Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.Br[C:7](Br)([F:9])[F:8].CN(C)P(=O)(N(C)C)N(C)C.[CH3:22][O:23][C:24]1[CH:58]=[CH:57][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:41]=[CH:40][C:39]([C:42]4[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:44]=[C:45]([CH:47]=O)[N:46]=4)=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>O.C(OCC)(=O)C>[F:8][C:7]([F:9])=[CH:47][C:45]1[N:46]=[C:42]([C:39]2[CH:38]=[CH:37][C:36]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:27]4[CH:57]=[CH:58][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:31][CH:32]=3)=[N:41][CH:40]=2)[N:43]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:55])[CH3:56])[CH:44]=1
Reactant: COc1ccc(COc2ccc(-c3ccc(-c4nc(C=O)cn4COCC[Si](C)(C)C)cn3)cc2)cc1
Reactant: FC(F)(Br)Br
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COc2ccc(-c3ccc(-c4nc(C=C(F)F)cn4COCC[Si](C)(C)C)cn3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a tetrahydrofuran (70 mL) solution containing dibromodifluoromethane (5.09 g) was added dropwise hexamethyl phosphoric triamide (8.81 mL) at −78° C. The temperature of the mixture was returned to room temperature, and the mixture was stirred for 30 minutes. The mixture was cooled to −78° C., and a tetrahydrofuran (20 mL) solution of 2-(6-{4-[(4-methoxybenzyl)oxy]phenyl}pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-carbaldehyde (1.25 g) was added dropwise thereto. The temperature of the mixture was returned to room temperature, and the mixture was stirred for 3 hours. To the mixture were added ethyl acetate, water and a saturated aqueous sodium bicarbonate solution, and the liquids were separated. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15 to 55:45) to obtain 5-[4-(2,2-difluoroethenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine (0.84 g).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([C:26]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH:30]=[CH:29][NH:28][CH2:27]1)[C:9]([NH:11]N1[C@@H](CC2C=CC=CC=2)COC1(C)C)=[O:10])(C)(C)C.[Li+].[OH-].[CH3:46][CH2:47][OH:48].Cl>C1COCC1.O>[CH2:26]([C@H:46]([NH:11][C:9](=[O:10])[C@H:8]([C:26]1([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:30]=[CH:29][NH:28][CH2:27]1)[CH2:7][C:6]([OH:5])=[O:43])[CH2:47][OH:48])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)C[C@H](C(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C)C1(c2ccc(-c3ccccc3)cc2)C=CNC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)C1(c2ccc(-c3ccccc3)cc2)C=CNC1
Reaction time: 12 h
Yield: 49 %

Procedure:
To a solution of N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-3(S)-[3-(biphenyl-4-yl)-1H-pyrrol-3-yl]succinamic acid t-butyl ester (80 mg, 0.14 mmol) in THF (5 mL) was added 2M aqueous LiOH (5 mL). EtOH (few drops) and H2O were added until a homogeneous solution was obtained. The resultant solution was heated at 50° C. After 12 hours, the mixture was acidified with 6N HCl to pH1. After another 5.5 hours at 50° C., the mixture was partitioned between EtOAc and 1 M pH 7 phosphate buffer. The aqueousueous phase was separated and extracted with EtOAc two times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to a residue which, upon trituration with CH2Cl2/hex, provided 32 mg (49%) of pure N-(1(S)-benzyl-2-hydroxyethyl)-3(S)-[3-(biphenyl-4-yl)-1H-pyrrol-3-yl]succinamic acid as a white solid, mp 151-4° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:12])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:6]([OH:12])=[CH:7][CH:8]=[CH:9][C:10]=1[CH2:11][Br:21])[CH3:2]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(O)cccc1CBr
Temperature: 25 °C

Procedure:
2-Hydroxy-6-methyl-benzoic acid ethyl ester (4.046 g), NBS (4.786 g), and AIBN (1.134 g) were weighed into a round-bottom flask equipped with a reflux condenser. CCl4 (40 mL) was added and the mixture was heated at reflux for 2 h. After cooling to RT, solid was removed by filtration and the filtrate was concentrated to give a yellow oil as crude, which solidified upon standing. The crude was purified by silica gel chromatography (300 g, 0-5% EtOAc/hexanes) to afford 2-bromomethyl-6-hydroxy-benzoic acid ethyl ester as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13](=[O:15])[NH:12][N:11]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13](=[O:15])[NH:12][N:11]=1
Reactant: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1-c1n[nH]c(=O)o1
Yield: 93.1 %

Procedure:
A solution of 2-nitrobenzoylhydrazine (9.05 g, 0.05 mol) in dioxane (30 mL) was slowly added to a solution of trichloromethyl chloroformate (4.6 mL, 0.04 mol) in dioxane (30 mL) at room temperature. On completion of the addition the reaction was heated to reflux for 4 hours. The solvent was evaporated off and the residue re-crystallised from 96% ethanol (50 mL) to give 7.15 g of the 5-(2-nitrophenyl)-3H-[1,3,4]oxadiazol-2-one. M.p. 157-158° C. A solution of the nitro compound (2 g, 9.7 mmol) in 96% ethanol (25 mL) was hydrogenated over 5% palladium on charcoal to give desired 1.6 g of the desired amine.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[N:17]=[CH:18][C:19]([C:22]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:23]=2)=[CH:20][CH:21]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 29.8 %

Procedure:
A mixture of methyl thiosalicylate (1.85 g, 11.0 mmol), 2-isopropoxy-5-cyanopyridine (1.62 g, 10.0 mmol), triethylamine (1.80 ml, 12.9 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 30 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.89 g, 30%).
Reaction SMILES: [CH3:1][C@@:2]1([OH:18])[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].B(F)(F)F.[CH3:23]COCC.[N+](=C)=[N-]>C(Cl)Cl>[CH3:1][C@@:2]1([O:18][CH3:23])[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15]
Reactant: CCOCC
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(O)[C@H](C)O1
Agent: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Product: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(OC)[C@H](C)O1
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 1 g (3.7 mmoles) of methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (II-A) in 10 ml of dry methylene dichloride was treated at -70° with 0.05 ml of boron trifluoride etherate. While maintaining the temperature at -70°, an excess of diazomethane dissolved in methylene dichloride was added until a faint yellow color persisted. After 60 minutes at -70°, a white solid (polymethylene) was removed by filtration, and the filtrate was washed successively with 10% sodium bicarbonate solution and with water, after which it was dried with anhydrous magnesium sulfate. The residue which was obtained by evaporation was chromatographed on a silica-gel column. Elution with a 95:5 chloroform:acetone mixture gave pure methyl 2,3,6-trideoxy-4-C-methyl-4-O-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (II-B, 0.68 g, 65%) as a syrup; [α]D =-129° (c=1.1 in CHCl3); mass spectrum m/e 285 (M+). The pmr spectrum (CDCl3) showed absorptions at 1.22 (s, CH3 -C-4), 1.28 (d, CH3 -C-5), 3.33 and 3.48 (two s, --OCH3) and 4.77δ (broad s, C-1-H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[N:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[CH2:10]2)=[O:4].C(N(CC)CC)C.CCCP(=O)=O.[CH:37]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([CH3:39])[CH3:38]>CN(C1C=CN=CC=1)C.ClCCCl>[CH:37]([C:40]1[CH:41]=[C:42]([NH:43][C:18]([C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=4[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=2)=[O:20])[CH:44]=[CH:45][CH:46]=1)([CH3:39])[CH3:38]
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)O)c1)C2
Reactant: CC(C)c1cccc(N)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
To a mixture of 3-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid (63 mg, 0.20 mmol), triethylamine (0.056 mL, 0.40 mmol), and catalytic DMAP in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.143 mL, 0.24 mmol). After 10 min at rt, 3-isopropylaniline (0.042 mL, 0.30 mmol) was added and the reaction stirred at rt for 1 hour. The reaction was quenched into aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc to give the title compound as a light yellow solid (59 mg, 68%). 1H NMR (Acetone-d6) δ: 9.39 (br. s., 1H), 8.89 (s, 1H), 8.66 (s, 1H), 7.72-7.74 (m, 1H), 7.66-7.71 (m, 2H), 7.35-7.44 (m, 2H), 7.25-7.30 (m, 2H), 7.00 (d, J=7.6 Hz, 1H), 4.60 (s, 2H), 3.91 (s, 3H), 3.66-3.71 (m, 2H), 3.37 (t, J=5.9 Hz, 2H), 2.91 (spt, J=6.9 Hz, 1H), 1.25 (d, J=7.0 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][NH2:29]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:3]=1
Reactant: NCc1ccc2ccccc2c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc3ccccc3c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and C-Naphthalen-2-yl-methylamine in DME. ES-MS m/e (%): 342 (M+H+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[N:18]1[CH2:17][C:16]([CH3:30])([CH3:31])[NH:15][CH2:20][C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(F)ccc2Cl)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(c2cc(F)ccc2Cl)C(=O)CN1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
4.2 ml of trifluoroacetic acid (54.7 mmol) was added to a solution of 1.80 g of 4-(2-chloro-5-fluorophenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (62c) (5.47 mmol) in methylene chloride (8.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 1.25 g of the title compound (yield: quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C[CH2:33][N:34](CC)CC.N#CBr>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH2:24][O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:33]#[N:34])[CH2:30][CH2:31]3)=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCNCC2)n1-c1ccc(F)cc1
Agent: N#CBr
Solvent: ClCCl
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COC2CCN(C#N)CC2)n1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine (prepared above) in anhyd DCM (2 mL) was added Et3N (37 uL, 0.27 mmol), followed by cyanic bromide (20 mg, 0.18 mmol). After stirring overnight, the reaction was diluted with DCM, washed with brine, dried over Na2SO4, and concentrated in vacuo to give 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carbonitrile as a white solid that was used directly for the next step.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=C[CH:9]=1.C(C(=O)C(=NO)C)C.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH:32]=[O:33]>>[I:1][CH2:2][C:3]1[N:4]=[C:32]([C:31]2[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:30]=2[CH3:29])[O:33][C:7]=1[CH2:8][CH3:9]
Reactant: Cc1cccc(C)c1C=O
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2c(C)cccc2C)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-ethyl-1,2-propanedione-2-oxime and 2,6-dimethylbenzaldehyde gave 4-iodomethyl-5-ethyl-2-(2,6-dimethylphenyl)oxazole.
Reaction SMILES: [CH3:1][N:2]([CH3:12])C(=S)SSC(=S)N(C)C.[CH:13]1C=C2[C:16]([CH:17]=[C:18]([C:23]([O-])=[O:24])C=C2)=[CH:15][CH:14]=1.[CH:26]1C=C2[C:29]([CH:30]=[C:31]([C:36]([O-])=[O:37])C=C2)=[CH:28][CH:27]=1.[Cu+2:39].ClC1C(O)=C(Cl)C(Cl)=C(Cl)C=1Cl.O([As]1C2C=CC=CC=2OC2C1=CC=CC=2)[As]1C2C=CC=CC=2OC2C1=CC=CC=2.C1C(Cl)=C(Br)C=C2OC(NC=12)=O.C([O-])(=O)/C=C\C([O-])=O.C([Sn+2](CCCC)CCCC)CCC>>[N:2]1[C:12]2[C:15](=[CH:16][CH:17]=[CH:18][C:23]=2[O-:24])[CH:14]=[CH:13][CH:1]=1.[Cu+2:39].[N:2]1[C:12]2[C:28](=[CH:29][CH:30]=[CH:31][C:36]=2[O-:37])[CH:27]=[CH:26][CH:1]=1
Reactant: CN(C)C(=S)SSC(=S)N(C)C
Reactant: O=C([O-])c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CCCC[Sn+2](CCCC)CCCC
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: [O-]c1cccc2cccnc12

Procedure:
mercaptan (0.2-4%, in, e.g., vinyl); tetramethylthiuram disulfide (0.4-4%, in, e.g., vinyl or cellulose nitrate); copper napthenate (0.2-4% in, e.g., PVC or PVA); pentachlorophenol (1-20%, in, e.g., lacquer or cellulose nitrate); phenyl mercuric formate (0.05-10%, in, e.g.,nylon); pentachlorophenol (0.2-4%, in, e.g., celluose nitrate); 10,10′-oxybisphenoxarsine (OBPA) (0.005-2%, in a variety of plastics, including vinyl, PVC, and others; sometime sold under trade names, “Intercide” or Vinyzene); organotins (0.005-2%, in, e.g., PVC) (examples of organotins are, e.g., bis (tri-n-butyltin)sulfosalicylate (0.25-0.5% of plasticizer, used in e.g., PVC), or the preferred tri-n-butyltin maleate (0.005-1%, in, e.g., urethanes, polypropylene, paint-compounds); brominated salicylanilide (0.04-1%, in, e.g., polyethylene).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:9]=2[S:8][C:7]=1[S:20][CH3:21])=[O:5])C.C(O)(=O)C.S(=O)(=O)(O)O>O>[C:4]([C:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:9]=2[S:8][C:7]=1[S:20][CH3:21])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(SC)sc2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CSc1sc2c(F)c(F)c(F)cc2c(=O)c1C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
A mixture of 300 mg (0.897 mmol) of the compound of Example 111, 0.54 ml of acetic acid, 0.072 ml of concentrated sulfuric acid and 0.36 ml of water was stirred for 3 hours at 100° C. After cooling by allowing to stand, the crystals deposited were collected by filtration, washed with water, and dried to obtain 147 mg (0.481 mmol) of title compound (yield 54%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1I.[CH3:21][Si:22]([CH3:39])([CH3:38])/[CH:23]=[CH:24]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C.O.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1/[CH:24]=[CH:23]/[Si:22]([CH3:39])([CH3:38])[CH3:21]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1/C=C/[Si](C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Methyl 6-amino-2-(4-chloro-2-fluorophenyl)-5-iodopyrimidine-4-carboxylate (400 mg, 0.981 mmol) and tetrakis(triphenylphosphine)palladium(0) (113 mg, 0.098 mmol) were added to a 20 mL Biotage microwave reaction vessel. The vessel was sealed and purged with nitrogen gas. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (497 mg, 1.276 mmol) in dioxane (4907 μl) was added and the reaction mixture was stirred overnight at 90° C. under nitrogen. The cooled reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto silica. Purification by flash chromatography (SiO2, 0-20% EtOAc:Hex gradient) provided the title compound as a tan solid (0.283 g, 76% yield): 1H NMR (400 MHz, DMSO-d6) d 0.16 (s, 9H), 3.78 (s, 3H), 6.14 (d, J=19.1 Hz, 1H), 6.80 (d, J=19.1 Hz, 1H), 7.21-7.68 (m, 4H), 7.92 (t, J=8.4 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −110.46; ESIMS m/z 380 ([M+H]+), 378 ([M−H]−).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].N1C=CN=C1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClC(Cl)C>[C:11]([Si:14]([CH3:16])([CH3:15])[O:4][CH2:1][C:2]#[CH:3])([CH3:13])([CH3:12])[CH3:10]
Reactant: C#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CC(Cl)Cl
Product: C#CCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To an ice cooled stirred solution of prop-2-yn-1-ol (10.0 g, 178.3 mmol) and imidazole (18.2 mg, 267.5 mmol) in dichloroethane (500 mL), was added TBDMSCl (40.24 g, 267.5 mmol) and stirring continued at 0° C. for 1.5 h. On completion, saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by solvent washings afforded the desired compound (20 g, 67%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]=[C:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20]I>CN(C)C=O>[CH3:20][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[O:3][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1cc2[nH]c3ccccc3c2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(o1)c1ccccc1n2C
Yield: 84.8 %

Procedure:
To a suspension of sodium hydride (2.5 g) in dimethylformamide (100 ml), a solution of ethyl furo[3,2-b]indole-2-carboxylate (20 g) in dimethylformamide (100 ml) was added dropwise with stirring, then the mixture was stirred for 0.5 hour at room temperature. Methyl iodide (30 g) was added, and the resulting mixture was stirred for 5 hours at room temperature to give ethyl 4-methyl-furo[3,2-b]indole-2-carboxylate (18 g), which was hydrolyzed in a solution of sodium hydroxide (20 g) in water (200 ml) with stirring for an hour to give 4-methyl-furo[3,2-b]indole-2-carboxylic acid (15 g). This carboxylic acid was treated with thionyl chloride (50 ml) in benzene (70 ml) with stirring for an hour at 50° C. to give 4-methyl-furo[3,2-b]indole-2-carbonyl chloride (12 g).
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH:17]O.[OH-].[Na+]>CS(C)=O>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:14])=[O:17])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=3)[CH2:2][CH:3]([CH2:5]1)[CH2:4]2
Reactant: CSc1ncc(C#N)c(NC23CC(C2)C3)n1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)-pyrimidine-5-carbonitrile (3.45 g, 14.9 mmol) in DMSO (15 mL) was added aqueous hydrogen peroxide solution (8.4 g, 30%, 74.5 mmol) and aqueous sodium hydroxide solution (12.4 mL, 6 mol/L, 74.5 mmol) at 0° C. The mixture was stirred at 50° C. for 15 min and then quenched by the addition of water (30 mL). The solid formed was collected and dried under vacuum to give the desired product (3.5 g, 14.0 mmol, 94% yield). MS (ESI)/m/z=251.2 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]([OH:20])[C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].[NH2:21][CH2:22][C:23]([OH:25])=[O:24].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:18]([OH:19])[C@H:16]([C@H:14]([C@@H:12]([C@@H:10]([CH2:9][OH:20])[OH:11])[OH:13])[OH:15])[OH:17].[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:21][CH2:22][C:23]([OH:25])=[O:24].[NH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CC(C)[C@H](N)C(=O)O
Agent: NCC(=O)O
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Mannitol-valine-glycine-glycine (mannitol-VGG) was prepared, isolated and analyzed as described in Example 1 for glucitol-VGG, except that mannose (Sigma Chemical Co., St. Louis, Mo. or Wako Pure Chemical Industries Ltd.) was used instead of glucose. The analyses indicated that the final purified material was mannitol-VGG.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:15])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: NCCCO
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)NCCCO
Temperature: 25 °C

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (100 mg, 0.338 mmol) was dissolved in DMF (5 mL). 3-aminopropan-1-ol (1.691 mmol, 5 equiv.) and DIPEA (1.353 mmol, 4 equiv.) were added to the reaction mixture and stirred at room temperature. HATU (1.014 mmol, 3 equiv.) was added to the reaction mixture and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash column chromatography through silica gel and MeOH:CHCl3 as eluent to afford the title compound, 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide (31).