Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[S-:12][C:13]#[N:14].[K+]>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([S:12][C:13]#[N:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: N#C[S-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70.9 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (12 g) was dissolved in AcOH (70 mL) and cooled to 0° C. Potassium thiocyanate (6.31 g) was added portion-wise to the solution over 2 h. The reaction was diluted with water and filtered. The filter cake was washed with cold ether to afford the desired 2-chloro-5-nitro-4-thiocyanatopyrimidine (9.5 g, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[N:26]([CH2:34][CH3:35])[N:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36].O1CCOCC1>ClCCl>[ClH:36].[ClH:36].[C:30]([C:28]1[CH:29]=[C:25]([NH:24][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)=[O:23])[N:26]([CH2:34][CH3:35])[N:27]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: CCn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
4-{4-[3-(5-tert-Butyl 2-ethyl-2H-pyrazol-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (105 mg, 0.216 mmol) is dissolved in dichloromethane (3 mL) and a 4M solution of HCl in 1,4-dioxane (0.86 mL, 3.5 mmol) is added and the mixture stirred at room temperature for 2 hours. After removal of solvent, the residue is triturated with diethyl ether and air-dried to obtain the title compound (99 mg, 99% yield, ES+(m/z) 385 [M+H]).
Reaction SMILES: [C:1]12([NH:12]C(=O)OC(C)(C)C)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([O:4][CH2:5]3)[CH2:2]1)[CH2:9]2.[ClH:20]>O1CCOCC1>[ClH:20].[C:1]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([O:4][CH2:5]3)[CH2:2]1)[CH2:9]2.[ClH:20]
Reactant: CC(C)(C)OC(=O)NC12CC3COC(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC12CC3COC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
The carbamate 16C (0.1 mmol) in 1,4-dioxane (1 mL) was diluted with a solution of 4 N HCl in dioxane (0.5 mL) and the reaction mixture was maintained at rt for 2 h. The reaction mixture was concentrated and the residue was dissolved in water (2 mL). The aqueous layer was washed with EtOAc (3×5 mL) and concentrated to provide amine 16 in 80% yield as a hydrochloric acid salt.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[Br:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[Br:17])=[CH:6][CH:5]=1)([OH:3])[CH3:2])[CH3:24]
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2Br)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Br)cc2Br)cc1

Procedure:
3.44 g. of 4-acetyl-2',4'-dibromobiphenyl and 1.5 g. of ethyl bromoacetate are added to a mixture of 6.5 g. of granulated zinc, previously washed with dilute hydrochloric acid, water and acetone and dried, and 0.2 g. of iodine in 70 ml. of benzene and 70 ml. of diethyl ether. The mixture is heated under reflux for 4 hours with occasional shaking. 5 g. of zinc and a trace of iodine are added after 1, 2 and 3 hours, respectively, and 1.5 g. of ethyl bromoacetate added after 2 hours. After cooling, acetic acid is added to decompose the resulting alcoholate and methanol is added to bring the product into solution. The mixture is poured into water and the organic phase is separated off and worked up to give 3-(2',4'-dibromo-4-biphenylyl)-3-hydroxybutyric acid ethyl ester.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:18][C:19]1[C:5]2[C:3](=[C:2]([I:1])[CH:8]=[C:7]([CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[CH:6]=2)[N:4]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(CC2CCOCC2)cc1I
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Temperature: 130 °C
Yield: 58 %

Procedure:
A mixture of 2-iodo-4-(tetrahydro-2H-pyran-4-ylmethyl)aniline (1.0 g) and diethyl ethoxymethylenemalonate (0.70 mL) is heated at 130° C. for 1 h. The mixture is cooled to room temperature. Diphenyl ether (20 mL) is added and the reaction is heated to 250° C. for 1 h. The mixture is cooled and the resulting solid is collected and washed with hexanes. The crude product is chromatographed (Biotage flash 40M, eluent 2% MeOH/CH2Cl2) to yield 0.80 g (58%) of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH2:47]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH:46]=[CH2:47]
Reactant: C=CCCCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 184 mg (1 mmole) of undecylenic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 172 mg (Yield: 38%) of the title compound having the following structure as a red oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][NH2:15].[CH3:16][S:17]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])=[O:18]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[CH2:14][NH:15][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([NH:20][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2ccccc2)CC1CN
Product: CN1CCN(c2ccccc2)CC1CNC(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to preparation 3, react 1-methyl-4-phenyl-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO.CCCCCC>[CH2:1]([NH:7][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: C=C1CC(=O)O1
Solvent: CO
Solvent: CCCCCC
Product: CCCCCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
A solution of 27.83 g (0.28 mol) N-n-hexylamine was added dropwise to a solution of 20.00 g (0.24) diketene in 100 ml MeOH at 0° C. After stirring for 4 hours at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off, and the obtained solid was taken up in 200 ml n-hexane, filtrated off and dried overnight under vacuum. 22.53 g of product was obtained as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.F[B-](F)(F)F.[CH3:16][O+](C)C>CCOC(C)=O>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:16])[N:7]=2)[CH:3]=1
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a solution of 5-iodo-1H-indazole (500 g, 2.05 mol) in EtOAc (4 L) is added trimethyloxonium tetrafluoroborate (450 g, 3.04 mol). After the resulting white suspension is stirred at room temperature for 2 h, it is concentrated under vacuum. Ice water (1 L) is added to the residue, and it is basified to pH 12 with 10% aqueous NaOH solution. The solids are collected by filtration, and redissolved in DCM (5 L). The insolubles are filtered off and the filtrate is washed with 10% aqueous NaOH solution (2×100 mL). The organic layer is dried over anhydrous Na2SO4, filtered through a short silica gel column, and concentrated. Methyl tert-butyl ether is added to the residue to give a slurry and the product is collected by filtration to give the title compound (360 g, 68.0%). MS (m/z): 259.0 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][NH2:18]>CO>[CH3:17][NH:18][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Solvent: CO
Product: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 100 %

Procedure:
A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (200 mg, 0.890 mmol) in 4 mL of 2M methylamine in MeOH was heated in a sealed tube for 12 h at 80° C. Removal of the solvent under vacuum afforded methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (209 mg, 100%). Mass spectrum (ESI, m/z): Calcd. for C12H17N3O2, 236.1 (M+H), found 236.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[N+:6]([O-])=[N:7][C:8]=1[O:9][CH3:10].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>O>[C:13]([O:16][CH2:12][C:5]1[N:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)[n+]([O-])nc1OC
Solvent: O
Product: COc1cc(COC(C)=O)nnc1OC

Procedure:
A mixture of 5,6-dimethoxy-3-methylpyridazine-2-oxide (0.5 g) in acetic anhydride (2 mL) is refluxed for 2 hours. After cooling the mixture is diluted with water and extracted with ethyl acetate (2×20 mL). The extracts are dried (MgSO4) and evaporated to give a brown oil which is purified by flash chromatography (ethyl acetate as eluent on silica) to give 6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) as a colourless oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Cl)[C:15]#[CH:16]>CS(C)=O>[CH2:16]([S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[C:15]#[CH:14]
Reactant: C#CCCl
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCSc1ccncc1
Temperature: 60 °C
Yield: 40.2 %

Procedure:
In 200 ml dimethyl sulfoxide (DMSO) was dissolved 25.0 g (0.225 mole) 4-mercaptopyridine. To this solution were added 15.5 g (0.112 mole) anhydrous potassium carbonate and 16.5 g (0.25 mole) propargyl chloride. This mixture was heated at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was added to an equal volume of water. This mixture was extracted with ether. After removal of the ether under reduced pressure, there remained 20.0 g crude product. Distillation gave 13.5 g 4-(2-propynylthio)pyridine. Yield 39% theory; b.p. 79°-81° C. (1.0 mm); mp 55°-56° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:21](OCC)(OCC)OCC>C(O)=O>[C:15]1([CH2:14][CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[CH:21]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCc1ccccc1
Solvent: O=CO
Product: c1ccc(CCn2cnc3cnc4ccccc4c32)cc1

Procedure:
Using the method of Example 49, 3-amino-4-[2(phenyl)ethylamino]quinoline was reacted with triethyl orthoformate and formic acid to provide 1-[2-(phenyl)ethyl]-1H-imidazo[4,5-c]quinoline, m.p. 105°-108° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.O>O1CCOCC1.C(=O)([O-])O.[Na+].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>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:40])([F:39])[F:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 78.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzyl)oxy]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 152-1 and 4-(trifluoromethyl)phenylboric acid (621 mg) were dissolved in dioxane (10 mL) and sodium hydrogen carbonate aqueous solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (162 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (900 mg) as a colorless oil.
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:25][C@@H:24]([CH:26]=O)[C:23]([CH3:29])([CH3:28])[CH2:22][O:21]2)=[CH:16][CH:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:29][C:23]1([CH3:28])[CH2:22][O:21][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[O:25][C@H:24]1[CH:26]=[CH2:2]
Reactant: COc1ccc(C2OCC(C)(C)[C@H](C=O)O2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@@H]1OC(c2ccc(OC)cc2)OCC1(C)C
Yield: 81 %

Procedure:
Following the general procedure for the methylenation by Wittig-olefination of Description 8, a phosphorous ylide generated from 73.4 g (205.5 mmol) of methyltriphenylphosphonium bromide and 125.7 mL of 1.6 M n-BuLi in hexane (201.1 mmol) in 440 mL of anhydrous tetrahydrofuran (THF), was reacted with 25.0 g (100.0 mmol) of (4R)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxan-4-carbaldehyde (8b). Aqueous work-up followed by purification using column chromatography with mixtures of diethyl ether (Et2O), ethyl acetate (EtOAc), and hexanes (Hxn) as eluent (Et2O/Hxn=1:25→EtOAc/Hxn=1:9) provided 20.0 g (81% yield) of the title compound (8c) as a yellow liquid. Rf=0.42 (MTBE/Hxn=1:9). 1H NMR (400 MHz, CHCl3): δ=0.81 (s, 3H), 1.15 (s, 3H), 3.65 (d, J=10.8 Hz, 1H), 3.76 (d, J=11.2 Hz, 1H), 3.81 (s, 3H), 4.03 (d, J=6.4 Hz, 1H), 5.23-527 (m, 1H), 5.29-5.35 (m, 1H), 5.50 (s, 1H), 5.86 (ddd, J=17.2, 10.8, 6.4 Hz, 1H), 6.87-6.92 (m, 2H), 7.43-7.48 (m, 2H) ppm. MS (ESI) m/z: 249.1 (M+H)+. The analytical data was consistent with the proposed structure and with the data given in the literature for the compound (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull Chem. Soc. Jpn. 2001, 74, 113-122).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Si:33]([O:40][CH2:41][CH2:42][N:43]([C@H:51]1[C:59]2[C:54](=[C:55]([C:60](=[NH:63])[NH:61]O)[CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C>[Si:33]([O:40][CH2:41][CH2:42][N:43]([C@H:51]1[C:59]2[C:54](=[C:55]([C:60]3[N:63]=[C:16]([C:9]4[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[O:18][N:61]=3)[CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C(=N)NO)cccc21
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Prepared using General Procedure 2. To a solution of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (0.109 g, 0.4 mmol) in DMF (3.0 mL) was added HOBt (0.088 g, 0.57 mmol) and EDC (0.109 g, 0.57 mmol) at room temperature. The reaction mixture was stirred for 0.5 h until the complete formation of the HOBt-acid complex. (R)-tert-butyl 2-(tert-butyldimethyl silyloxy)ethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-61 (0.200 g, 0.44 mmol) was added and the mixture was stirred at room temperature for 0.5 h until the formation of the intermediate (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(N-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)-2,3-dihydro-1H-inden-1-yl) carbamate was observed. The reaction mixture was heated at 85° C. for 4 h. Upon cooling, the mixture was extracted with DCM and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to produce a brown oil. The crude product was purified by silica gel flash chromatography (MeOH/DCM) to yield 0.108 g (40%) of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxa-diazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-63 as a light yellow oil. LCMS-ESI (m/z) calculated for C35H42F3N3O4SSi: 685.9; found 411.0 [M+H−tert-butyl 2-(tert-butyldimethylsilyloxy)ethylcarbamate]+, tR=4.01 min.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[C:21]([CH3:30])=[C:22]([S:26]([NH:16][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[C:14]([CH3:15])[N:13]=2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc(N)ccc1COCc1ccc(F)cc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)ccc1COCc1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 1 from 5-(4-fluoro-benzyloxymethyl)-6-methyl-pyridin-2-ylamine (0.08 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.08 g) as an amorphous light yellow solid (0.067 g). MS (ESI−): 433.1 ([M−H]−)
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([I:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-iodouracil (commercially available from Aldrich, 2 g, 8.4 mmol) in dry pyridine (20 mL) was added dropwise to a solution of benzoyl chloride (3.5 g, 25.3 mmol) in pyridine (10 mL). The mixture was stirred at room temperature for 3 hours. Water (70 mL) was added and the product extracted with ethyl acetate. The organic phase was washed with a saturated solution of NH4Cl and then with 2% HClaq(40 mL×4 times) The solvent was removed under vacuum and the residue was triturated with i-Pr2O to give the title compound as white solid (2.6 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:19]#[N:20])=[C:5]([NH2:18])[C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[NH2:11]>[OH-].[Na+].CCO>[NH2:18][C:5]1[C:4]([C:19]#[N:20])=[C:3]([OH:2])[N:11]=[C:10]2[O:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=12
Reactant: COC(=O)C(C#N)=C(N)c1c(-c2ccccc2)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1c(O)nc2onc(-c3ccccc3)c2c1N
Reaction time: 3 h

Procedure:
0.5 g (1.76 mmole) of 3-amino-2-cyano-3-(5-amino-3-phenyl-isoxazol-4-yl)-acrylic acid methyl ester [compound (3a)] is dissolved in 7 ml of 2 N NaOH and 10 ml of EtOH, and is heated to boiling for 3 hours. Then the undissolved residue is filtered off. Colorless plates are precipitated during cooling off, which are sucked off (removed) and washed with a small amount of MeOH.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:36])([F:35])[CH:25](OS(C(F)(F)F)(=O)=O)[CH3:26]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:25]([CH3:26])[C:24]([F:36])([F:35])[F:23]
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)OC)c1
Temperature: 90 °C

Procedure:
To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester, and the mixture was heated at 90° C. for 16 h. The mixture was then cooled to RT, poured onto water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Under a nitrogen atmosphere, 3,6-dibromocarbazole (9.75 g, 30 mmol) was slowly added to a suspension of sodium hydride (45 mmol) in dried THF (100 mL), and then stirred for 30 minutes at room temperature. Benzylbromide (6.72 g, 40 mmol) was dropped into the reaction mixture to be stirred for 20 hours. After addition of water (about 100 mL), a precipitated solid was filtrated, and the filtrate (residuum of the filtration) was washed with an aqueous sodium hydrogencarbonate solution, and then was dissolved in ethanol. The solution was dried by magnesium sulfate, filtrated and concentrated. The residuum was recrystallized with ethanol to give N-benzyl-3,6-dibromocarbazole as a white solid. The yield was 61%.