Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:41][S:42]([O:38][C@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in pyridine (0.12 M) was added MsCl (7.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 45% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.60 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([O:14][C:15]([NH:17][C:18](=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>N1CCCCC1.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][CH:18]([CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:16])([CH3:12])([CH3:13])[CH3:11]
Reactant: COc1cccc(S)c1
Reactant: COC(=O)C(=Cc1cccc(OC)c1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)C(NC(=O)OC(C)(C)C)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Temperature: 60 °C

Procedure:
A solution of 0.091 g (0.65 mmol) of 3-methoxy-benzenethiol in 4 drops of piperidine is stirred at room temperature for 5 minutes. A quantity of 0.200 g (0.65 mmol) of 2-tert-butoxycarbonylamino-3-(3-methoxyphenyl)acrylic acid, methyl ester of Example 30 is added and the solution is heated at 60° C. for 24 hours. Ethyl acetate (120 mL) is added and the solution is washed with 3×80 mL of 1N sodium hydroxide and brine (80 mL). After drying (magnesium sulfate), the solution is evaporated and the residue is purified by silica gel chromatography, eluting with 20% ethyl acetate-hexane to give the product as an inseparable mixture of diastereomers; wt 0.26 g (89%);
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:20])[CH:3]=1.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH2:27]1)=[O:25])[CH3:22].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.O1CCOCC1>[F:11][C:8]1[CH:9]=[C:10]2[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:27][C:28]3=[O:32])=[CH:3][N:4]([CH3:20])[C:5]2=[N:6][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cn1cc(Br)c2cc(F)c(OCc3ccccn3)nc21
Reactant: CCOC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(c2cn(C)c3nc(OCc4ccccn4)c(F)cc23)C(=O)C1
Reaction time: 5 h
Yield: 20.9 %

Procedure:
3-Bromo-5-fluoro-1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.233 g, 0.693 mmol), 3-oxo-piperazine-1-carboxylic acid ethyl ester (0.131 g, 0.762 mmol), N,N′-dimethylethane-1,2-diamine (0.031 mL, 0.284 mmol), copper(I) iodide (0.029 g, 0.152 mmol), potassium phosphate (tribasic, n-hydrate) (0.162 g, 0.762 mmol), and 1,4-dioxane (15 mL) are added together under a nitrogen atmosphere, and heated to reflux overnight with stirring. Further copper (I) iodide (0.120 g, 0.630 mmol) and N,N′-dimethylethane-1,2-diamine (0.120 mL, 1.099 mmol) are then added and the reaction kept at 105° C. for a further 5 h. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 3×30 mL). The combined organic extracts are diluted with MeOH, and poured on to a SCX2 ion-exchange column. This is flushed with one column volume of MeOH, and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is then concentrated in vacuo to give a brown oil. This is purified by supercritical fluid chromatography (RT=4.7 minutes (UV); SFC Column. Benzenesulphonamide 21.2 mm×500 mm 5 μm; CO2 Gradient: 15-30% MeOH w/0.2% DMEA in 5.5 mins and then ramped up to 50% MeOH and held for 3.5 mins; Column Temp: 40° C.; Flow Rate: 50.0 ml/min) to give an orange solid. This is then further purified by HPLC chromatography (RT=4.67 minutes (UV); LC Column. Waters Xbridge C18 100 mm×30 mm 5 μm; H2O w/0.2% NH4HCO3 Gradient: 9-100% ACN w/0.2% NH4HCO3 in 6.0 min then held at 100% for 3.0 min; Column Temp: 50° C.; Flow Rate: 3.0 ml/min) to give the title compound as a white solid (0.0621 g, 0.145 mmol). MS (m/z): 428 (M+1). 1H-NMR (300.13 MHz, CDCl3): δ 1.32 (t, 3H), 3.72 (s, 3H), 3.73-3.80 (br, 2H), 3.84-3.89 (br, 2H), 4.22 (q, 2H), 4.34 (br, 2H), 5.66 (s, 2H), 7.03 (s, 1H), 7.21 (t, 1H), 7.49 (d, 1H), 7.51-7.55 (m, 1H), 7.70 (td, 1H), 8.60 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[O:9][C:8]([C@H:10]3[C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][CH2:13][CH2:12][N:11]3C(OC(C)(C)C)=O)=[N:7][N:6]=2)[CH2:2]1.[C:29](Cl)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[C:29]([N:1]1[CH2:4][CH:3]([C:5]2[O:9][C:8]([C@H:10]3[C@@H:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:14][CH2:13][CH2:12][NH:11]3)=[N:7][N:6]=2)[CH2:2]1)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](c2ccccc2)[C@@H]1c1nnc(C2CNC2)o1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(=O)N1CC(c2nnc([C@@H]3NCCC[C@@H]3c3ccccc3)o2)C1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of tert-butyl cis-2-(5-azetidin-3-yl-1,3,4-oxadiazol-2-yl)-3-phenylpiperidine-1-carboxylate (3C.3, 20.0 mg, 0.05 mmol) in dichloromethane (1 ml) was added valeryl chloride (0.007 ml, 0.06 mmol) and triethylamine (0.007 ml, 0.05 mmol). The reaction was allowed to stir for 0.5 h. TFA (0.3 ml) was added to the reaction and allowed to stir for an additional 1 h. The reaction was concentrated and purified via reverse phase preparative HPLC. Product containing fractions were treated with aqueous sodium bicarbonate. The product was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to yield cis-2-[5-(1-pentanoylazetidin-3-yl)-1,3,4-oxadiazol-2-yl]-3-phenylpiperidine (52%). 1H NMR (400 MHz, CD3OD) δ 7.22-7.08 (m, 5H), 4.59 (d, J=5.2 Hz, 1H), 4.47 (dt, J=4.4 Hz, 1H), 4.23 (q, J=9.3 Hz, 1H), 4.11 (dd, J=9.0, 5.8 Hz, 0.5H), 4.05 (dd, J=8.4, 5.6 Hz, 0.5H), 3.95 (m, 1H), 3.84 (m, 1H), 3.33 (m, 2H), 2.89 (m, 1H), 2.34 (m, 1H), 2.10 (m, 2H), 1.92 (m, 2H), 1.74 (m, 1H), 1.54 (quint, J=7.5 Hz, 2H), 1.35 (m, 2H), 0.93 (dt, J=7.4, 2.9 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>Cl>[Cl:13][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: Clc1nc2ccccc2[nH]1
Yield: 87.9 %

Procedure:
A solution of 2-benzimidazolinone (11.0 g.) and conc. hydrochloric acid (1 drop) in phosphorus oxychloride (126 g.) was stirred for 14 hours at 110° C. After cooling, the mixture was concentrated under reduced pressure to remove excess phosphorus oxychloride. Water was added to the residue and sodium bicarbonate was added thereto to neutralize the mixture. The resulting mixture was extracted four times with ethyl acetate. The combined ethyl acetate extracts were washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystals of 2-chlorobenzimidazole (11.0 g.). To the crystals were added aminoacetaldehyde diethyl acetal (35.5 g.) and dried toluene (80 ml.) and the resulting solution was stirred for 17 hours at 115° C. After cooling, the reaction mixture was extracted by adding a sodium bicarbonate aqueous solution and ethyl acetate. The aqueous layer was further extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give oil. The oil was crystallized by adding benzene and hexane to give 2-benzimidazolylaminoacetaldehyde diethyl acetal (11.0 g.), mp 117° to 121° C. The mother liquor was purified by column chromatography on silica gel (100 g.) using a mixture of ethyl acetate and benzene (1:1) to give the same compound (1.5 g.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([OH:10])=[O:9])[N:6]=1.[C:12]1([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:19][C:20]([C:22]([O:25][NH2:26])([CH3:24])[CH3:23])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:25][C:22]([C:20]([O:19][CH:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21])([CH3:24])[CH3:23])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 92.9 %

Procedure:
135 g of (2-amino-4-thiazolyl)glyoxylic acid are added whilst cooling with ice to a solution of 245 g of O-(1-diphenylmethoxycarbonyl-1-methylethyl)-hydroxylamine in 400 ml of dimethylformamide. The solution is stirred for 5 hours without cooling, and is then added to 4 l of methanol. In order to complete precipitation, stirring continues for 5 hours at 10°, and the product is then filtered off by suction and dried. 320 g (93%) of the title compound are obtained as colourless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O-:11].[Na+].Cl>>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1cc(Cl)cc(N)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(C)nc(N)c1
Temperature: 130 °C

Procedure:
To 4-chloro-6-methylpyridin-2-amine (1.0 g, 7.0 mmol) was added sodium methoxide (25% solution in methanol, 9.2 ml, 35 mmol) under a nitrogen atmosphere. The reaction mixture was heated in a microwave at 130° C. for 12 hours. The reaction mixture was quenched with hydrochloric acid (1.0 M in water, 42 ml, 42 mmol), and the reaction mixture was partially concentrated under reduced pressure to remove methanol. The residue was diluted with ethyl acetate, and the pH was adjusted to ˜7.5 with saturated aqueous sodium bicarbonate solution. The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol with ammonium hydroxide, linear gradient) to afford 4-methoxy-6-methylpyridin-2-amine. MS ESI calc'd. for C7H11N2O [M+H]+ 139. found 139. 1H NMR (500 MHz, DMSO-d6) δ 5.96 (d, J=1.5 Hz, 1H), 5.75 (d, J=2.0 Hz, 1H), 5.70 (br s, 2H), 3.66 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: C1C2C(COC(=O)[NH:17][S:18]([NH:21][CH2:22][CH2:23][NH:24][C:25]3[C:29]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Br:42])[CH:36]=5)C(=O)[O:32][N:31]=4)=[N:28][O:27][N:26]=3)(=[O:20])=[O:19])C3C(=CC=CC=3)C=2C=CC=1.C1COCC1.NCCN(CCN)CCN.Cl>COC(C)(C)C.C(Cl)Cl>[NH2:17][S:18]([NH:21][CH2:22][CH2:23][NH:24][C:25]1[C:29]([C:30](=[N:31][OH:32])[NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Br:42])[CH:36]=2)=[N:28][O:27][N:26]=1)(=[O:19])=[O:20]
Reactant: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
Into a 1 L 4-neck round bottom flask was charged 9H-fluoren-9-ylmethyl({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (25.0 g, 36.4 mmol) and anhydrous THF (250 mL) at ambient temperature to produce a homogeneous solution. The solution was then cooled to 0-5° C. in an ice bath before N,N-bis(2-aminoethyl)ethane-1,2-diamine (114 mL, 728 mmol) was added dropwise over 35 minutes via an addition funnel. The addition funnel was rinsed with anhydrous THF (50 mL) and the rinse was added to the reaction mixture. The cold bath was removed and the reaction was gradually warmed to ambient temperature and stirred at ambient temperature for 2.5 h. EtOAc (400 mL) was added and the resulting mixture was transferred to a 2 L 4-neck round bottom flask and cooled to about 0-5° C. in an ice bath. A solution of 2.0 M aqueous HCl (400 mL, 800.0 mmol) was added dropwise via an addition funnel, while maintaining the internal temperature at below 10° C. The two phases were separated and the aqueous phase was extracted with EtOAc (200 mL). The organic fractions were combined and cooled to about 6-7° C. A solution of 2.0 M aqueous HCl (200.0 mL, 400.0 mmol) was added dropwise to the cold organic fraction, maintaining the internal temperature at below 10° C. The two phases were separated and the organic phase was washed with water (2×400 mL), dried over MgSO4, and concentrated under reduced pressure to a light yellow syrup. The syrup was dissolved in EtOAc (60.0 mL) to yield a homogeneous solution. To the solution was added a solution of DCM (250.0 mL) and tert-butyl methyl ether (TBME, 100.0 mL) dropwise. The resulting slurry was stirred overnight at room temperature, then cooled in an ice bath for 1 h. The solids were collected by filtration, washed with an ice cold 250 mL solution of DCM (150 mL) and TBME (100 mL), and dried under vacuum to give 14.4 g of the crude desired product as white solids.
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]\[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2\[C:11]([CH:13]=[CH:14][CH:15]=[CH:16]\2)=[O:12])/[CH:2]=1.O>C(O)(=O)C>[CH:4](=[N:5][CH2:6][CH2:7][N:8]=[CH:9][C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12])[C:3]1[C:17](=[CH:19][CH:20]=[CH:1][CH:2]=1)[OH:18]
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O

Procedure:
Approximately 1 mmol of SALEN ligand dissolved in acetic acid solution was loaded into each reactor tube of the Multiclave™, and 5 ml of 4:1 (weight ratio) water/EO was added at 100° C. The results are shown in Table 3.
Reaction SMILES: [CH:1]1([CH:4]([S:9][CH2:10][C:11]([O:13]CC)=O)[CH2:5][N+:6]([O-])=O)[CH2:3][CH2:2]1>CC(O)=O.[Zn]>[CH:1]1([CH:4]2[CH2:5][NH:6][C:11](=[O:13])[CH2:10][S:9]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CSC(C[N+](=O)[O-])C1CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CSC(C2CC2)CN1
Temperature: 70 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
Ethyl 2-((1-cyclopropyl-2-nitroethyl)thio)acetate (4-12, 1.46 g, 6.26 mmol) was taken up in AcOH (30 ml). To this was added zinc powder (4093 mg, 62.6 mmol) then the mixture was heated to 70° C. After stirring overnight the mixture was cooled to rt, diluted with AcOH, filtered through a pad of Celite washing with AcOH, and concentrated. The crude product was subjected to silica gel chromatography (40 g, 0-100% EtOAc/hexanes, 10 minute gradient) to afford 6-cyclopropylthiomorpholin-3-one (4-13, 355 mg, 36%) as an amber oil which solidified slowly under vacuum. 1H NMR (399 MHz, CDCl3): δ 6.65 (s, 1H); 3.65 (dt, J=13.2, 4.4 Hz, 1H); 3.54-3.46 (m, 1H); 3.32 (s, 2H); 2.47-2.39 (m, 1H); 0.98-0.89 (m, 1H); 0.67-0.58 (m, 2H); 0.41-0.25 (m, 2H).
Reaction SMILES: C([O:8][C:9]([N:11]1[C@@H:16]([C@@H:17](O)[C@@H:18]([NH:27][C:28](=[O:30])[CH3:29])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH2:15][O:14][C@@H:13]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@@H:12]1[CH3:38])=[O:10])C1C=CC=CC=1.[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH:39]1([CH2:42][O:26][C:22]2[CH:21]=[C:20]([CH2:19][C@H:18]([NH:27][C:28](=[O:30])[CH3:29])[C@H:17]3[C@H:16]4[CH2:15][O:14][C@@H:13]([O:32][CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@H:12]([CH3:38])[N:11]4[C:9](=[O:8])[O:10]3)[CH:25]=[CH:24][CH:23]=2)[CH2:41][CH2:40]1
Reactant: BrCC1CC1
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1cccc(OCC2CC2)c1)[C@@H]1OC(=O)N2[C@@H]1CO[C@@H](OCC(C)(C)C)[C@@H]2C
Yield: 85.9 %

Procedure:
Heat a mixture of (2R,3S,5R)-5-[(1S,2S)-2-Acetylamino-1-hydroxy-3-(3-hydroxy-phenyl)-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid benzyl ester (69 mg, 0.13 mmol), cyclopropylmethyl bromide (0.019 ml, 0.195 mmol), cesium carbonate (127 mg, 0.39 mmol) and N,N-dimethylformamide (2 mL) to 60° C. for 18 hours. Cool and dilute with ethyl acetate and wash with saturated sodium chloride, dry with magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound (53 mg). MS(ESI): m/z=475 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:22][C:23]1[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([CH:32]=[O:33])[CH:30]=[CH:31][C:23]=1[O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(C(=O)N(Cc2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 36.5 %

Procedure:
N-Phenylbenzylamine (0.72 g, 3.9 mmol, 2 eq) was added to a solution of 2-benzyloxy-5-formylbenzoic acid (500 mg, 1.95 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (530 mg, 3.9 mmol, 2 eq), and N-methylmorpholine (0.58 mL, 5.3 mmol, 2.73 eq) in N,N-dimethylformamide (10 mL). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (750 mg, 13.9 mmol, 2 eq) and the stirred reaction mixture was heated overnight at 50° C. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 10% HCl (3×20 mL), brine (20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and brine (20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica with petroleum ether:ethyl acetate (3:1) as eluent, to give the product as a white powder (300 mg, 37%). RF (petroleum ether:ethyl acetate 1:1) 0.55. 1H NMR (CDCl3) δ9.78 (s, 1H, O═C—H), 5.08 (s, 2H, OCH2Ph), 5.02 (s, 2H, NCH2Ph).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[C:15]([O:18][CH2:19][CH:20]([CH2:31][O:32][NH2:33])[CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])(=[O:17])[CH3:16].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:33][O:32][CH2:31][CH:20]([CH2:19][O:18][C:15](=[O:17])[CH3:16])[CH2:21][CH2:22][P:23]([O:24][CH2:25][CH3:26])([O:27][CH2:28][CH3:29])=[O:30])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CCOP(=O)(CCC(CON)COC(C)=O)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCOP(=O)(CCC(CONc1nc(NC=O)nc(Cl)c1NC=O)COC(C)=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
4,6-Dichloro-2,5-diformamidopyrimidine (0.390 g, 1.66 mmol), diethyl 3-(acetoxymethyl)-4-(aminooxy)-butylphosphonate (0.380 g, 1.275 mmol) and N,N-diisopropylethylamine (0.58 ml, 3.22 mmol) were dissolved in diglyme (15 ml) and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was then allowed to cool, N,N-diisopropylethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel (eluting with chloroform:ethanol 97:3) to give the title compound (0.480 g, 76%). 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7Hz (OCH2CH3), 1.75 (4H, m, CH2CH2P), 2.01 (4H, m, COCH3, CHCH2) 4.0 (8H, m, CH2OAc, NOCH2, (OCH2)2) 8.15 (1H, s, 5-NHCHO), 9.25 (1H, s, 2-NHCHO), 9.40 (1H, br.s, D2O exchangeable, NHOCH2) 10.80 (2H, br.s. D2O exchangeable, 2x NHCHO). Found: C,41.97, H,5.80; N,13.17%. C17H27N5O8PCl requires: C,41.17; H,5.49; N,14.12%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[OH:29][C@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:32]4[CH2:33][CH2:34][CH2:35][C@H:30]([OH:29])[CH2:31]4)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: O[C@H]1CCCNC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC[C@H](O)C3)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and (S)-3-hydroxypiperidine were coupled to give 110bp. LCMS (ESI) m/z: 485.0
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH2:10]([S:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, benzyl mercaptan and DBU in dioxane. ES-MS m/e (%): 320 (M{37Cl}+H+, 45), 318 (M{35Cl}+H+, 100).