Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:6][OH:7].[Si]=[Ti:9]=[Si].O.[NH3:12]>>[S:2](=[O:3])(=[O:1])([OH:5])[OH:4].[OH:6][OH:7].[N:12]#[Ti:9]
Reactant: [Si]=[Ti]=[Si]
Reactant: N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: N#[Ti]

Procedure:
In this embodiment, the first wet etching is performed using a mixed solution of the composition of H2SO4 :H2O2 =5:1 at an etchant temperature of 140° C. for 20 minutes. The amount of the titanium disilicide film of the C49 structure etched off during the first etching by this mixed solution is extremely less than the amount of the titanium disilicide film of the C49 structure etched off during the first etching by the mixed solution of ammonia water and hydrogen peroxide (under this condition, about 1 nm of the film is etched off) (FIG. 5). During the first etching by the mixed solution of sulfuric acid and hydrogen peroxide, the titanium nitride film formed during the first rapid thermal annealing is removed in about 10 minutes. In this embodiment, therefore, the first wet etching is performed for 20 minutes including margin. Since the first wet etching is performed at 140° C., the maintenance of the composition of the mixed solution is required. During the first wet etching, the titanium-excess titanium silicide (Ti5 Si3) film is only little removed. In this embodiment, therefore, the second wet etching is performed using the mixed solution having a composition of NH4OH:H2O2 :H2O=1:1:5 at room temperature for 30 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:35])=O>C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([Cl:35])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
2-(Benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) was dissolved in THF (6.0 ml) and oxalyl chloride (71 μl) and DMF (1 drop) were added at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times and dried to give 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH2:10][O:11][CH2:12][O:13][CH3:14].[H-].[Na+]>CN(C=O)C>[CH3:14][O:13][CH2:12][O:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: COCOCCI
Reactant: O=Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOCCn1ccnc1C=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 79.5 %

Procedure:
In DMF (15 ml), 2-imidazole carboxaldehyde (300 mg) was dissolved. Then, the compound (1.01 g) obtained in Example 92-1 and sodium hydride (137 mg) were added to the solution, and the whole was stirred at room temperature for 5 days. After completion of the reaction, the solvent was distilled off and the residue was then added with chloroform, followed by washing with water and saturated saline solution. The resultant was dried with anhydrous sodium sulfate, and the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (457 mg) as a yellow viscous liquid.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[C:9]([I+]C1C=CC=CC=1)#[CH:10].[C:18]([O-:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>C(Cl)Cl.O>[C:18]([O:26][C:9]#[CH:10])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#C[I+]c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#COC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
Ethynyl(phenyl)iodonium trifluoromethanesulfonate (3.78 grams, 10 millimoles) dissolved in 10 milliliters of methylene chloride was mixed with sodium benzoate (7.2 grams, 50 millimoles) dissolved in 20 milliliters of water. The reactants were stirred for 5 minutes at 0° C. The organic layer was concentrated by evaporation and chromatographed on silica gel columns to isolate 0.77 grams of ethynyl benzoate (53% yield). The product was identified by spectroscopic means, and had a melting point of 43° C.(dec).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:32]([CH:33]=O)=[N:31][C:30]2[NH:29][C:28](=[O:35])[CH2:27][S:26][C:25]=2[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Cl:22][C:23]1[C:32]([CH2:33][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)=[N:31][C:30]2[NH:29][C:28](=[O:35])[CH2:27][S:26][C:25]=2[CH:24]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1nc2c(cc1Cl)SCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1CSc2cc(Cl)c(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 10 mL of a chloroform solution containing 325 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 234 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 64 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 367 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=100:1] to give 478 mg of 1-(2-(4-((7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH2:22][CH2:23][O:24][CH2:25][C:26]([NH2:28])=[NH:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:28][C:26](=[NH:27])[CH2:25][O:24][CH2:23][CH2:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[F:14])=[O:6]
Reactant: CCc1cnc(Cl)c(C(=O)O)c1
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(Cl)c(C(=O)NC(=N)COCCc2cc(F)ccc2F)c1

Procedure:
In analogy to the procedure described in example 78.3, 2-chloro-5-ethyl-nicotinic acid was reacted with 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (example 78.2) in the presence of TBTU and DIPEA to give 2-chloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-5-ethyl-nicotinamide as yellow oil. MS: m/e=382.3 [M+H+].
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[N:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:8]([NH:7][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[N:25]=[CH:26][C:27]([C:30]([NH2:31])=[O:32])=[N:28][CH:29]=2)=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2cnc(C(N)=O)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Oc2ccc(CNCCc3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
Dissolve [4-(5-carbamoylpyrazin-2-yloxy)benzyl]phenethylcarbamic acid tert-butyl ester (0.015 g, 0.0334 mmol) in dichloromethane (1 mL). Add TFA (1 mL). Stir at room temperature for 6 hours. Load directly onto an SCX (5 g) column. Wash the column with methanol thien elute with 2.0 M NH3 in methanol to give the title compound (11.5 mg, 98%): MS ES+ 348.9 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.4 min, 98.4 purity.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH3:15])=[O:12])=[CH:10][C:2]=2[Cl:1])=[O:5])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)c2ccc(C(=O)NC(C)c3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-acetylpiperazine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.99 minutes; C23H23Cl2N5O3 (488.37); mass spectrum: (M−H)−=487/489/491 (chlorine isotope).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:26]([C:24]3[CH:25]=[N:21][NH:22][CH:23]=3)=[O:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: NCCCCCOc1cc(CN2CCCCC2)ccn1
Product: O=C(NCCCCCOc1cc(CN2CCCCC2)ccn1)c1cn[nH]c1

Procedure:
Following a procedure similar to that described in Example 64, but using 5-(4-piperidinomethyl-2-pyridyloxy)pentylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 105°-106° C., in a yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: Fc1ccc(N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.31 g=0.28 ml) of 4-chlorostyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetatein-hexane gives the product 1-(4-fluorophenyl)-4-[2-(4-chlorophenyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.547 ml, 4.6 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 155 (1.5 g, 4.6 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.5 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 9:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1oc(-c2ccc(OCc3cccnc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 57 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) and 3-(bromomethyl)pyridine hydrobromide. MS (m/e): 378.3 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: CO
Reactant: Cc1cccc(Nc2ccccc2C(=O)O)c1C
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1cccc(C)c1C
Yield: 86 %

Procedure:
A suspension of 2-[(2,3-dimethylphenyl) amino]benzoic acid (mefenamic acid) 35 g, 145 mmol) in methanol (600 ml) and concentrated sulfuric acid (15 ml) is heated at reflux for two days. The reaction mixture is cooled in an ice bath. The resulting solid is collected by filtration and recrystallized from methanol to give 2-[(2,3-dimethylphenyl)amino]benzoic acid, methyl ester (32.0 g, 86%); mp 98°-100° C.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](O)([C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=1)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:11]1[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccc3ccccc3c1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Yield: 100 %

Procedure:
3-Hydroxy-3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.80 g, 19.3 mmol) and 10 mL TFA are stirred at 23° C. in 80 mL of CH2Cl2 for 2.5 h. The volatiles are removed and the residue partitioned between 100 mL of saturated NaHCO3 and 100 mL EtOAc. The aqueous layer is extracted with 2×50 mL EtOAc, and the combined organics are washed with 3×50 mL H2O, 1×50 mL brine, dried over MgSO4, filtered, and stripped to give 4.50 g (19.1 mmol, a 100% yield) of the title compound as a white solid. MS (ES) m/z (relative intensity): 236 (M++H, 100).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:8]([F:16])=[C:9]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:10]=[O:11])(C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C)C=O>[F:16][C:8]1[C:7]([OH:6])=[CH:14][CH:13]=[C:12]([F:15])[C:9]=1[CH:10]=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c(F)ccc(O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-(tert-butyl-dimethyl-silanyloxy)-2,6-difluoro-benzaldehyde (37, 3.50 g, 12.9 mmol) in N,N-dimethylformamide (50 mL) was added tetrabutylammonium fluoride trihydrate (4.40 g, 14.0 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 38 that was used in the next step.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH3:10][C:11]1[CH:12]=[C:13]([C:17](=O)[CH3:18])[CH:14]=[CH:15][CH:16]=1.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)(=O)C.O>[CH3:10][C:11]1[CH:12]=[C:13]([C:17](=[C:21]([C:20]#[N:24])[C:22]#[N:23])[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: N#CCC#N
Reactant: CC(=O)c1cccc(C)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1cccc(C)c1
Temperature: 70 °C
Yield: 106.4 %

Procedure:
To a stirred solution of acetic acid (10 mL) was added dropwise hexamethyldisilazane (3.89 mL, 18.65 mmol) over ca. 30 min with the temperature kept below 40° C. throughout the addition. This resulting solution was subsequently added to a stirred solution of 1-(3-methylphenyl)ethanone (2.03 mL, 14.91 mmol) and malononitrile (1.88 mL, 29.8 mmol) in acetic acid (10 mL) and the mixture heated to 70° C. under nitrogen overnight. The reaction mixture was then cooled to RT, diluted with water (ca. 50 mL) and extracted with toluene (ca. 50 mL×2). The combined organic layer was passed through a phase separator and the solvent concentrated in vacuo, to give the title compound (2.89 g) which was used in next step without further purification. LCMS (A) m/z: 181 [M−1]−, Rt 1.23 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N)c(N)c1

Procedure:
Alternate synthesis of a substituted 2-aminobenzimidazole. A mixture of 5-fluoro-2-nitro-phenylamine (1 mmol), an amine (2 mmol) in THF (20 mL) is heated at about 60° C. overnight. After cooling the mixture to room temperature, the reaction mixture is concentrated. The crude material is purified on a silica gel column to yield a 5-amino-2-nitro-phenylamine. The 5-amino-2-nitro-phenylamine (1.0 mmol) is dissolved in an ethyl acetate-methanol mixture (about 1:1, 10 mL) in a round-bottom flask. To this solution Pd—C is added, and the mixture is stirred under a hydrogen atmosphere, while monitoring the reaction with thin-layer chromatography (TLC). After TLC shows completion of the reaction, the solution is filtered on celite and then washed with methanol and concentrated to obtain a 4-amino-benzene-1,2-diamine. The 4-amino-benzene-1,2-diamine (1 mmol) is dissolved in ethanol and CNBr (1.5 mmol) is added. The resulting dark brown solution is heated at 60° C. for 30 minutes. Thereafter, the mixture is cooled to room temperature, and the solvent is evaporated. Then, the mixture is co-evaporated with toluene about two times to obtain a 5-amino-1H-benzoimidazol-2-ylamine as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:29]=[CH:28][C:20]4[C:21](=[O:27])[N:22]([CH3:26])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:13]=[C:12]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33]C)[CH:11]=2)=[N:4]1)[CH3:2].C[Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:29]=[CH:28][C:20]4[C:21](=[O:27])[N:22]([CH3:26])[CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:13]=[C:12]([O:30][C@@H:31]([CH3:35])[CH2:32][OH:33])[CH:11]=2)=[N:4]1)[CH3:2]
Reactant: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3)OCCN(C)C4=O)cc(O[C@@H](C)COC)c2)n1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3)OCCN(C)C4=O)cc(O[C@@H](C)CO)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.6 %

Procedure:
A solution of N-(1-ethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzamide (125 mg, 0.25 mmol) in acetonitrile (5 mL) was treated with trimethylsilyl iodide (0.178 mL) drop wise and stirred at RT under argon for 2.5 hours. Aqueous sodium thiosulphate solution (30 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated to give a yellow oil. Purification was carried out by column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired compound as a pale yellow foam (50 mg).
Reaction SMILES: Cl.[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.[N:15]([C@H:18]([C@H:28]1[CH2:30][O:29]1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N+:16]=[N-:17]>CC(O)C>[N:15]([C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C@H:28]([OH:29])[CH2:30][NH:5][CH2:4][C:3]([F:2])([CH3:7])[CH3:6])=[N+:16]=[N-:17]
Reactant: CC(C)(F)CN
Reactant: COc1ccc(C[C@H](N=[N+]=[N-])[C@H]2CO2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@H](N=[N+]=[N-])[C@H](O)CNCC(C)(C)F)cc1
Temperature: 60 °C
Yield: 50 %

Procedure:
To a solution of 2-fluoro-2-methylpropan-1-amine-HCl (2.0 eq) and triethyl amine (4.0 eq) in iPrOH was added an iPrOH solution of (S)-2-((S)-1-azido-2-(4-methoxyphenyl)ethyl)oxirane. The mixture was heated at 60° C. for 6 h. Upon completion the reaction mixture was concentrated then dissolved in ethyl acetate and washed with H2O. The organic layer was combined washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography. 50% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.4 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.80 (s, 3H), 3.64-3.57 (m, 2H), 2.96-2.88 (m, 2H), 2.78-2.68 (m, 4H), 1.42 (d, J=3.1 Hz, 3H), 1.37 (d, J=3.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:23][N:24]=[C:25]=[S:26]>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:25](=[S:26])[NH:24][CH3:23])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2c2c1ncn2CCC1CCNCC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)N1CCC(CCn2cnc3c(N)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A suspension of 0.50 g of 4-amino-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]-quinoline and 0.37 g of methylisothiocyanate in 10 ml of methylene chloride was stirred at room temperature for 1 hour, and then the precipitated crystals were collected by filtration to give 0.56 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless crystals having the melting point of from 216 to 218° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: CC(C)Oc1cccc(CC2NC(=O)OC2c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-[3-(isopropyloxy)benzyl]-1,3-oxazolidin-2-one (5.85 g, 17.8 mmol) in ethanol (30 ml) was added 8N aqueous sodium hydroxide solution (8.9 ml, 71.0 mmol), and the mixture was heated under reflux for 5 hrs. The reaction solution-was concentrated under reduced pressure. To the solution was added water (100 ml) and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane-diethyl ether to give the objective substance (5.0 g, 93%).