Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=1>ClS(O)(=O)=O>[F:15][C:2]([F:1])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: O=C(O)CCc1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)Cl
Product: O=C1CCc2cc(OC(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 9.6 %

Procedure:
158e (9.0 g, 38.5 mmol) was added portionwise to chlorosulfonic acid (100 mL) while cooling with an iced bath. See FIG. 4. The resulting mixture was stirred at 0° C. for 1.5 h, poured into ice-water (1 L), and extracted with EtOAc (200 mL×3). The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified with by column chromatography on silica gel (ethyl acetate:petroleum ether=1:3) to afford 5-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one 158f (800 mg, 9.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 3.11 (t, J=5.6 Hz, 2H), 2.69-2.66 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24]>CC(C)=O>[CH:23]([C:22]1[CH:21]=[C:20]([CH:27]=[CH:26][CH:25]=1)[O:19][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:24]
Reactant: O=Cc1cccc(O)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cccc(C=O)c2)cc1
Yield: 28 %

Procedure:
A slurry of methyl 4-(bromomethyl)benzoate (1.4 g, 6.14 mmol), K2CO3 (1.02 g, 7.37 mmol), 3-hydroxybenzaldehyde (899 mg, 7.37 mmol) in acetone (20 mL) was stirred at room temperature for 16 hours. The solids were filtered, the filtrate partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and the aqueous phase back-extracted with EtOAc (3×30 mL) The combined organic phases were washed with brine (30 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was purified via silica gel chromatography (eluting with 0-20% isohexane/EtOAc) to give the title compound (464 mg, 28% yield) as a white solid.
Reaction SMILES: C(Cl)(Cl)Cl.CO.[O:7]=[P:8]1([CH:18]=[CH2:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.ClP1(=O)C2C(=CC=CC=2)CCC1>C(O)C>[O:7]=[P:8]1([CH:18]=[CH2:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH2:9]1
Reactant: C=CP1(=O)CCCc2ccccc21
Agent: O=P1(Cl)CCCc2ccccc21
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CP1(=O)CC=Cc2ccccc21

Procedure:
A solution of the crude 4-bromo-1-oxo-1-vinyl-1,2,3,4-tetrahydrophosphinoline (5.5g) in anhydrous dimethyl formamide (30 ml) was heated under nitrogen at 110° for 45 min, after which time an n.m.r. spectrum indicated that dehydrobromination was complete. The excess of dimethyl formamide was evaporated in vacuum, and the brown semi-solid residue was dissolved in chloroform. This solution was washed with water, dried, and evaporated. Distillation of the residue through a short Vigreux column gave a colourless liquid b.p. 134°-138°/0.005 (3.6g, 90%). Preparative t.l.c. on silica gel plates developed with chloroform-methanol 30-1, followed by bulb-to-bulb distillation gave the "pure" compound. However, complete removal of water was not achieved, nor was a unique hydrate obtained, and the compound failed to give satisfactory microanalytical figures. Infrared spectrum νmax : 3030, 2930, 2860, 1630, 1590, 1475, 1440, 1390, 1275, 1180, 1140, 990, 865, 785, 720 cm-1. N.m.r. spectrum (CDCl3): 7.0-8.0, m. 4H (aromatic); 5.6-6.8, m, 5H (olefinic); 2.6-3.1, m, 2H (methylene). Mass spectrum: m/e 190 (57%), 141 (41), 128 (38), 116 (66), 115 (100), 89 (27), 65 (34), 51 (50). Ultraviolet spectrum λmax (ethanol): 222 (19600) 262 (4200), 298 (2300).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2=[C:6]([C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[O:14])[C:7]3[C:12]([N:4]2[CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:38][OH:39].Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.CCN(CC)CC>[OH:39][NH:38][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]3[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]=23)=[O:14])=[CH:23][CH:22]=1
Reactant: NO
Reactant: CN1CCc2c(C(=O)c3ccc(C(=O)O)cc3)c3ccccc3n2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCc2c(C(=O)c3ccc(C(=O)NO)cc3)c3ccccc3n2C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a solution of 4-(2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indole-5-carbonyl)benzoic acid (60 mg) in 4 mL of DMF was added 100 mg of carbonyldiimidazole (CDI). The reaction mixture was stirred at 40° C. for 1 h and then treated with 280 mg of NH2OH.HCl, followed by 0.6 mL of Et3N. After stirring for 20 min at r.t., 5 mL of pH7 potassium phosphate buffer and 10 mL of brine were added and reaction mixture was extracted with 3×20 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and the residue was purified by silica gel chromatography eluted with up to 10% MeOH/CH2Cl2 to give 10 mg of the title product as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NN.CCOC(C)=O>CCO.O.[Ni]>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To 1-(4-tert-butylbenzyl)-5-nitro-1H-indole (1.00 g, 3.24 mmol) in EtOH (35 ml) at ambient temperature under a nitrogen atmosphere was added hydrazine (2.0 g, 62.5 mmol) and Raney-Ni (0.20 g of a 50% slurry in H2O). The yellow mixture was stirred at 45° C. for 1 hr. The mixture was cooled to room temperature and filtered through a celite pad (1×4.25 cm). The pad was washed with EtOH (10 ml) and concentrated in vacuo to afford a dark yellow powder. Gradient SiO2 chromatography (Hex:EtOAc) afforded 1-(4-tert-butylbenzyl)-5-amino-1H-indole as a yellow powder (0.87 g, 96% yield): MS (ESI) m/z 279.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Br:14])[N:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O>[Br:14][C:7]1[N:6]=[C:5]([N:4]([CH2:20][C:19]2[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:18]=2[Cl:17])[C:1](=[O:3])[CH3:2])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: CC(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(Cc1ccc(C#N)cc1Cl)c1nc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2-(Acetamido)-6-bromo-3-nitropyridine (3.21 g) was dissolved in dry N,N-dimethylformamide (16 ml), and sodium hydride (60% in oil, 326 mg) was added under ice-cooling. The mixture was stirred for 30 min. A solution of 2-chloro-4-cyanobenzyl bromide (2.34 g) in dry N,N-dimethylformamide (4 ml) was dropwise added at the same temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the objective compound (4.17 g) as a pale-yellow powder.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH:16]1([C:19]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=2)[CH2:18][CH2:17]1>>[CH:16]1([C:19]2[CH:24]=[CH:23][C:22]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:18][CH2:17]1
Reactant: OB(O)c1ccc(C2CC2)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-cyclopropylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C19H16N4, 301. Found, 301.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16]([O:18]CC)=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=3[CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O>CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16]([OH:18])=[O:17])[S:14][CH2:13][C:12](=[O:21])[C:11]=3[CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1SCC(=O)c2cc(C3CCCCC3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CSC(C(=O)O)c2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
In methanol (200 ml) was suspended ethyl 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (52 g) followed by addition of 2N-KOH (100 ml). The mixture was stirred at room temperature for one hour, poured into water, acidified and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (33 g, yield 73%). Recrystallization from ethyl acetate-hexane gave colorless plates.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:19][C@H:18]2[C@H:14]([N:15]=[C:16]([N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])[S:17]2)[C@@H:13](O)[C@@H:12]1[O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:46])CC>C(Cl)Cl>[C:1]([O:9][CH2:10][C@H:11]1[O:19][C@H:18]2[C@H:14]([N:15]=[C:16]([N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])[S:17]2)[C@@H:13]([F:46])[C@@H:12]1[O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](OC(=O)c3ccccc3)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OC(=O)c3ccccc3)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (-(3aR,5R,6S,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate (0.49 g, 0.88 mmol) in anhydrous DCM (3 mL), at −40° C. under N2, was added DAST (1.0 g, 6.2 mmol). After addition the mixture was stirred at room temperature overnight. After the reaction mixture was again cooled at −40° C., it was diluted with DCM (20 mL), and then quenched by adding satd. aqueous NaHCO3 dropwise. The organic layer was collected, and the aqueous was extracted with DCM (2×15 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 1:5 to 2:7), affording (-(3aR,5R,6R,7R,7aR)-6-(benzoyloxy)-2-((tert-butoxycarbonyl)(ethyl)amino)-7-fluoro-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl benzoate as a white solid (0.14 g, impure, ˜28%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[NH:25][C:26]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[N:28]=3)[C@H:20]([CH3:47])[CH2:19]2)=[N:4][CH:5]=[C:6]([CH2:8][O:9]COCC[Si](C)(C)C)[CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24]2[NH:25][C:26]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=3)=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)[N:28]=2)[C@H:20]([CH3:47])[CH2:19]1
Reactant: C[C@@H]1CN(c2ncc(COCOCC[Si](C)(C)C)cc2Cl)CCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc(-c2ccc(F)c(F)c2)c(-c2ccc(C(F)(F)F)cc2)[nH]1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of (2R)-4-(3-chloro-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)pyridin-2-yl)-1-(4-(3,4-difluorophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)-2-methylpiperazine from step (b) above (160 mg, 0.23 mmol) in TFA (3 mL) was stirred at RT for 1.5 h. The solvent was removed and the residue was added solution of MeOH:DCM (1:1, 3 mL). The mixture was cooled to 0° C. and potassium carbonate (200 mg) was added. The mixture was then stirred at RT for 2.5 h and the solvents were removed. The residue was purified on silica gel using ISCO Combiflash® system with EtOAc/Hexanes (1:1) as the eluant to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 564 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[Na].Cl[CH2:15][C:16]1[N:20]=[C:19]([CH3:21])[O:18][N:17]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:15][C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: Cc1nc(CCl)no1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1nc(Cn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Temperature: 100 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 3.76 g of (20 millimoles) of 3-methylxanthine-sodium, 100 ml of dimethyl formamide and 2.60 g (19.6 millimoles) of 3-chloromethyl-5-methyl-1,2,4-oxadiazole is stirred at 100° C. for one hour and a half. The hot reaction mixture is filtered and to the filtrate 50 ml of methanol are added. Thus 3.65 g of 3,7-dihydro-3-methyl-7-([5-methyl-1,2,4-oxadiazole-3-yl]-methyl)-1H-purine-2,6-dione are obtained, m.p.: 262°-264° C. Yield: 69%.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][CH:17]=C2>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][CH:17]=[C:2]2[CH:1]=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1cc2cc[nH]c2cc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of oxalyl chloride (1.21 mL, 13.8 mmol) in CH2Cl2 (40 mL) was added a solution of DMF (2.02 mL) in CH2Cl2 (40.0 mL). The reaction was stirred for 30 min, then 5,6-difluoro-1H-indole [169674-01-5] (2.00 g, 13.1 mmol) was added in one portion. The reaction mixture was allowed to warm to RT overnight. Volatiles were evaporated, and the residue was taken up in THF (20 mL) and 20% aqueous ammonium acetate solution (20 mL). The resulting mixture was heated to reflux for 30 min. After cooling, the mixture was treated with saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were dried (phase separator) and evaporated in vacuo to afford the title compound as a beige solid: MS (LC/MS): 182.0 [M+H]+; tR (HPLC conditions c): 3.94 min. The material thus obtained was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1>O1CCCC1.C(=O)(O)[O-].[Na+].[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[C:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: Fc1ccc(I)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: Fc1ccc(-c2cccnc2Br)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 33 %

Procedure:
Dissolve 2-bromopyridine (5 mL, 51.3 mmol) in tetrahydrofuran (125 mL). Cool to −78° C. and add lithium diisopropylamide (28.2 mL, 56.4 mmol, 2 M solution in heptane/tetrahydrofuran/ethylbenzene). Stir for 45 min. at −78° C., add zinc chloride (102.5 mL, 51.3 mmol, 0.5 M solution in tetrahydrofuran) and warm to 25° C. for one hr. Add 1-fluoro-4-iodobenzene (5.91 mL, 51.3 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (2.96 g, 2.56 mmol) and reflux the mixture for 18 hr. Cool the mixture to room temperature, dilute with saturated aqueous sodium bicarbonate and extract 3 times with DCM. Combine the organic extracts, dry (sodium sulfate), filter and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give 2-bromo-3-(4-fluorophenyl)-pyridine (4.27 g, 33% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.[Br-:18].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:18][C:9]1[C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)CC1CCc2c1[nH]c1ccc(F)cc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: O=C(O)CC1CCc2c1[nH]c1c(Br)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.20 g of the acid from Step 2 (>90% purity) in 30 mL of pyridine, 6.85 g of pyridinium tribromide (90% purity) was added at −40° C. The suspension was stirred for 10 min at 0° C. and warmed to room temperature for 30 min. Then, the solvent was removed without heating under high vacuum. The crude material was dissolved in 40 mL of AcOH and 2.88 g of Zn dust was added portion wise to the cold solution at 0° C. The suspension was stirred for 15 min at 15° C. and warmed to room temperature for an additional 15 min. At this time, the reaction mixture was quenched by the addition of 1N HCl and this mixture was poured into a separatory funnel containing brine/EtOAc. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. This material was used without further purification in the next step.
Reaction SMILES: [I:1]I.C[Si](C)(C)[CH:5]=[CH:6][C:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=1[CH3:13].ClCCl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[I:1][CH:5]=[CH:6][C:7]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][C:12]=1[CH3:13]
Reactant: II
Reactant: CC1=C(C=C[Si](C)(C)C)C(=O)CCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1=C(C=CI)C(=O)CCC1
Reaction time: 8 h

Procedure:
Iodine (750 mg, 2.96 mmol) was dissolved in 10 mL of THF and the solution was added to a solution of 2-(2-(trimethylsilyl)ethenyl)-3-methyl-2-cyclohexen-1-one (Compound 3, 560 mg, 2.70 mmol) and dichloromethane (50 mL) at room temperature. The solution was stirred overnight, and then treated with 10% aqueous Na2S2O3 to remove the excess iodine. The layers were separated and the aqueous layer was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (9:1, hexane:ethyl acetate) to give the product as a brown oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc(C2CCCCC2)cc1
Reaction time: 15 h
Yield: 75 %

Procedure:
67 g (0.5 mol) of aluminium chloride are added in portions to a mixture of 80 g (0.5 mol) of cyclohexylbenzene 70 g (0.5 mol) of benzoyl chloride and 500 ml of methylene chloride at room temperature. After 15 hours, the reaction mixture is poured onto ice/hydrochloric acid. The organic phase is washed with water until neutral, dried over sodium sulphate and evaporated. The crude product is purified by distillation. 93.3 g (75% of theory) of 4-cyclohexylbenzophenone of boiling point 160° to 175° C./0.1 mm are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
To a suspension of 3,5-dibromophenol (20 g, 79.39 mmol) and potassium carbonate (21.95 g, 158.78 mmol) in acetone (100 mL) was added iodomethane (24.79 g, 174.65 mmol) at room temperature. The resulting light yellow color mixture was heated to reflux and stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL) and ethyl acetate (200 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 330 g column chromatography, eluting with 0-3% ethyl acetate in hexanes to obtain 1,3-dibromo-5-methoxy-benzene (20.47 g, 97%) as a white solid: EI(+)-HRMS m/e calcd for C7H6Br2O (M)+ 263.8780, found 263.8785.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=O)=[CH:6][CH:5]=1)(O)=O.[C:18]([O:21]C(=O)C)(=[O:20])C.C([O-])(=O)C.[Na+]>>[O:16]=[C:14]1[CH:13]=[CH:12][C:11](=[O:17])[N:10]1[C:7]1[C:6]([C:18]([OH:21])=[O:20])=[CH:5][CH:4]=[CH:9][CH:8]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)c1ccccc1N1C(=O)C=CC1=O
Temperature: 80 °C
Yield: 33 %

Procedure:
A mixture of N-(4-carboxyphenyl)maleamic acid (5.0 g, 21.2 mmol), acetic anhydride (4 ml, 42.5 mmol) and sodium acetate (3.48 g, 42.5 mmol) Was heated at 80° C. for 3h. After heating, excess acetic anhydride was removed under reduced pressure and the residue purified by column chromatography using 0-4%. MeOH/DCM as an eluent to give 3k (33%) as a solid.15 mp: 165-168° C.; 1H NMR (400 MHz, DMSO-d6): δ 7.20 (s, 2H), 7.47 (d, J=8.4 Hz, 2H), 8.02 (d, 8.0 Hz, 2H), 12.75 (brs, 1H); HRMS (m/z): [M−H]− calcd for C11H6NO4, 216.0302; found, 216.0296.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cc(C(F)(F)F)ccc3F)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)nccc12
Yield: 79.3 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 1-(2-fluoro-5-(trifluoromethyl)phenoxy)-5-nitroisoquinoline (320 mg, 0.90 mmol), iron powder (500 mg, 9.09 mmol), and NH4Cl (389 mg, 7.2 mmol) in EtOH (8 mL) and water (2 mL) to afford 230 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.89 (d, J=5.7 Hz, 1H), 7.75-7.59 (m, 4H), 7.50 (d, J=7.8 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.03 (s, 2H); MS (m/z): 323.28 (M+H)+.