Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2Cl)cc1Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 1.17 g (7.54 mmol) of 2-chloro-4-fluorobenzonitrile and 0.97 g (7.54 mmol) of 2-chlorophenol in 40 mL DMSO was combined with 3.2 g (23.16 mmol) of potassium carbonate and stirred overnight at 120° C. Then the mixture was evaporated to dryness in vacuo, the residue was mixed with water and extracted with ethyl acetate. The extracts were washed with water and saturated sodium chloride solution, dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:5]2[CH3:17].[Cu][C:19]#[N:20]>>[CH3:17][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:19]#[N:20])[CH:3]=2)[NH:7][C:6]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Br)cc12
Reactant: N#C[Cu]
Product: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Temperature: 200 °C
Reaction time: 8 h

Procedure:
5-Bromo-3-methyl-2-pyridin-3-yl-1H-indole (5.0 g, 16.7 mmol) and copper (I) cyanide (1.9 g, 20.1 mmol) are placed in a round bottom flask which is flushed with N2. N-Methylpyrrolidinone (40 mL) is added via syringe. The resulting mixture is heated to 200° C. under N2 with vigorous stirring overnight. The mixture is cooled to room temperature and dichloromethane (200 mL) is added. The mixture is filtered through a pad of celite. The filtrate is washed with 10% aqueous ammonia in saturated aqueous ammonium chloride. The aqueous phase is extracted with dichloromethane. The combined organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:0) to give 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 7.45-7.60 (m, 3H), 8.06-8.11 (m, 1H), 8.15 (s, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.91 (d, J=1.5 Hz, 1H), 11.94 (br. s., 1H). HRMS (ESI) m/z 234.1031 [(M+H)+ Calcd for C15H11N3, 234.1031].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][CH2:53][N:52]1C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][CH2:53][NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@H](C)C4)c3)c2)c1
Reaction time: 1.5 h

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (48 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 1.5 h. LC-MS showed the reaction to be complete and the solution stripped to dryness. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP Column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as an ivory colored solid [62.1 mg (53%)]. LC-MS m/z 747.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:11]1
Reactant: CSc1cccc(N2CCNCC2)c1F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(c2cccc(SC)c2F)CC1

Procedure:
Preparation according to preparation 26: 1-[2-fluoro-3-(methylthio)phenyl]piperazine (1.25 g, 5.53 mmol), triethylamine (1.2 ml, 7.2 mmol), methylen chloride (50 ml), methyl chloroformate (0.49 g, 6.6 mmol). Yield: 1.56 g. MS m/z (rel. intensity, 70 eV) 284 (M+, 99), 196 (bp), 184 (44), 169 (54), 56 (60)
Reaction SMILES: [C:1]([C:3]1(O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(O)=[O:13]>CCOCC>[CH:3]1([C:1](=[O:13])[CH3:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4]1
Reactant: C#CC1(O)CCCCCCC1
Reactant: O=CO
Solvent: CCOCC
Product: CC(=O)C1C=CCCCCC1

Procedure:
At 35° C., a solution of lithium acetylide-ethylene diamine (50 g, 0.49 mol) in THF (500 ml) was slowly treated (reaction temperature ≦35° C.) with a solution of cyclooctanone (51.4 g, 0.41 mol) in THF (100 ml). The resulting mixture was stirred for 4 h at 20° C., 15 h at 45° C., cooled to 5° C., treated with aqueous sat. NH4Cl solution (250 ml) and washed with 3M aqueous HCl. After extraction with Et2O, the organic phases were washed with water, aqueous sat. Na2CO3 solution, dried (Na2SO4), and concentrated to give 1-ethynylcyclooctanol (66.6 g). A solution of crude 1-ethynylcyclooctanol (65 g) in formic acid (130 ml) was heated for 2.5 h at 80° C. The resulting mixture was taken up in Et2O and washed successively with water, 5M NaOH, water, aqueous sat. NH4Cl solution, dried (Na2SO4), and concentrated to give 56 g of crude product. A fraction (8 g) was purified by flash chromatography (hexane/Et2O 95:5→9:1) to give 4.1 g of 1-cyclooct-2-enylethanone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=3[OH:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cc1ccc(O)c(NCc2nnn(C)n2)c1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2cc(C)ccc2O)[C@H]1O
Yield: 39 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (400 mg, 1.43 mmol) obtained in step 1 of example 2 and N-(2-hydroxy-5-methylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (280 mg, yield: 39%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1c(F)cccc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2c(F)cccc2F)O3)nc1

Procedure:
2-(2,6-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.9 g of 2-(2,6-difluorophenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 9.03 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.52 (m, 1H), 7.26-7.16 (m, 4H), 7.01 (dd, 1H, J 8.8, 2.9 Hz), 6.83 (d, 1H, 8.8 Hz), 5.69-5.64 (m, 2H), 4.98 (m, 1H), 2.37 (m, 1H), 2.29 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: ClCCCBr
Product: Fc1cccc(SCCCCl)c1

Procedure:
Prepared by Procedure R and Scheme Z using 3-fluorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13].CN(C)C=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([C:16]([CH3:22])([C:15]([O:14][CH2:12][CH3:13])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 50.0 g (0.31 mol) of 2,4-difluoronitrobenzene II, 56.1 g (0.32 mol) of diethylmethylmalonate and 400 ml of dimethylformamide are vigorously stirred. To the stirring mixture is added 13.1 g (0.33 mol) sodium hydroxide in one portion at 25° C., cooling with ice to keep the temperature of the reaction mixture at 25°-30° C. during the first hour. Thereafter, stirring is maintained for 3.5 hours, then 800 ml of water is added, the organic layers removed, and the aqueous layer extracted with three 180-ml portions of ethyl acetate-water.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][C:7]([OH:9])=[O:8])C.[CH:11]1[CH:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20](C=O)[C:14]2=[CH:13][CH:12]=1.[H-].[Na+]>C(O)C>[C:16]1([CH:6]([CH:5]=[CH2:4])[C:7]([OH:9])=[O:8])[C:15]2[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCC(=O)O
Reactant: O=Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: C=CC(C(=O)O)c1cccc2ccccc12

Procedure:
To a solution of 8.71 g of succinic acid ethyl ester and 7.81 g of 1-naphthylaldehyde in 50 ml of absolute ethanol was added 3.02 g of a 50% sodium hydride (suspension in oil) under ice-cooling, and then the mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether to remove neutral materials. The aqueous layer was acidified by adding concentrated hydrochloric acid and extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The ethereal solution was concentrated under reduced pressure to obtain 11.8 g of 3-ethoxycarbonyl-4-(1-naphthyl-3-butenoic acid as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[O:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[C:24]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:24][O:1][C:2]1[O:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: Cc1ccccc1
Reactant: COc1cccc(Oc2ccccc2-c2c(O)on(C)c2=O)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COc1cccc(Oc2ccccc2-c2c(OC)on(C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
5-Hydroxy-4-[2-(3-methoxyphenoxy)phenyl]-2-methyl-3(2H)-isoxazolone (2.5 g) was dissolved in 3 mL of methanol and 15 mL of toluene and cooled in an icebath. Trimethylsilyldiazomethane (5 mL of a 2.0M solution in hexane) was added dropwise. Gas evolution was observed. The resulting yellow solution was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (1:1 hexane:ethyl acetate as eluant). The second eluting component was collected to yield 950 mg (36%) of the title compound of Step D. 1H NMR (CDCl3): δ7.51 (dd,J=1.7, 7.5Hz,1H), 7.27 (dt,J=1.7, 7.5Hz,1H), 7.17 (m,2H), 6.97 (dd,J=1, 8Hz,1H), 6.5 (m,3H), 3.92 (s,3H), 3.74 (s,3H), 3.33(s,3H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)=[O:15])=[C:9]([C:25]3[CH:30]=[C:29]([C:31](=[O:44])[NH:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)[CH:28]=[CH:27][N:26]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH3:57][NH:58][CH2:59][CH2:60][N:61]1[CH2:66][CH2:65][N:64]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:63][CH2:62]1>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:57][N:58]([CH2:59][CH2:60][N:61]1[CH2:66][CH2:65][N:64]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:63][CH2:62]1)[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:25]2[CH:30]=[C:29]([C:31](=[O:44])[NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=3)[CH:28]=[CH:27][N:26]=2)[CH:17]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)-benzoic acid (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (5 mL), EDC.HCl (48 mg, 0.25 mmol, 1.50 equiv), 4-dimethylaminopyridine (31 mg, 0.25 mmol, 1.50 equiv). The mixture was stirred for 5 min at room temperature. To the above was added tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate (53 mg, 0.22 mmol, 1.30 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 5 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN (25% CH3CN up to 45% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 33.6 mg product was obtained. This resulted in 33.6 mg (21%) of PH-RDX-002-1129-0 as a light yellow solid. MS (ES, m/z): 828 [M−+H]+. H-NMR (300 MHz, CD3OD, ppm) 8.98 (d, J=5.1 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.18˜8.11 (m, 3H), 7.89˜7.53 (m, 8H), 4.72 (s, 2H), 4.00˜3.11 (m, 16H), 3.08 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=5.7 Hz, 2H), 1.49 (s, 9H)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:6]1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.C(Cl)Cl>[N:32]([C@@H:6]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:26][C@H:5]1[O:4][C:1](=[O:3])[CH3:2])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C
Yield: 80.6 %

Procedure:
To a solution of mannose triflate 56 (1.28 g, 2.66 mmol) in 14 mL of DMF is added sodium azide (0.69 g, 10.5 mmol). The reaction mixture is heated at 40° C. for 1.75 h, cooled to room temperature, diluted with 100 mL of CH2Cl2, washed with H2O (100 mL), saturated NaCl (100 mL), dried over MgSO4, filtered, and concentrated to afford a yellow oil. The product is purified by flash chromatography (33% EtOAc/hexane) to afford 0.80 g (81%) of 2-azido-2-deoxy-1,3,4,6-tetra-O-acetyl-β-D-glucopyranose 57: Rf 0.31 (33% EtOAc/hexane) δ 5.55 (d, J=8.6 Hz, 1H, H-1), 5.015.15 (m, 2H, H-3, H-4), 4.31 (dd, J=12.7, 4.5 Hz, 1H, H-6), 4.08 (d, J=12.5 Hz, 1H, H-6), 3.77-3.84 (m, 1H, H-5), 3.69 (app t, J=9.1 Hz, 1H, H-2), 2.10 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[O:23].[Li+].[BH4-]>C1COCC1>[OH:23][CH2:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[C:6]2[C:10]([CH2:9][O:8][C:7]2=[O:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CCO)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde (97 mg, 0.29 mmol) in THF (5 mL) was added an aliquot of a 2 M LiBH4 in THF (150 μL, 0.300 mmol). The reaction mixture was stirred at room temperature for 1 hour when complete consumption of the starting materials was observed by TLC. The reaction mixture was worked up by addition of an aqueous 1N HCl solution and extraction with EtOAc. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography to provide the product. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H), 2.97 (t, 2H, J=6 Hz), 3.76 (t, 2H, J=6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])=[S:48])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=S)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To the solution of methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XIV (610 mg, 1.12 mmol) in THF (10 mL) under argon was added Lawesson's reagent (680 mg, 1.68 mmol) and DMAP (13 mg, 0.11 mmol). The mixture was stirred at r.t. for 2 h and then refluxed over weekend. An additional two portions of Lawesson's reagent (900 mg, 2.24 mmol) and was added and the reaction was refluxed for another 4 h. The solvent was evaporated under reduced pressure and the crude product was purified on a silica gel column (1:6 EtOAc/hexane) to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamothioyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XV (290 mg, 0.51 mmol, 45% yield). ESIMS found for C25H46N4O8S m/z 563 (M+H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][N:13]=2)[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[NH:16][C:12]([C:10]3[C:9]([OH:25])=[C:8]4[C:3]([CH:4]=[CH:5][CH:6]=[N:7]4)=[C:2]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:11]=3)=[N:13][N:14]=2)=[CH:19][CH:20]=1
Reactant: C1COCCN1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Product: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(N2CCOCC2)c2cccnc12
Yield: 55 %

Procedure:
A solution of 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (34 mg, 0.09 mmol) in neat morpholine was heated in a sealed tube at 150° C. for 16 hours. The excess amine was removed in vacuo and the residue purified by preparative HPLC to provide the title compound (19 mg, 55%) as a white solid. 1H NMR (CDCl3): δ 9.14 (dd, J=4.4, 1.6 Hz, 1 H), 8.45 (dd, J=8.4, 1.6 Hz, 1 H), 7.57 (dd, J=8.4, 4.4 Hz, 1 H), 7.36 (dd, J=8.4, 5.2 Hz, 2 H), 7.01 (t, J=8.4 Hz, 2 H), 4.19 (s, 2 H), 3.98 (t, J=4.4 Hz, 4 H), 3.33 (t, J=4.4 Hz, 4 H); 13C NMR (CDCl3): δ 168.49, 161.79 (d, JCR=243.6 Hz), 154.85, 153.95, 153.40, 146.07, 144.75, 133.88, 132.99 (d, JCF=3.0 Hz), 130.40 (d, JCF=130.4 Hz), 122.67, 120.81, 119.70, 115.37 (d, JCF=21.2 Hz), 66.88, 52.06, 33.71; MS m/z 407 (M+1).
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=O)C.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:22]O>>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:22])=[O:10])=[C:7]([CH3:14])[CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)cc1C

Procedure:
15 g (78 mmol) 4-acetamido-2-methyl-benzoic acid are suspended in 150 ml of methanol and combined with 11.2 ml (210 mmol) conc. sulphuric acid. The mixture is refluxed for three hours. Then excess methanol is eliminated in vacuo. The residue is poured onto ice water, made alkaline with 5 N sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness.