Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:8][CH2:9][CH:10]=O>ClCCCl.CC(O)=O.[OH-].[Na+]>[Cl:8][CH2:9][CH2:10][N:5]1[CH2:6][CH2:7][C@H:3]([F:2])[CH2:4]1
Reactant: O=CCCl
Reactant: FC1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: F[C@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-fluoropyrrolidine hydrochloride (0.59 g, 4.7 mmol) in 1,2-dichloroethane (8.2 mL) and AcOH (0.54 mL) was added chloroacetaldehyde (0.74 mL, 4.7 mmol, 50% in H2O solution) and Na(AcO)3BH (3.7 g, 17 mmol). The reaction mixture was stirred at ambient temperature for 1 h, and then the reaction mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×50 mL). The organics were washed with brine (2×25 mL), dried (Na2SO4) and concentrated to yield the title compound (0.242 g, 33%) as a red-orange oil: 1H NMR (500 MHz, DMSO-d6) δ 5.24-5.11 (m, 1H), 4.25-4.23 (m, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.95-2.82 (m, 4H), 2.60-2.56 (m, 1H), 2.20-2.04 (m, 2H); ESI MS m/z 152 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[F:22]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[CH:17][C:16]=1[F:22]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(Nc1ccc(Br)c(F)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 4-Bromo-3-fluoro-phenylamine to produce N-(4-Bromo-3-fluoro-phenyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 13A, 13B and 13C to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]3[C:12](=[O:18])[C:13]([CH:16]=O)=[CH:14][CH:15]=[C:10]3[N:9]2[S:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])(=[O:29])=[O:28])=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:11]3[C:12](=[O:18])[C:13]([CH2:16][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:14][CH:15]=[C:10]3[N:9]2[S:27]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])(=[O:28])=[O:29])=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(S(=O)(=O)N2c3ccc(C=O)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Reactant: C1COCCN1
Product: N#Cc1cccc(S(=O)(=O)N2c3ccc(CN4CCOCC4)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1

Procedure:
rac-3-[cis-2,3-Bis-(4-chloro-phenyl)-6-morpholin-4-ylmethyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile was prepared according to general method E by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-6-formyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzonitrile with Morpholine. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 621.06; the expected mass is 620. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C.CCOC(C)=O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][O:32][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH3:31]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 57.7 %

Procedure:
To a solution of N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (150 mg, 0.327 mmol, example 48) in DMF (5 mL) was added K2CO3 (90 mg, 0.654 mmol) and methyl chloroacetate (0.06 mL, 0.654 mmol, CAS RN 96-34-4) at 25° C. and the resulting mixture was heated to 70° C. for 16 hours. The mixture was diluted with EtOAc (25 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude material thus obtained was purified by column chromatography over silica gel (30% EtOAc in n-hexane) to give 100 mg of the title compound. Pale yellow solid (58%). MS (ESI): m/z=531.0 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:8]2[C:9](=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=2[OH:28])[S:18][N:19]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccccc3F)c2c1O
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-7-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 422.0 (M−1).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=1)N.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[N:24]1([C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:16]3[C:4](=[O:15])[C:5]([N:10]4[CH:14]=[CH:13][N:12]=[N:11]4)=[CH:6][NH:7]3)[CH:19]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: NNc1cc(N2CCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 5 °C
Yield: 61.5 %

Procedure:
1.9 g (8.8 mmol) of the compound from Example 3A and 1.9 g (9.7 mmol) of the compound from Example 16A are initially introduced into 25 ml ethyl acetate and 504 mg (4.4 mmol) TFA are added at RT. The mixture is stirred under reflux for 16 h, then cooled to 5° C. and subsequently stirred for a further 2 h. The solid formed is filtered off, washed with ethyl acetate and dried first in air and thereafter under a high vacuum. 1.7 g of product are obtained.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(N(CC)CC)C>C(O)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[4-(bromo)butyl]phthalimide (6.21 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 45 minutes. After the solvent was distilled off, chloroform was added to the residue, which was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 4.50 g of the desired product (64.1%, pale yellow crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl.N1C=CC=CC=1>[CH3:38][S:39]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:19]([CH3:21])[CH3:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(N)cc23)c1)C(=O)NCC(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(NS(C)(=O)=O)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of N2-[5-(5-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 5-1b (50 mg, 0.093 mmol) in DCM (2 mL) and pyridine (0.5 mL) was added methanesulfonyl chloride (7.62 μl, 0.098 mmol) and mixture was stirred for 18 h. The residue 5-3a was used without further purification. MS APCI: [M+H]+ m/z=615.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1.C([O-])([O-])=[O:27].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:27])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1

Procedure:
To a solution of 4-chloro-3-{5-[(2-cyclohexylethylamino)methyl]pyridin-2-yl}benzonitrile (170 mg, 0.48 mmol) in DMSO (4 mL) was added K2CO3 (66 mg, 0.48 mmol) and 70% hydrogen peroxide (0.5 mL, 4.8 mmol). The mixture was stirred at rt for 5 h before water (5 mL) was added and the mixture partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with water (3×20 mL), brine (20 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.57 min; m/z (ES+)=372.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH2:20][Cl:21])[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:15][CH:16]([CH2:20][Cl:21])[C:17]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: O=C(Cl)C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)C(Cl)CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a stirred solution of 12.8 grams (0.10 mole) of 4-chloroaniline in 85 ml of chloroform was added 8 ml of pyridine. The mixture was cooled to 10° and 16.1 grams (0.10 mole) of 2,3-dichloropropionyl chloride was added dropwise at such a rate that the reaction mixture temperature did not exceed 35°. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a solid residue. The solid was slurried with water and collected by filtration. The dried solid was recrystallized from methylcyclohexane-ethyl acetate using silica gel as a decolorant to give 19.7 grams of 2,3-dichloro-N-(4-chlorophenyl)propanamide; mp 127.5°-129°.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH:24](=[N:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(N)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CC)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of the product from step (a) (149.6 g), magnesium sulphate (74.3 g), and triethylamine (246 ml) in dichloromethane (1500 ml) was stirred at room temperature under nitrogen and benzaldehyde (94.9 g, Aldrich) was added dropwise. The mixture was stirred at room temperature for 3 hours then filtered. The filtrate was concentrated, triturated in diethyl ether, filtered and concentrated to yield the desired product as a yellow oil (174 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O.C(Cl)Cl>[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]2[CH:26]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)([OH:5])[C:3]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=3[CH2:1]2)[C:25]1=[O:30])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: Cc1ccc(C)c(C(=O)c2ccccc2)c1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(O)(c1ccccc1)C1C(=O)N(Cc3ccccc3)C(=O)C1C2
Yield: 52.9 %

Procedure:
A solution of 35 g of 2,5-dimethylbenzophenone and 31.5 g of N-benzylmaleimide in 500 cc of acetone or methylene chloride is irradiated with a mercury high pressure lamp through a pyrex filter, until all the material has reacted (20 to 130 hours), filtration and concentration by evaporation are then effected. After crystallization from ether, the residue yields 35 g of 2-benzyl-3a,4,9,9a-tetrahydro-6-methyl-4-phenyl-benz[f]isoindolin-4-ol-1,3-dione, having a M.P. of 162-164°, which are dissolved in 170 cc of trifluoroacetic acid. The solution is stirred at 25° for 3 hours and concentrated by evaporation. After crystallization from methylene chloride/methanol, the residue yields 30 g of (9aRS)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz[f]isoindoline-1,3-dione, having a M.P. of 156°-158°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][Br:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt](=O)=O.[Pt]>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:21])[CH2:12][CH2:11]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CN(CC1CCC(/C=C\CCCBr)CC1)C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: [Pt]
Solvent: CCO
Product: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)C(=O)OC(C)(C)C

Procedure:
1.15 g (3.07 mmol) trans-E/Z-[4-(5-bromo-pent-1-enyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester dissolved in 15 ml of ethanol were added to a suspension of 300 mg platinum dioxide freshly reduced to platinum by hydrogenation immediately prior to use. Hydrogenation was then continued at ambient pressure until 95% of the calculated amount of hydrogen had been consumed. Then, the reaction mixture was filtered over celite and evaporated giving 0.950 g (82%) trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 375 (M+, 1Br).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.C[O-].[Na+]>CO>[Cl:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:2][C:3]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])[CH:39]=[CH:40][CH:41]=1
Reactant: COc1cccc(C(=O)O)c1CBr
Reactant: O=Cc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1cccc(C(=O)O)c1C=Cc1cccc(Cl)c1

Procedure:
For the synthesis of the title compound, 45.6 g (0.186 mol) of 2-bromomethyl-3-methoxybenzoic acid, 48.8 g (0.186 mol) of triphenylphosphine, 26.1 g (0.186 mol) of 3-chlorobenzaldehyde and 84.0 g (0.435 mol) of NaOMe (28%) in 150 ml of methanol are reacted by method I. Purification is carried out by recrystallization from methanol with water.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.[C:15]([NH:18][NH2:19])(=[O:17])[CH3:16]>CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:19][NH:18][C:15](=[O:17])[CH3:16])=[NH:14]
Reactant: CC(=O)NN
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Solvent: CO
Product: CC(=O)NNC(=N)c1ncc([N+](=O)[O-])n1C

Procedure:
In 200 ml. of methanol, 12 g. (0.06 mole) of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate and 4.9 g. (0.066 mole) of acetyl hydrazine are refluxed for 30 hours. The yellow compound is collected, washed with cold methanol and dried to give 12.97 g. of the title compound, melting point 294° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][OH:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][C:5]([Si:2]([O:1][CH2:9][CH2:10][CH2:11][O:12][S:31]([C:28]1[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=1)(=[O:32])=[O:33])([CH3:4])[CH3:3])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCOS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
A solution of 3-t-butlydimethylsiloxy-1-propanol, prepared by the method of McDougal, et al. JOC, 1986, 51, 3388, which is incorporated herein by reference, (7.6 g, 40 mmol) and diisopropylethylamine (10.4 mL, 60 mmol) in methylene chloride (200 mL) at 0° C. was treated with p-nitrophenylsulfonyl chloride (9.7 g, 44 mmol), stirred for 3 h, poured into saturated NaHCO3 and extracted with diethyl ether. The extracts were washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel with 5% ethyl acetate/hexanes to provide 6.00 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[C:4]([F:12])[CH:3]=1.[OH-].[NH4+:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:14])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc(Br)cc1F
Temperature: 0 °C
Yield: 64.1 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429 mmol) in sulfurous dichloride (5 mL, 0.429 mmol) was added DMF (3.32 μL, 0.043 mmol). The resulting mixture was stirred at 60° C. After 2 h, TLC analysis (PE/EA=1/1) showed the starting material had disappeared. The solvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.416 mmol, 97% yield). A solution of 2-(4-bromo-2-fluorophenyl)acetyl chloride (110 mg, 0.437 mmol) in THF (5 mL) was added to ammonium hydroxide (10 mL, 257 mmol). The resulting mixture was stirred at 0° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (50 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried and concentrated to give a white solid of 2-(4-bromo-2-fluorophenyl)acetamide (100 mg, 0.280 mmol, 63.9% yield), which was used into the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J=8.2 Hz, 1H), 3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:16][N:23]=[C:2]3[C:7]=2[CH:6]=[N:5][C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]3=2)=[CH:10][CH:11]=1
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(Cl)cc3)cnc21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccc(Cl)cc4)c3cnc21
Reaction time: 8 h
Yield: 43 %

Procedure:
4-Chloro-5-(4-chlorobenzoyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine (3.76 g) was suspended in 75 ml of glacial acetic acid, and to this was added 1.05 g of hydroxylamine hydrochloride. The reaction mixture was stirred overnight at 80° and the next morning yet another 1.05 g of hydroxylamine hydrochloride was added. After stirring the mixture for additional two hours the solvent was evaporated and the residue washed first with sodium bicarbonate solution and then methanol. The resulting product was then chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane), giving 1.51 g of product, mp 248°-250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][N:14](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(C#N)c1
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of methyl 3-bromo-5-iodobenzoate (4.5 g, 13.2 mmol) in N,N-dimethylformamide (36 mL) was treated with zinc cyanide (1.7 g, 14.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 1.5 g, 1.3 mmol). The reaction mixture was heated, under an argon atmosphere, for 1 hour at 80° C. After cooling the mixture was diluted with ethyl acetate. The resulting organic solution was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using a gradient of hexane to 10% ethyl acetate in hexane afforded 1.9 g (61%) of methyl 3-bromo-5-cyanobenzoate.