Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([CH3:12])=[N:5]1)[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:3][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:13])=[O:10])[C:6]([CH3:12])=[N:5]1)[CH3:1]
Reactant: Cc1nn(C(C)C)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cn(C(C)C)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 11.9 mmol) in benzene (15.9 mL) and methanol (7.93 mL) at room temperature was added 2M trimethylsilyldiazomethane (23.8 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotary evaporator to yield the title compound (2.17 g, 111.89 mmol, 100% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1oncc1C(=O)O
Solvent: Cc1ccccc1
Product: Cc1oncc1C(=O)Cl
Temperature: 80 °C

Procedure:
127.1 g (1.0 mol) of 5-methylisoxazole-4-carboxylic acid are initially introduced into 1 l of toluene, 129.8 g (1.1 mol) of thionyl chloride are added dropwise and the mixture is then heated at 80° C. for 6 h. The volume is concentrated under reduced pressure to approximately one half and the toluene solution is used directly for further reactions.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[N:8]=1)=O.O.[NH2:23][NH2:24]>C(O)C>[CH3:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:5]3[C:4]([CH2:17][CH2:18][CH3:19])=[C:3]([S:2][CH3:1])[NH:24][N:23]=3)=[N:8][C:9]=2[CH:15]=1
Reactant: CCCC(C(=O)c1nc2cc(C)ccc2[nH]1)=C(SC)SC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCc1c(-c2nc3cc(C)ccc3[nH]2)n[nH]c1SC

Procedure:
A mixture of 2-(bis-methylsulfanyl-methylene)-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one [˜0.49 mmole, Reference Example 2(l)] and hydrazine hydrate (200 μL) in ethanol (6 mL) was heated at reflux temperature for 2 days, then evaporated. The mixture was then treated with hydrochloric acid (4 mL, 4N) and heating was continued at reflux temperature for a further 24 hours. The reaction mixture was cooled, then neutralised by addition of sodium hydroxide solution (4N) and then extracted with dichloromethane. The extract was evaporated to give 5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole. MS: 287 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:2].[CH3:15][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])[CH3:15]
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)c(OC)c1
Reaction time: 1 h

Procedure:
To a mixture of methyl 4-formyl-3-methoxybenzoate (3.30 g) and THF (30 mL) was added dropwise methyl magnesium bromide (3 M diethyl ether solution, 3.60 mL) under ice-cooling. After dropwise addition, the mixture was stirred for 1 hour under ice-cooling. A saturated aqueous ammonium chloride solution was added thereto to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over an aqueous anhydrous sodium sulfate solution. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-(1-hydroxyethyl)-3-methoxybenzoate (1.92 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([CH2:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[N:5][N:4]=[N:3]1.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[NH:28][N:27]=[N:26][CH:25]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][N:2]1[C:6]([S:7]([CH2:9][CH2:10][C:11]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]4[NH:28][N:27]=[N:26][CH:25]=4)[CH2:20][S:21][C@H:16]23)=[O:13])=[O:8])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S(=O)CCC(=O)O
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Product: Cn1nnnc1S(=O)CCC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12

Procedure:
408 mg. of 3-(1-methyl-1H-tetrazol-5-ylsulfinyl)propionic acid and 7-amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 120 mg. of 7-[3-(1-methyl-1H-tetrazol-5-ylsulfinyl)propionamido]-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccccc4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.17 mmol), aniline (16 mg, 0.17 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (33 mg, 0.17 mmol) and DMF (20 drops) were suspended in dry DCM (5 ml) and stirred at room temperature under nitrogen for 4 h. The mixture was absorbed onto an SPE (silica, 10 g), eluted with DCM and then with a DCM/ethanol/ammonia gradient (250:8:1 to 100:8:1). The solvent was evaporated from the product fractions under vacuum to yield 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-phenyl-1,1′-biphenyl-4-carboxamide as a white solid (32 mg, 51%). NMR; δH [2H6]—DMSO 10.34,(1H, b), 8.06,(2H, d), 7.91,(1H, dd), 7.80,(3H, m), 7.57,(3H, m), 7.36,(2H, t), 7.11,(1H, t), 2.57,(3H, s), 2.34,(3H, s). LCMS; retention time 3.39 min, MH+ 370.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-cyano-p-toluenesulfonanilide (1153 g (4.23 mol) in acetic anhydride (2306 ml), fuming nitric acid (294.3 g (4.53 mol) was added dropwise, keeping the temperature at 50° C. with stirring, over a period of 100 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 1.5 hours. Then, 1.75 ml (0.042 mol) of fuming nitric acid was further added and stirring was continued for another one hour at 50° C. To the resulting mixture, after being left to cool to room temperature, water (7000 ml) was then added to make crystals to deposite. After stirring under cooling with ice for one hour, the crystals were filtered and washed with water to give 1305 g (97%) of 4′-cyano-2′-nitro-p-toluenesulfonanilide as yellow crystals.
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]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][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)CCC(c1ccc(F)cc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1

Procedure:
2-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 720 mg of 2-(2,4-difluorophenyl)chroman-6ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.0, 3.0 Hz), 7.61 (m, 1H), 7.31 (m, 1H), 7.21 (d, 1H, 9.0 Hz), 7.17 (m, 1H), 7.02 (d, 1H, J 2.9 Hz), 6.97 (dd, 1H, J 8.9, 2.9 Hz), 6.91 (d, 1H, 8.9 Hz), 5.34 (dd, 1H, J 9.9, 2.0 Hz), 3.03 (m, 1H), 2.78 (m, 1H), 2.17 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]2[C:9]([O-:11])=[O:10])[CH2:3]1.[Na+].Cl>>[O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:7]2[C:9]([OH:11])=[O:10])[CH2:3]1
Reactant: Cc1ccc(OC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(OC2=C(C(=O)O)N3C(=O)CC3S2)cc1
Yield: 48.2 %

Procedure:
An aqueous solution of 32 mg of sodium 7-oxo-3-(4-tolyloxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate was acidified to pH 2.0 with dilute hydrochloric acid, and was then extracted with ethyl acetate. The organic layer was backwashed with water, and then dried and evaporated in vacuo to afford 14.3 mg of the above acid as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:31][CH:32]([CH3:34])[CH3:33])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]3[N:9]=[C:10]4[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]4)=[CH:6][CH:7]=3)[CH2:29][CH2:30]2)[CH:24]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CC(C)Oc1ccc(Cl)cc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(Cl)cc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.241 g, 1.02 mmol, 1 eq) and 1-(5-chloro-2-isopropoxy-phenyl)-piperazine (0.382 g, 1.13 mmol, 1.1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.583 g, 2.75 mmol, 2.67 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (100% EtOAc) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.219 g, 25%). MS: APCI: M+1: 473.2 (Exact Mass: 472.22).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[C:19]([NH2:23])=[N:20][CH:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:31])C(=O)C1.O>CN(C=O)C>[I:31][C:22]1[C:17]2[S:16][CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)[C:18]=2[C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of Example 10A (1.69 g, 5.3 mmol) in DMF (20 mL) was treated with NIS (1.26 g, 5.6 mmol), stirred at room temperature for 3 hours, poured into water, and filtered. The filter cake was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide 1.64 g (70% yield) of the desired product. MS (ESI(+)) m/e 444.8 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]([CH3:9])([OH:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[H-].[Na+].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1.CC(OC)(C)C>[CH:2]([C:4]([O:8][C:14](=[O:15])[N:13]([CH3:17])[CH3:12])([CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:1]
Reactant: CC(C)C(C)(O)C(C)C
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)C(C)(OC(=O)N(C)C)C(C)C
Temperature: 100 °C
Reaction time: 19 h
Yield: 61 %

Procedure:
A solution of 2,3,4-Trimethyl-pentan-3-ol (13.0 g, 100 mmol, 1 equiv.) in toluene (50 ml) was added to a suspension of NaH (55% in mineral oil, 4.80 g, 110 mmol, 1.1 equiv.) in toluene (50 ml). The mixture was heated to 100° C. for 1 h, then cooled to 0° C. A solution of dimethyl carbamoyl chloride (12.9 g, 120 mmol, 1.2 equiv.) in toluene (30 ml) was added over 45 min. The resulting suspension was stirred at room temperature for 19 h, then diluted with MTBE and worked up as describe in Example 1. Distillation of the crude at 0.05 mbar/52-61° C. yielded 61% of product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].CO.[CH3:19][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[CH3:19][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 95 %

Procedure:
A 250 ml three-necked conical flask equipped with a nitrogen inlet and a stirrer was purged with nitrogen, and was added with 2,4-dinitrophenylacetic acid (2.26 g, 0.01 mole), methanol (20 ml) and toluene (83 ml). Stirring was conducted at room temperature until 2,4-dinitrophenylacetic acid was dissolved. Trimethylsilyldiazomethane (8.3 ml) was then added, and reaction was conducted for 3 hours at room temperature. Solvent was removed by distilling under a reduced pressure and by drying at 70° C. to obtain 2,4-dinitrophenylacetic acid methyl ester (2.28 g, yield: 95%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:32]3[N:31]=[CH:30][N:29]=[C:27]([OH:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1.CCN(C(C)C)C(C)C>C1COCC1>[N:40]1([O:28][C:27]2[C:26]3[N:25]=[CH:24][N:23]([C:32]=3[N:31]=[CH:30][N:29]=2)[C@@H:11]2[O:12][C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.1 %

Procedure:
In a 50 mL round-bottomed flask equipped with a stirring bar were placed 3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (22) (1.005 g, 2.090 mmol) and BOP (1.850 g, 4.181 mmol). THF (20 mL) and DIPEA (0.55 mL, 3.135 mmol) were added and the mixture was allowed stir at room temperature for 23 h. The mixture was evaporated and CH2Cl2 (50 mL) added. The mixture was washed with water, dried over Na2SO4 and concentrated. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 1.038 g (83% yield) of compound 26 as a white foam. Rf (20% EtOAc in hexanes)=0.14. 1H NMR (500 MHz, CDCl3): δ 8.54 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 8.14 (d, 1H, Ar—H, J=8.3), 7.55-7.41 (m, 3H, Ar—H), 6.55 (t, 1H, H-1′, J=6.1), 4.65 (m, 1H, H-3′), 4.06 (q, 1H, H-4′, J=3.1), 3.92 (dd, 1H, H-5′, J=11.2, 3.9), 3.80 (dd, 1H, H-5′, J=11.2, 2.7), 2.65 (app quint, 1H, H-2′, Japp˜6.3), 2.52 (m, 1H, H-2′), 0.93, 0.92 (2 s, 18H, tert-Bu), 0.11 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 159.0, 153.6, 151.3, 143.5, 128.9, 128.7, 124.8, 120.6, 120.0, 108.6, 88.2, 85.0, 71.6, 62.6, 41.7, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C28H44N7O4Si2 (M++H) 598.2993. found 598.2986.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A solution of 2-bromo-1-(2,4-difluorophenyl)ethanone (5.0 g, 21.3 mmol) and potassium thiocyanate (2.07 g, 21.3 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture. A crystal was collected by filtration and washed with 50% aqueous ethanol to give 3.39 g (74.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[C:6]([N:10]=[N:11][C:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7].O>CCCCC>[C:6]([N:10]=[N:11][C:12]1([NH:18][C:19]([O:3][CH2:1][CH3:2])=[S:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Product: CCOC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 50 ml of ethanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The next morning the reaction mixture was poured into 200 ml water and the product extracted with 50 ml pentane. The pentane extract was washed twice with water, once with 10% NaHCO3, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a mushy solid. The solid was slurried in a small amount of cold pentane and filtered. The solids were air dried and weighed 7.1 grams (52% crude yield) and melted at 57°-62° C. The product had a strong broad band at 1515 cm-1 and a sharp NH band at 3300 cm-1 in its infrared spectrum.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 32.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added N-methyl piperazine (0.122 mL, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (72 mg, 32%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.25 (m, 2H), 3.88 (s, 3H), 2.50-2.25 (m, 10H), 2.15 (s, 3H), 1.95 (m, 2H), 1.23 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2S[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:4])([CH3:3])[CH3:2].[S:20]([O-:25])(O[O-])(=O)=[O:21].[K+].[K+].C([O-])(=O)C.[Na+].C(O)(C)(C)C>O>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:20](=[O:25])(=[O:21])[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc2c(c1)Oc1ccccc1S2
Reactant: O=S(=O)([O-])O[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 1.05 gm (3.85 mmole) of 3-tert-butoxyphenoxathiin, 3.53 gm (11.5 mmole) of potassium peroxymonosulfate compound [OXONE™] (Dupont), 1.14 gm (14 mmole) of sodium acetate, 20 mL of water, and 20 mL of tert-butanol was stirred overnight. The reaction was diluted with 50 mL of water and extracted with 3×75 mL of chloroform. The combined organic layers were then washed with 2×100 mL of water and concentrated in vacuo (water pump). The residue was then chromatographed on silica gel using methylene chloride to yield 0.89 gm of 3-tert-butoxyphenoxathiin 10,10-dioxide, m.p. 108-110°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([S:16]([N:19]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1F)#[N:8].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([I:40])[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:14]2[CH:13]=[CH:12][C:11]([S:16]([N:19]([C:27]3[N:28]=[CH:29][S:30][CH:31]=3)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:17])=[CH:10][C:9]=2[C:7]#[N:8])=[C:35]([I:40])[CH:34]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Reactant: Oc1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2I)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a suspension of potassium carbonate (0.0549 g, 0.000397 mol) in N,N-dimethylformamide (3.0 mL) was added tert-butyl [(3-cyano-4-fluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 250, 0.1004 g, 0.000167 mol) and stirred at room temperature under nitrogen for 10 minutes. 4-chloro-2-iodophenol (0.067 g, 0.000263 mol) was added and stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed saturated aqueous sodium chloride solution (2×10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil, 162 mg, 100% yield.