrophenyl methyl ether (Example 113, step B) (5.0 g, 27 mmol), K2CO3 (11.2 g, 81 mmol), and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (8.0 g, 35 mmol) were weighed into a 150 mL sealed tube, taken up in 85 mL of DMSO and heated to 100° C. for 24 h. The mixture was poured into 500 mL of H2O, filtered, washed with H2O, air dried for 15 min, washed with hexanes (200 mL), washed with 20% Ether/Hexanes (200 mL), and air dried for 2 h to give the title compound of step C (6.6 g, 18.5 mmol, 68%). An additional (540 mg, 5.5%) of product was obtained by extraction of the H2O layer, followed by flash chromatography. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1H), 6.70 (s, 1H), 3.90 (s, 3H), 3.31-3.35 (m, 2H), 3.04 (s, 3H), 2.99-3.03 (m, 4H), 2.77 (t, J=6.60 Hz, 2H), 2.56-2.63 (m, 4H), 2.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][NH2:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (1.00 g, 5.38 mmol) in CH2Cl2 (20 mL) was added methylamine (4.04 mL, 2M/THF, 8.08 mmol) then to the stirred solution was added sodium triacetoxyborohydride (1.37 g, 6.46 mmol). After stirring at rt for 18 h, the mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The layers were separated then the aqueous extracted with CH2Cl2 (2×30 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification via flash column chromatography (5% MeOH/CH2Cl2) afforded the desired compound: δH (CDCl3): 2.49 (3H, s), 3.86 (2H, s), 7.31 (1H, d), 7.38 (1H, d), 7.53 (1H, t).
Reaction SMILES: ClCCl.[NH:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[C:23](=[O:47])[N:24]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH:40]5[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]5)=[CH:35][N:34]=4)[C:25]([CH3:32])=[N:26][C:27]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=2)=[N:7][N:6]=[N:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[NH:7]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[C:23](=[O:47])[N:24]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH:40]5[CH2:41][CH2:42][C:43](=[O:46])[CH2:44][CH2:45]5)=[CH:35][N:34]=4)[C:25]([CH3:32])=[N:26][C:27]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=2)=[N:4][N:5]=[N:6]1
Reactant: CCCCc1nc(C)n(-c2ncc(OC3CCC(O)CC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ncc(OC3CCC(=O)CC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the dichloromethane (0.5 mL) solution of 5-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-6-butyl-3-[5-(4-hydroxycyclohexyloxy)pyrimidin-2-yl]-2-methylpyrimidin-4 (3H)-one (10 mg, 0.017 mmol), Dess-Martin reagent (11 mg, 0.026 mmol) was added and stirred at room temperature for 1 hr. Dess-Martin reagent (11 mg, 0.026 mmol) was added, and further stirred at room temperature overnight. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform:methanol=5:1) to obtain the target compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[F:22][C:23]1[CH:24]=[C:25]([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Fc1cccc(C(Br)c2cccc(F)c2)c1
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3cccc(F)c3)c3cccc(F)c3)nc1-2
Yield: 47 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphto[1,2-d]thiazol-6-yl)oxy]acetate and bis(3-fluorophenyl)methylbromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].C(O)C.C[O-].[Na+].Br[CH2:17][C:18]([OH:20])=[O:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Sc1c(Cl)cccc1Cl
Reactant: O=C(O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C(O)CSc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-dichlorothiophenol, 50.0 gm, was added to 250 ml of ethanol. 63.8 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 3 hours. Afterwards, 20 ml of bromoacetic acid was added and the system was then heated to reflux. The system was continued at reflux for 16 hours. The reaction was then stopped and the solvent removed by stripping. The resulting material was dissolved with a basic aqueous solution and then washed with methylene chloride. Concentrated HCl was next added to the aqueous solution to acidify it. The product was extracted with methylene chloride. The methylene chloride solution was stripped and then triturated with hexane. The product was then filtered, washed with water and air dried to yield 55.3 gm of the 2,6-dichlorothiophenoxyacetic acid.
Reaction SMILES: S(O[CH2:9][C:10]([CH3:23])([N+:20]([O-:22])=[O:21])[CH2:11]OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(N(C(C)C)C(C)C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[CH3:23][C:10]1([N+:20]([O-:22])=[O:21])[CH2:9][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11]1
Reactant: NCc1ccccc1
Reactant: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1([N+](=O)[O-])CN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2-methyl-2-nitro-1,3-propanediol ditriflate [the product of step 1] (4.0 g, 10 mmol) in acetonitrile (70 ml) is cooled to 0° C.-5° C. and N-ethyl-diisopropylamine (3.23 g, 25 mmol) is added, followed by benzylamine (1.60 g, 15 mmol) and the mixture is stirred at a temperature of 80° C. for 12 hours. The cooled reaction mixture concentrated under reduced pressure, dissolved in ethyl acetate and transferred to a separating funnel. This is then washed with water (2×) and brine, dried (Na2SO4), filtered, and concentrated. The crude liquid product is used in the next step without further purification. The crude product is purified by chromatography using a 3:1 mixture of Hexane: Ethyl acetate as eluant; the product is obtained as an oil. 1H-NMR (CDCl3): 7.3 (m, 5H), 3.75 (d, 2H), 3.68 (s, 2H), 3.42 (d, 2H), 1.88 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1/[CH:31]=[CH:32]/[CH:33]=O.C([BH3-])#N.[Na+]>ClCCl.CO>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1/[CH:31]=[CH:32]/[CH2:33][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=C/C=C/c1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 30.9 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1.5 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (202 mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were reacted as described under Example 21. Chromatography on silica gel with dichloromethane/methanol gave 168 mg (25%) product
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][O:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: Clc1ncnc2ccccc12
Reactant: COC(=O)CCCc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(CCOc2ncnc3ccccc23)cc1
Reaction time: 3.5 h
Yield: 42.6 %

Procedure:
A dry 50 mL flask was fitted with an addition funnel. To the flask were added 4-chloroquinazoline (592 mg, 3.6 mmol), anhydrous tetrahydrofuran (10 mL), and 60 wt % sodium hydride (187 mg, 4.7 mmol). A solution of Example 1B (800 mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise using the addition funnel. The reaction was stirred for 3.5 hours. The reaction was diluted with ethyl acetate and quenched by the addition of aqueous 0.1 N hydrochloric acid. The mixture was transferred to a separatory funnel and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Column chromatography [silica gel; eluent hexanes-ethyl acetate (4:1)] provided the desired product (538 mg, 43%). 1H(CDCl3) δ(ppm): 1.92-1.98 (m, 2H); 2.33 (t, 2H); 2.64 (t, 2H); 3.19 (t, 2H); 3.66 (s, 3H); 4.79 (t, 2H); 7.15 (d, 2H); 7.27 (d, 2H); 7.57 (t, 1H); 7.83 (t, 1H); 7.94 (d, 1H); 8.15 (d, 1H); 8.80 (s, 1H). 26.68, 33.59, 34.93, 35.03, 51.67, 67.89, 116.48, 123.72, 127.23, 127.82, 128.87, 129.24, 133.74, 135.76, 139.90, 151.08, 154.56, 166.89, 174.10.
Reaction SMILES: FC1C=C(F)C(F)=CC=1C(O)=O.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17](O)=[O:18].S(Cl)([Cl:28])=O>>[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:17]([Cl:28])=[O:18]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1cc(F)c(F)cc1F
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F

Procedure:
The chlorination of 2,4,5-trifluorobenzoic acid in chlorosulphonic acid leads to 3-chloro-2,4,5-trifluorobenzoic acid which is reacted, as the crude product, with thionyl chloride to give 3-chloro-2,4,5-trifluorobenzoyl chloride (boiling point: 94°/18 mbar; nD20 =1.5164): ##STR13##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:32][C:27]=4[S:26][C:25]=3[CH:54]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C1C=C(Cl)C=C(C(OO)=[O:64])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:55])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:32][C:27]=4[S:26](=[O:64])[C:25]=3[CH:54]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)sc2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)S(=O)c2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc2-3)[nH]1)C(C)C
Temperature: -40 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
(1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.0041 mmol., 4 mg) was dissolved in 1 mL DCM and cooled to −40° C. mCPBA (0.4 mg, 0.9 eq.) was added. The reaction mixture was stirred at −40° C. for 2 hours and warmed up to 0° C. over 2 hours, then warmed up to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give a yellow powder (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5-oxo-5H-5λ4-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DD) (0.6 mg).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[CH:20]=[CH:19][C:17]([NH2:18])=[N:16][C:14]1=[O:15])[CH2:2][CH3:3].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[OH-]>O.N1C=CC=CC=1>[C:26]([NH:18][C:17]1[CH:19]=[CH:20][N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]2[O:4][CH2:1][CH2:2][CH3:3])[C:14](=[O:15])[N:16]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.5 h

Procedure:
To the 2'-O-propylcytidine reaction mixture of Example 82 in an ice bath was added pyridine (60 ml) and trimethylsilyl chloride (60 ml). The reaction was stirred for 30 mins followed by the addition of benzoyl chloride (55 ml). The resulting reaction mixture was stirred for 2.5 hrs and then cooled in an ice bath. H2O (100 ml) and conc. NH4OH (100 ml) were added. After stirring for 30 mins, the reaction mixture was evaporated and the residue partition between H2O and CH2Cl2. The organic phase was washed once with dil Na2CO3, once with dil HCl, dried over MgSO4 and evaporated. The resulting residue was loaded on a silica gel column (150 g) and eluted with first CH2Cl2 then 5 to 10% MeOH in CH2Cl2 as the elution solvent. The product containing fractions were evaporated to a foam. The foam was crystallized from EtOAc/Hexanes to give the product (6.5 g total) in several crystal batches.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:22][C:10]([F:9])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:18])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COC(C)(C)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(C)(C)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (2.8 g, 24 mmol) and TEA (1.6 g, 16 mmol) in CH2Cl2 (15 mL) was added o-(trifluoromethyl)benzenesulfonyl chloride (1.9 g, 8 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at rt for 4 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (2.1 g, 81%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.91 (m, 1H), 7.74 (m, 2H), 4.25 (t, 2H, J=7.5 Hz), 3.10 (s, 1H), 1.92 (t, 2H, J=7.5 Hz) 1.13 (s, 6H). Anal. Calcd. For C13H17F3O4S: C, 47.85; H, 5.25. Found: C, 47.95; H, 5.11.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[NH:48]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[N:49]1>>[NH:48]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])=[N:49]1
Reactant: NCc1cc[nH]n1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc[nH]n1
Yield: 72 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-pyrazol-3-yl)methanamine, the title compound was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.46 (t, J=5.0 Hz, 1H), 6.28 (s, 1 H), 6.09 (s, 1H), 5.70 (br s, 1H), 4.60 (d, J=5.0 Hz, 2H), 4.43 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 436.2 (M+23).
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:13])[CH2:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[NH:12][C:10](=[O:11])[CH2:9][C@@H:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](CC(N)=O)Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccccc1
Temperature: -10 °C
Yield: 82 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (S)-3-phenylamino-butyramide (3.25 g, 0.018 mmol) in THF (65 mL) and the mixture was cooled to −10° C. Benzyl chloroformate (3.12 mL, 0.022 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (18 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction (starting material gone by TLC) was quenched by adding EtOAc (65 mL) and 1.0 M hydrochloric acid (10 mL). The aqueous phase was then basified with 1N NaOH. The aqueous phase was extracted 3× EtOAc. The organics were collected together and with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated. Flash chromatography using a Biotage system (10% EtOAc/90% hexane to 20% EtOAc/80% Hexane) afforded the title compound in 82% yield.