Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:6][C:16]1[CH:17]=[C:10]([O:9][CH3:8])[C:11]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:26]([CH3:28])[CH3:27])=[CH:12][C:13]=1[CH:14]=[O:15]
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Br)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 10.9 g of sodium hydrogen carbonate and 2.32 ml of bromine to a solution of 10g of 4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 200 ml of chloroform at 0° C., the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium sulfite was then added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (11.7 g) as a light yellow oil.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6])C.[CH2:18](N)[CH2:19][NH2:20]>C(O)C>[NH:20]1[CH2:19][CH2:18][N:6]=[C:5]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(C(=O)OCC)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C2=NCCN2)cc1

Procedure:
2.96 g (11.5 mmol) of ethyl 4-ethoxycarbonimidoylbenzoate hydrochloride and 690 mg (11.5 mmol) of ethylenediamine were stirred in 100 ml of ethanol at 60° C. for 4 hours. The solvent was evaporated. 1 N aqueous sodium hydroxide solution was added to the residue. After the extraction with dichloromethane followed by the washing with saturated Aqueous NaCl solution and drying over anhydrous magnesium sulfate, the solvent was evaporated to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[C:12](=O)[N:13]([C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]=O)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)=[O:32])=[CH:26][CH:25]=1)C)(C)(C)C>>[CH3:12][NH:13][C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Reactant: C1COCCN1
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN3CCOCC3)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from morpholine and (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester by the same techniques as in Example 168.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cc(-c2ccccc2)on1
Yield: 58 %

Procedure:
3-Hydroxymethyl-5-phenylisoxazole (2.10 g, 12 mmol) was refluxed with triphenylphosphine (3.14 g, 12 mmol) in carbon tetrachloride (40 ml) overnight. After cooling the solvent was removed under reduced pressure and the residue taken up in ether, the solution filtered and concentrated to give an oil. This material was filtered through a plug of silicagel (5 g, ether-hexane 1:1) to remove triphenylphosphine oxide then crystallised to give the title compound (1.33 g, 6.9 mmol, 58%); m.p. 48°-9° C.; νmax (CHCl3) 3000, 1610, 1590, 1570, 1450, 1265, 945, 690 cm-1 ; δH (CDCl3) 4.55(2H,s,CH2Cl), 6.55(1H,s,CH-het) 7.2-8.0(5H,m,Ph).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Cl:5][C:6]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:7]=1[O:8][C:9]1[CH:10]=[C:11]([C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[CH2:12][OH:13].S(=O)(=O)(O)O>ClCCCl>[C:2]([O:13][CH2:12][C:11]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:9]([O:8][C:7]2[CH:20]=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:6]=2[Cl:5])[CH:10]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CC(C)(C)OCc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Isobutylene gas was passed into a solution of 17.4 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl alcohol in 100 parts by volume of 1,2-dichloroethane and 0.5 parts by weight of sulfuric acid at 40° C. for two hours. The reaction mixture was then washed with dilute aqueous sodium bicarbonate solution and twice with water, and the organic phase was dried with magnesium sulfate, filtered and concentrated. 18 parts by weight (89% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl tert.-butyl ether (compound No. 16) of melting point 75°-78° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][Br:18])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1cc(Br)cc(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 101 %

Procedure:
A mixture of 3-bromo-5-methylbenzonitrile (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 62.7 %

Procedure:
To stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (126 g, 0.59 mol) in DMF (1.0 L) was added sodium carbonate (249 g, 2.34 mol) and methyl iodide (145 mL, 2.34 mol). The reaction mixture was heated at 60° C. for 4 h. On completion, the reaction mixture was filtered and the residue washed with DCM. The aqueous phase was separated and extracted with DCM. The combined organic layers were dried, concentrated under reduced pressure and purified by column chromatography over silica eluting with ethyl acetate:hexane to afford the title compound (85 g, 63%). 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (d, 1H), 8.05 (s, 1H), 3.9 (s, 1H), 2.4 (s, 1H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CO>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:28])[CH2:26][S:1][CH2:2][CH2:3][OH:4])[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCS
Reactant: O=C(CCl)NCCCOc1cc(CN2CCCCC2)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(CSCCO)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
0.12 ml of 2-mercaptoethanol was added to a solution of 0.13 g of 85% potassium hydroxide and 0.50 g of N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-2-chloroacetamide [prepared as described in step (a) above] in 10 ml methanol, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, the concentrate was mixed with water, and the resulting aqueous mixture was extracted with chloroform. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.43 g (yield 77%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[S:32]([CH3:31])(=[O:34])=[O:33])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/S(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in dichloromethane (1.5 mL). Diisopropylethylamine (31 μl, 0.18 mmol, 2 equiv.) was added followed by the methanesulfonyl chloride (0.1 mmol, 1.1 equiv.). The reaction was stirred at room temperature for 4 hours. The reaction mixture was passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess sulfonyl chloride and washed with additional dichloromethane. The resulting solution was dried, concentrated, and purified by reverse phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.24 (3H), 2.90-2.96 (3H), 7.31 (1H), 7.56 (1H), 7.68 (1H), 7.8 (1H); MS (ESI) m/z 398.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N:28]=[C:29]=[S:30]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[Cl:19]
Reactant: COc1ccc(N=C=S)c(Cl)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)cc2Cl)c1NCCCCO
Yield: 45.3 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(4-hydroxybutyl)amino]benzoate (2.00 g, 7.33 mmol) and 2-chloro-1-isothiocyanato-4-methoxybenzene (2.94 g, 14.7 mmol) in tetrahydrofuran (20 mL) was stirred for 36 h at 70° C. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture to give the title compound as a pale yellow oil (1.57 g, 3.32 mmol, 45%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:4][C:3]3[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=3[F:1])=[O:21])[N:19]=2)[CH:16]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1cc(F)ccc1F
Product: O=C(Nc1cc(F)ccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 2,5-difluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH:12](C)[C:13](Cl)=O.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:12]([CH3:13])=[CH:9][C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)=Cc1ccc([N+](=O)[O-])o1
Reaction time: 0.67 h

Procedure:
To a solution of 9 g of 5-nitro-2-furaldehyde and 11.0 g of 2-chloropropionyl chloride in 100 ml of benzene was added dropwise at 25°-30° over a 20-minute period a solution of 10 g of triethylamine in 30 ml of benzene. After an additional 40 minutes, the mixture was stirred at reflux for 1.5 hours. The cooled mixture was washed with water, dried and concentrated under reduced pressure to leave a residue which was distilled to give a liquid product, b.p.: 92°-100° at 0.15 torr. This product was triturated with n-hexane to give 3 as a mixture of stereisomers, a tan solid, m.p.: 55°-65°.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:66]([O:70][C:71]([NH:73][C@H:74]([CH2:77][CH:78]([CH3:80])[CH3:79])[CH2:75]O)=[O:72])([CH3:69])([CH3:68])[CH3:67]>C1C=CC=CC=1>[C:66]([O:70][C:71]([NH:73][C@H:74]([CH2:77][CH:78]([CH3:80])[CH3:79])[CH2:75][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=[O:32])=[CH:33][CH:34]=1)=[O:72])([CH3:68])([CH3:69])[CH3:67]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CC(C)C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 35 %

Procedure:
2.1 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 11] were added to a mixture of 2.28 g of 1,1'-azodicarbonyl-dipiperidine, 3.34 ml of tributylphosphine and 100 ml of anhydrous benzene. The resulting mixture was stirred at room temperature for one and a half hours, after which 2 g of 2(R)-t-butoxycarbonylamino-4-methylpentanol [prepared as described in Preparation 15] were added. The mixture was then stirred for a further five hours at the same temperature. At the end of this time, insolubles were filtered off and the filtrate was concentrated. The resulting residue was then purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 1.05 g of the title compound, having an Rf=0.54 (thin layer chromatography on silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([O:27][CH3:26])=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-[(3-Chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (2.72 g, 7.54 mmol) and 0.5 M sodium methoxide in methanol (40 mL) were heated under nitrogen at 60° C. for 2 days, cooled, evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with brine, dried and solvent evaporated to afford crude material, purified by flash chromatography on silica (gradient 25 to 100% EtOAc hexane) to give the desired compound as a solid. The solid was stirred with approx. (10 ML) 2:1 isopropyl acetate:hexane and filtered to give the title compound as white solid. M.S. (M+1): 357
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:18]3[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[F-].[NH4+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Reaction time: 2 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (4.22 g, 8.88 mmol), and methanol (60 mL). Add ammonium fluoride (1.97 g, 53.3 mmol). Heat to reflux. After 2 hours, cool the reaction mixture and partition between dichloromethane (300 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL). Separate the layers and extract the organic layer three times with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.32 (silica gel, ethyl acetate).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=3[O:11][C:10]=2[CH3:20])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Na+].Cl>O1CCCC1>[CH:1]1([CH:7]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=3[O:11][C:10]=2[CH3:20])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(C(=O)C3CCCCC3)c(C)oc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(C(O)C3CCCCC3)c(C)oc2c1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a mixture of cyclohexyl(6-methoxy-2-methyl-1-benzofuran-3-yl)methanone (1.18 g) synthesized above, methanol (1 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (246 mg) at 0° C., and the mixture was stirred for 30 min. 1N Hydrochloric acid was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (906 mg, 76%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ccc(C(=O)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
(6-Fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (Example 103) (1.5304 g, 6.1387 mmol) was dissolved in DCM (60 mL) and manganese (IV) oxide (Aldrich less than micron, activated, 2.546 g, 29.28 mmol) was added. The reaction was stirred at room temperature for 90 minutes, and then more activated manganese (IV) oxide (2.736 g, 31.47 mmol) was added. The reaction was stirred overnight and then was filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM. The filtrate was concentrated, and dried under high vacuum to give (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanone (1.334 g). 1H NMR (CDCl3, 400 MHz) δ 8.64 (d, J=2.35 Hz, 1H), 8.26 (td, J=8.07 Hz, 2.45 Hz, 1H), 7.75 (d, J=8.61 Hz, 2H), 7.33 (d, J=8.41 Hz, 2H), 7.09 (dd, J=8.41 Hz, 2.54 Hz, 1H), 2.56 (s, 3H). m/z (ESI, pos. ion) 248 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]2)[CH:3]=1.[NH2:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]3)[CH:3]=[C:2]([NH:28][C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
50 mg of ethyl (S)-1-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}-1H-pyrazole-4-carboxylate, 15 mg of 2-aminopyrazine, 12 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 17 mg of sodium t-butoxide and 7 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder.
Reaction SMILES: CO[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1.B(Br)(Br)[Br:19]>C(Cl)Cl.O>[Br:19][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[S:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: COCCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cc2cc(CCBr)ccc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
To a solution of 5-(2-methoxyethyl)-2sulfamoylbenzo[b]thiophene (8.3 g, 0.031 mol) in 550 ml of methylene chloride at -78° C. was added dropwise under nitrogen, 100 ml of a solution of boron tribromide (BBr3) (lM in hexane, 0.1 mol). The reaction was stirred at room temperature overnight (15 hours) following the addition. The mixture was cooled and diluted with 100 ml of cold water. The aqueous phase was separated and extracted 2X with methylene chloride. The original organic phase and the extracts were combined, dried, filtered and concentrated to dryness to yield 8.3 g (86%) of product with m.p. 118°-120° C.