Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[C:4]([CH2:3][NH:2][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)#[N:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride in 200 ml chloroform, 20.2 g (0.2 moles) triethylamine were added at once. After stirring one hour, 18.6 g (0.1 mole) p-nitrobenzoyl chloride were added in portions over about 15 minutes. The reaction mixture was stirred about 11/2 hours. Ice water, 100 ml, was added, resulting in separation of solids. The reaction mixture was allowed to stand in an ice bath for 30 minutes and then was filtered. The solids were air dried, washed with 200 ml water and then filtered to give yellow solids. The solids were dried in a vacuum oven at 50° C. until constant weight was attained, yielding 18.0 g of the above-identified product as a light yellow solid, melting point 147° C. to 149° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][O:7]1)=[O:6]>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][O:7][C:5]2=[O:6])=[CH:10][CH:11]=1)([O-:4])=[O:2]
Reactant: O=C1OCc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OCc2ccc([N+](=O)[O-])cc21

Procedure:
Three portions of a mixture of concentrated nitric acid (0.6 ml. each portion) and concentrated sulfuric acid (0.66 ml. each portion) were added to a mixture of 3-(2,4-bis(dimethylamino)phenyl)-3-(4-dimethylamino)phenyl)phthalide (4.17 g.) and concentrated sulfuric acid (20 ml.) with cooling. After each addition the temperature was allowed to rise to room temperature. The resulting mixture was poured onto ice and the resulting mixture was basified, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)5 or 6-nitrophthalide (I: X= Y 4 = (CH3)2N, Y 2 = Z4 = Z7 = H, Z5 or Z6 = O2N and the other of Z5 or Z6 = H) or a mixture of both.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]2[N:7]=[C:8]([NH:11][C@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13]3)[O:9][CH2:10][C:5]=2[CH:4]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>O1CCCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:22]=[CH:21][C:6]3[N:7]=[C:8]([NH:11][C@H:12]4[C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH2:14][CH2:13]4)[O:9][CH2:10][C:5]=3[CH:4]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (example 129) (200 mg, 0.68 mmol) and triethylamine (76 mg, 0.75 mmol) in tetrahydrofuran (4 ml) was added 4-fluorobenzoyl chloride (119 mg, 0.75 mmol) and the mixture was allowed to stir at 0° C. for 1 h and afterwards at room temperature for 16 h. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as white foam (191 mg, 67%). MS (ISP): m/e=416.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:19]([O-:21])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2ccccc2)CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 1-methyl-4-phenylpiperidine (2.663 g, 15.19 mmol) was added carefully H2SO4 (15.2 ml). The reaction was cooled in an ice bath and a solution of H2SO4 (1.66 ml) and fuming HNO3 (0.67 ml, 15.95 mmol) was added dropwise over 45 min. The mix was stirred at 0° C. for 3 h then at RT for 1.5 h before being poured over about 90 g ice and basified with 24 g solid NaOH. The mix was extracted with CH2Cl2. The organic layer was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The crude was eluted on a silica gel column with a MeOH/CH2Cl2 gradient to yield 1-methyl-4-(4-nitrophenyl)piperidine which was hydrogenated under H2 to furnish the title compound.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[NH:10][N:9]=[C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([NH:18][CH3:19])=[O:17])[CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:19][NH:18][C:16]([C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[CH:7]=[C:6]([NH:5][C:34](=[O:35])[C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:39][CH:38]=3)[NH:10][N:9]=2)[CH:22]=[CH:21][CH:20]=1)=[O:17]
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cc1
Reactant: CNC(=O)c1cccc(CCc2cc(N)[nH]n2)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CNC(=O)c1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(C)CC4)cc3)[nH]n2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
A 2M solution of trimethylaluminium (0.936 mL, 1.87 mmol) in toluene, was added drop-wise to a stirred suspension of 3-(2-(5-amino-1H-pyrazol-3-yl)ethyl)-N-methylbenzamide (0.183 g, 0.75 mmol) and methyl 4-(4-methylpiperazin-1-yl)benzoate (0.176 g, 0.75 mmol) in toluene (5 mL) at room temperature. The solution was then stirred at 60° C. for 18 h. The reaction mixture was cooled, poured into methanol (5 ml) and acidified with 2N HCl (15 ml). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford an oil. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.109 g, 32.6%) as a white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[Cl:13]>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[Cl:13]
Reactant: Clc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
Sodium cyanide (10.91 g, 222.52 mmol) in water (10 mL) was added to a solution of chloroform (20 mL) of N-benzyl-N,N-diethylethanaminium chloride (25.3 g, 111.26 mmol). 1-Bromo-4-(bromomethyl)-2-chlorobenzene (31.64 g, 111.26 mmol) in chloroform (5 mL) was added dropwisely at room temperature. The mixture was stirred at room temperature for 1 h then heated to 45° C. for additional 2 h. The reaction mixture was cooled, separated into two layers and the organic layer was washed with 0.5 N NaOH then brine. The chloroform layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash Silica chromatography {CombiFlash Companion—Presearch Ltd}, column size=330 g, flow rate=100 mL/min, elution gradient 0 to 100% EtOAc in isohexane over 40 minutes. Pure fractions were evaporated to dryness to afford 2-(4-bromo-3-chlorophenyl)acetonitrile (2.430 g, 9.48%) as a orange/yellow oil which solidified on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC1(C)C(C)(C)OB([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH2:27])O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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:28]1([C:26]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH2:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(Br)cc(-c2ccccn2)c1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: C=C(c1ccccc1)c1cc(C(=O)OC)cc(-c2ccccn2)c1

Procedure:
Methyl 3-bromo-5-(pyridin-2-yl)benzoate (137 mg, 0.47 mmol), 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborolane (162 mg, 0.70 mmol), Pd(PPh3)4 (19 mg, 0.023 mmol) and K2CO3 (195 mg, 1.41 mmol) were taken up in DME (5 mL) and water (1 mL) and heated to about 80° C. overnight. The reaction mixture was combined with water and the product was extracted into EtOAc (3×10 mL). The combined organic extracts were washed with water (1×10 mL), brine (1×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified via automated flash chromatography (silica gel; 0 to 25% EtOAc in hexanes) to afford methyl 3-(1-phenylvinyl)-5-(pyridin-2-yl)benzoate. MS m/z=316 [M+1]+. Calc'd for C21H17NO2: 315.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[CH:4]([NH2:21])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:9]=[CH:8]2.[NH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:26]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.Cl>[NH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[C:26]=1[S:33]([NH:21][CH:4]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[N:9]=[CH:8]2)[C:3]([F:2])([F:22])[F:23])(=[O:35])=[O:34]
Reactant: NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: Nc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Nc1cc(Cl)cc(Cl)c1S(=O)(=O)NC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
A mixture of 60 mg (0.19 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethylamine hydrochloride and 51 mg (0.19 mmol) of 2-amino-4,6-dichlorobenzenesulfonyl chloride in 8 mL of pyridine was stirred at room temperature for 1 hour and then warmed at 65° C. for 4 hours. The mixture was cooled to room temperature and diluted with 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was first purified by Combiflash chromatography using EtOAc-hexanes (0-60% gradient) and then by preparative TLC using EtOAc-hexanes (2:8) to provide 20 mg (17%) of the title compound as a colorless foam. MS m/z 534 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([CH:9]=O)[CH2:8][O:7][CH2:6]1)[CH3:4].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]#[N:36])=[C:16]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][N:21]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20](=[O:34])[CH:19]=2)[CH:17]=1>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]#[N:36])=[C:16]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][N:21]([C:26](=[CH:9][C:5]3([CH2:3][CH3:4])[CH2:6][O:7][CH2:8]3)[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C:20](=[O:34])[CH:19]=2)[CH:17]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCC1(C=O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C=C(C(=O)OC(C)(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)COC1
Reaction time: 0.25 h

Procedure:
38.4 mg (1.60 mmol, 2 eq., 60% in mineral oil) of sodium hydride and 457 mg (4.00 mmol) of 3-ethyloxetane-3-carbaldehyde in 1 ml of dimethylformamide were added in succession to a solution of 300 mg (800 μmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 8 ml of dimethylformamide. After 15 min at RT, the reaction was terminated by addition of 10 ml of saturated aqueous ammonium chloride solution and the reaction mixture was then extracted three times with 20 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (24 g cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 320 mg (82% of theory)
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20](=[O:36])[CH2:19][C:18]=2[CH2:37][C:38]2[O:42][C:41]([C:43]([O:45]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:44])=[CH:40][CH:39]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:43]([C:41]1[O:42][C:38]([CH2:37][C:18]2[CH2:19][S:20](=[O:36])[C@@H:21]3[C@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:23](=[O:35])[N:22]3[C:17]=2[C:15]([OH:16])=[O:14])=[CH:39][CH:40]=1)([OH:45])=[O:44]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)o3)CS(=O)[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cc3ccc(C(=O)O)o3)CS(=O)[C@H]12

Procedure:
By treating 0.70 g of 3-(5-diphenylmethoxycarbonylfurfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid diphenylmethyl ester 1-oxide with 5 ml of trifluoroacetic acid and 2 ml of anisole, the 3-(5-carboxy-furfuryl)-7β-phenylacetylamino-ceph-3-em-4-carboxylic acid 1-oxide is obtained; thin-layer chromatogram (silica gel): Rf = 0.15 (system: n-butanol/ethanol/water 40:10:50).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]([NH2:12])=[NH:11])[N:3]=1.CS[C:15](=[NH:17])[NH2:16]>CO>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:10]([NH2:12])=[NH:11])[N:3]=[C:2]([NH:1][C:15]([NH2:17])=[NH:16])[CH:7]=1
Reactant: N=C(N)Nc1nc(N)cc(N)n1
Reactant: CSC(=N)N
Solvent: CO
Product: N=C(N)Nc1cc(N)nc(NC(=N)N)n1

Procedure:
A mixture of 1.7 g (0.01 m) of 4,6-diamino-2-guanidinopyrimidine prepared as in Example 2, 0.9 g (0.01 m) of S-methylisothiourea and 150 ml of methanol is heated at reflux overnight. Evaporation of the volatiles gives 6-amino-2,4-diguanidinopyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (218 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as a light brown solid (260 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([Br:19])C(=O)C1.O>CC(O)=O>[Br:19][C:3]1[C:2]([Cl:1])=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (6.0 g, 34.88 mmol) and NBS (6.06 g, 34.0 mmol) in HOAc (240 mL) was stirred at 130° C. for 1 h. The reaction mixture was poured into water. The precipitate was collected by filtration and washed with petroleum ether to give 4-bromo-5-chloro-2-nitroaniline as a light brown solid (8.25 g, 96.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.62 (br s, 2H), 7.29 (s, 1H). LCMS (ESI) m/z 251 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:11])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1F
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(F)c1
Yield: 73.8 %

Procedure:
The title compound was prepared from 5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.5 g, 1.3 mmol), cyclohexene (0.33 mL, 3.25 mmol) and 1.0 M boron tribromide in dichloromethane (7.8 mL, 7.8 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting sequentially with dichloromethane and ethyl acetate to yield 2-fluoro-4-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.35 g, 0.96 mmol, 74%) as a light-yellow solid, m.p. 172-174° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.30 g (1.6 mmol) of 2,6-dichlorobenzamide and 0.22 g (1.8 mmol, 1.1 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2,6-dichlorobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.3 g (1.6 mmol) of 2-chloro-4-fluoro-3-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.58 g (Yield 84%) of the title compound as a solid.
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][C:10]1[S:11][C:12]([NH2:15])=[CH:13][N:14]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[CH3:9][C:10]1[S:11][C:12]([NH:15][C:17](=[O:18])[CH3:16])=[CH:13][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(N)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of Et3N (1.4 ml, 10 mmol) and 2-methylthiazol-5-amine hydrochloride (1 g, 6.6 mmol) in DCM (30 mL) was added Ac2O (0.94 mL, 10 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.8 g, yield: 77%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].O.COC1C=CC(O)=CC=1>CO>[C:12]([O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CCCCCCCC(O)CC
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)OC(CC)CCCCCCC

Procedure:
In the same reactor as used in Example 1, 760 kg (5 kmoles) of tricyclo[5.2.1.02,6 ]deca-8-yl alcohol and 1500 kg (15 kmole) of methyl methacrylate were placed and well mixed with stirring. The water content of the resulting mixture was 2500 ppm. To the mixture, 550 g of hydroquinone monomethyl ether was added and heated while introducing thereinto dried air at a rate of 4 m3/ hr and reluxing methyl methacrylate through the distillation column to remove water by azeotropic distillation. After 1 hour from the beginning of the reflux of methyl methacrylate, the water content in the reactor became 630 ppm. Then, 3 kg of anhydrous lithium hydroxide was charged into the reactor to carry out the reaction. While removing methanol by-produced by the reaction from the reaction system by distillation, the reaction was continued until almost no methanol was distilled (about 7 hours), followed by removal of unreacted methyl methacrylate under reduced pressure. After cooling, the mixture was filtered under pressure (2 kg/cm2) using a filter paper (pore size 0.1 mm, area 5 m2) placing thereon 10 kg of diatomaceous earth to yield 990 kg of tricyclo[5.2.1.02,6 ]deca-8-yl methacrylate with the filtrating time of 2 hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[CH:7]=1.[Cl:8][C:6]1[CH:7]=[C:2]([O:12][CH3:11])[C:3]([C:9]#[N:10])=[N:4][CH:5]=1
Reactant: C[O-]
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cnc1C#N
Product: COc1cnc(C#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
To a solution of 3,5-dichloropicolinonitrile (22.5 g, 130 mmol) in DMF (500 mL) at 0° C. was added sodium methoxide (6.67 g, 124 mmol) slowly. The reaction was stirred for 5 minutes at 0° C., then allowed to warm to RT and stir for 30 minutes. The solution was partitioned between water and EtOAc. The organic layer was washed with water and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-75% ethyl acetate in heptanes, to afford a 1:1 ratio of the desired isomer 3-chloro-5-methoxypicolinonitrile and 5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material was used without further purification. MS m/z=169 (M+H).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[C:13](=O)[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][CH:17]=1.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:13]1[C:12]([O:11][CH3:10])=[CH:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[N:14]=1
Reactant: COc1cnc(-c2ccc([N+](=O)[O-])cc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1cnc(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Yield: 61 %

Procedure:
In ice bath, dimethyl-phenyl-amine (1.19 mL, 1.0 eq) was added dropwise to a slurry of 5-Methoxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one (2.3 g, 1.0 eq) in POCl3 (4.4 mL, 5.0 eq) and the mixture was refluxed overnight. Excess POCl3 was evaporated in vacuo and the residue was poured into ice-water. After formation of precipitates, the mixture was filtered and the residue was dried solid in vacuo. A product was obtained as a white solid (2.47 g, 61%).