Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].C(N(CC)CC)C.Cl>CCOC(C)=O>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[F:7]
Reactant: CCOC(=O)Cl
Reactant: Oc1cccc(F)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Step M (1): Ethyl chloroformate (16.6 g, 153 mmol) was added to a solution of 2,3-difluorophenol (20 g, 153 mmol) and triethylamine (20.7 mL, 146 mmol) in EtOAc (200 mL). The resulting mixture was stirred at rt for 2 h. The crude reaction was poured into 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (5% EtOAc/hexane) to afford 2,3-difluorophenyl ethyl carbonate (20 g, 64% yield).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Br
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2F)CCC1

Procedure:
using isopropyl 2-bromo-4-fluoro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate in toluene there is obtained isopropyl 2-bromo-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 150°-154° C.,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.C(O)(=[O:14])C.C([O-])(=O)C.[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][OH:14]
Reactant: Fc1cc(Br)c(CBr)cc1Cl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Product: OCc1cc(Cl)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 227 mmol of 1-bromo-2-bromomethyl-4-chloro-5-fluoro-benzene (example 10d) in 300 ml of glacial acetic acid containing 495 mmol of potassium acetate is heated to reflux for 3 hours. The mixture is concentrated and then partitioned between water and diethyl ether. After repeated extractions with diethyl ether, the combined organic layers are washed successively with saturated sodium bicarbonate-solution solution and water, dried over magnesium sulfate and concentrated. The crude acetate is dissolved in 200 ml of methanol and treated slowly with a methanolic KOH solution (33.4 g in 100 ml). The reaction mixture is stirred for 35 minutes at room temperature, then neutralized with acetic acid and concentrated under reduced pressure. The residue is partitioned between water and diethyl ether. Concentration of the organic phase affords the crude title compound which is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](O)([CH3:14])[CH3:13].S(=O)(=O)(O)O>CCCCCC>[CH:12]([O:1][C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5])([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1C(=O)O
Temperature: 75 °C
Reaction time: 8 h

Procedure:
210 g mixture of 2,5-dihydroxy benzoic acid and isopropanol was added to 1201 g of 80% sulfuric acid and stirred for 8 hours at 75° C. The solution was allowed to cool, and was added with 2 liters of ice water and 140 ml of hexane and was stirred in an ice bath. Resultant crystal deposit was filtrated, and the residue was washed with hexane. Then, it was dispersed in a mixture liquid consisting of methanol and water in a ratio of 6:4, and filtration was conducted. The substance was dried for 48 hours at 60° C., and 65.4 g of isopropyl-salicylic acid intermediate was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:33]5[CH2:34][CH2:35][CH2:36][CH:32]5[CH3:31])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CC1CCCN1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 2-methylpyrrolidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(2-methylpyrrolidin-1-yl)isonicotinamide (35 mg). NMR; δH [2H6]—DMSO 10.27,(1H, s), 8.62,(1H, t), 8.20,(1H, d), 7.93,(2H, d), 7.70,(1H, d), 7.66,(1H, s), 7.44,(2H, d), 7.30,(1H, d), LCMS: retention time 2.89 min, MH+469.
Reaction SMILES: [F:1][C:2](=[CH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])[C:3](OC)=[O:4].[H-].[Li+]>C(OCC)C>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]([CH3:9])([CH3:10])[CH:7]=[C:2]([F:1])[CH2:3][OH:4])=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(C(C)(C)C=C(F)C(=O)OC)cc1
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCOc1ccc(C(C)(C)C=C(F)CO)cc1
Yield: 89.4 %

Procedure:
The method of Example 6 was repeated using methyl 2-fluoro-4-(4-ethoxy-phenyl)-4-methylpent-2-enoate (Example 4) (0.2 g), diethyl ether (15 ml) and lithium hydride (0.1 g) to yield the title compound (0.16 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18](O)[CH2:19][CH3:20])=[CH:15][C:14]([F:22])=[CH:13][C:12]=3[N:11]3[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([OH:29])=[O:28])[C:10]=23)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH2:18][CH2:19][CH3:20])=[CH:15][C:14]([F:22])=[CH:13][C:12]=3[N:11]3[CH2:23][CH2:24][CH:25]([CH2:26][C:27]([OH:29])=[O:28])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CCC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a solution of [9-[(4-chlorophenyl)thio]-6-fluoro-8-(1-hydroxypropyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 19, 36 mg, 0.08 mmol) in CH2Cl2 were added trifluoroacetic acid (0.5 mL) and triethylsilane (0.2 mL). The mixture was stirred for 1 hour at r.t. and solvent was removed. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane containing 1% of AcOH to give 10 mg the title compound as a white foam.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH3:19])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1>O>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH3:19])[CH2:11][CH2:10]1
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 62.9 %

Procedure:
tert-Butyl (S)-1-(trans-4-(t-butyldimethylsilyloxy)cyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (18 g, 34 mmol) was treated with 4 M nBu4NF/THF (50 mL) at 50° C. for 6 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and evaporated to give crude tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (9 g, 64%) that was purified by silica chromatography. 1H NMR (CDCl3, 400 MHz) δ 1.41 (d, 9H), 1.65 (m, 6H), 1.95 (m, 3H), 2.98 (d, 3H), 3.10 (m, 1H), 3.52 (m, 1H), 3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](OC)(OC)(OC)[CH2:26][CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[CH2:26]([C:25]1[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)cnc2ccccc12
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCO[Si](C)(C)C(C)(C)C

Procedure:
A solution of N4-[4-(tert-butyldimethylsilanyloxy)butyl]quinoline-3,4-diamine (62.9 g, 182 mmol) and trimethyl orthovalerate (45.2 g, 278 mmol) in toluene (200 mL) was heated at reflux for 2 hours and then concentrated under reduced pressure to provide 2-butyl-1-[4-(tert-butyldimethylsilanyloxy)butyl]-1H-imidazo[4,5-c]quinoline as an oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:12][CH2:11][OH:10])[CH2:8][OH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC(CO)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
In anhydrous THF (80 ml) was dissolved α,α-diphenyl-γ-butyrolactone (7 g) followed by addition of lithium aluminum hydride (1 g) with ice-cooling, and the mixture was stirred under the same conditions for 3 hours. Then, under ice-cooling, a saturated aqueous solution of Rochelle salt was added dropwise to precipitate the aluminum and other inorganic matter. The supernatant was taken by decantation, dried and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to provide 2,2-diphenyl-1,4-butanediol (7 g).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([O:14][N:15]=[C:16]([C:23]2[N:27]([CH3:28])[N:26]=[N:25][N:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])[N:7]=1)=O.[OH-].[K+]>C(O)C>[CH3:28][N:27]1[C:23]([C:16](=[N:15][O:14][CH:12]([C:8]2[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=2)[CH3:13])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:24][N:25]=[N:26]1
Reactant: CC(ON=C(c1ccccc1)c1nnnn1C)c1cccc(NC(=O)C(C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(ON=C(c1ccccc1)c1nnnn1C)c1cccc(N)n1
Yield: 68.5 %

Procedure:
To a stirred solution of 2,2-dimethyl-N-{6-[1-({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)ethyl]pyridin-2-yl}propanamide (19.7 g, 48.3 mmol, 1 eq.) in 200 ml of ethanol, was added potassium hydroxide (88.4 g, 1.57 mol, 32.6 eq.). The reaction mixture was stirred and heated to reflux for 4 hrs. After evaporation of the solvent, The residue was taken up with water (300 ml) and extracted with EtOAc (100 ml). The aqueous layer was separated and extracted twice with EtOAc (100 ml). The organics were combined, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give 6-[1-({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)ethyl]pyridin-2-amine (10.7 g, 90% pure, 61% yield)
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10](=[O:22])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Sn](CCCC)(CCCC)[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)CCC>C(OCCOCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:9]=2)=[O:22])=[CH:14][C:15]=1[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(C#N)c(Br)c2)cc1C
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCOCCOCC
Product: COc1ccc(C(=O)C(=O)c2ccc(C#N)c(-c3cccnc3)c2)cc1C
Temperature: 145 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 2-bromo-4-[(4-methoxy-3-methylphenyl)(oxo)acetyl]benzonitrile (200 mg, 0.56 mmol) and 3-(tributylstannyl)pyridine (268 mg, 0.73 mmol) in 1,2-diethoxyethane is treated with dichlorobis(tri-o-tolylphosphine)palladium(II) (39.6 mg, 0.05 mmol), heated at 145° C., stirred for 30 min. and filtered to remove the catalyst. The filtrate is evaporated to dryness. The resultant residue is purified by flash chromatography (SiO2, 2/1 hexanes/EtOAc as eluent) and crystallization from ethyl ether/hexanes to afford the title compound as a yellow solid, 181 mg (91% yield), identified by HNMR and mass spectral analyses. MS m/e 357 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 3H), 3.93 (s, 3H), 7.18 (d, J=8.69 Hz, 1H), 7.61 (m, 1H), 7.82 (d, J=8.54, 1H), 7.84 (dd, J=8.54, 1.99 Hz 1H), 8.07 (dd, J=7.76, 1.67 Hz, 1H), 8.12 (m, J=1.38 Hz, 2H), 8.25 (d, J=8.08 Hz, 1H), 8.74 (m, 1H), 8.85 (d, 1.68 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[O:21][C:20]([C:23](=[O:25])[NH2:24])=[C:19]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:18]=3[CH:17]=[C:16]([CH3:33])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[CH2:26]([C:19]1[C:18]2[CH:17]=[C:16]([CH3:33])[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:22]=2[O:21][C:20]=1[C:23]([NH2:24])=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2oc(C(N)=O)c(Cc3ccccc3)c2c1
Agent: Cl
Product: Cc1cc(N2CCNCC2)c2oc(C(N)=O)c(Cc3ccccc3)c2c1

Procedure:
4-(3-Benzyl-2-carbamoyl-5-methyl-benzofuran-7-yl)-piperazine-1-carboxylic acid tert-butyl ester was deprotected using ethanolic HCl, following the procedure of step 4 of Example 2, to provide 3-benzyl-5-methyl-7-piperazin-1-yl-benzofuran-2-carboxylic acid amide as a hydrochloride salt, (M+H)+ 350.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][NH:8]2)([O-:3])=[O:2].[Br:19]N1C(=O)CCC1=O>CC(O)=O>[Br:19][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1c[nH]c2cccc([N+](=O)[O-])c12
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(Br)[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (4-nitro-1H-indol-3-yl)acetate from Step A (1.00 g, 4.03 mmol) in AcOH (40 mL) was added N-bromosuccinimide (789 mg, 4.43 mmol) in AcOH (40 mL) dropwise over 30 min. The resulting mixture was stirred at ambient temperature for 1 h, then concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:9]=2)[C:5](C)=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c3c(C)ccc(Cl)c3nn2C2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2c3cccc(Cl)c3nn2C2CCCC2)cc1
Yield: 106.6 %

Procedure:
Prepared according to Method D step C from 7-chloro-2-cyclopentyl-3-(4-methoxyphenyl)-methyl-2H-indazole (0.004 g, 0.012 mmol), boron tribromide (0.10 mL, 1.05 mmol) and 0.3 mL of cyclohexene to give the product (0.004 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[N:25][N:26]=2)[N:23]=1>CN(C=O)C>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:24]1[N:22]2[N:23]=[C:18]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:19]=[CH:20][C:21]2=[N:26][N:25]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Clc1ccc2nnc(-c3ccco3)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc2nnc(-c3ccco3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (60 mg, 0.32 mmol) in DMF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 15 mg, 0.35 mmol). The mixture was stirred at room temperature overnight. After addition of a solution of 6-chloro-3-(2-furanyl)-1,2,4-triazolo[4,3-b]pyridazine (77 mg, 0.35 mmol) in DMF (2 mL) the mixture was stirred at room temperature overnight. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (105 mg, 67%) as a white foam. MS: m/e=374.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:14]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.O.NN.C(#N)C>C(O)COCCO>[NH2:14][N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:6]=[C:2]1[NH2:1]
Reactant: Nc1nc(-c2ccc(F)cc2)cn1N=Cc1ccccc1
Agent: NN
Solvent: CC#N
Solvent: O
Solvent: OCCOCCO
Product: Nc1nc(-c2ccc(F)cc2)cn1N
Temperature: 80 °C

Procedure:
A solution of 5.3 g (0.0189 mol) of 2-amino-1-benzylideneamino-4-(4-fluorophenyl)-imidazole and 12.5 ml of hydrazine hydrate in 18.8 ml of diethylene glycol is stirred at 140° C. for 15 hours. After cooling to 80° C., 70 ml of acetonitrile are added to the reaction mixture, which is then cooled further to 0° C. The product that has separated out is filtered off and washed with acetonitrile and diethyl ether. In that manner there is obtained the title compound, m.p. 227°-230° C., 1H-NMR (DMSO): δ=7.57-7.68 (m, 2H); 7.06-7.15 (m, 2H); 7.01 (s, 1H); 5.52 (s, 2H); 5.36 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([OH:27])=[CH:12][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=1.O>C1(C)C=CC=CC=1>[C:3]([O:27][C:11]1[CH:12]=[C:13]([O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:20])[CH3:19])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:10])([CH3:4])[CH3:2]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2O)c1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-4-((triisopropylsilyl)oxy)-[1,1′-biphenyl]-2-ol (207 mg) in toluene (3.55 mL) was added N,N-dimethylformamidide-tert-butylacetal (636 μL) at room temperature, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled, poured into water, and the mixture was extracted with ethyl acetate. The extract 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 column chromatography (ethyl acetate/hexane) to give the title compound (96 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[N:19]=1>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[N:19]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)n1c(CBr)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2nc3ccccc3n2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (746 mg, 5.2 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.18 g, 15.8 mmol) and 2-(bromomethyl)-1-(propan-2-yl)-1H-benzimidazole (1.99 g, 7.9 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM in MeOH to afford 6-methyl-2-({[1-(propane-2-yl)-1H-benzimidazol-2-yl]methyl}sulfanyl)pyrimidin-4-ol (1.01 g, 41% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.55 (s, 3H), 1.56 (s, 3H), 2.20 (s, 3H), 4.76 (s, 2H), 4.84-4.92 (m, 1H), 6.06 (bs, 1H), 7.13-7.20 (m, 2H), 7.54-7.57 (m, HA 7.68-7.71 (m, 1H); LRMS (ES) m/z 315 (100%, M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15].O>CO.C1C=CC=CC=1.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C(Oc1ccc(F)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 2.8 g of p-fluorophenol, 1.19 g of sodium methoxide, and 50 mg of potassium iodide in 40 ml of methanol was added 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate in 10 ml of benzene. The mixture was refluxed overnight and cooled to room temperature. The mixture was poured into 100 ml of water and extracted with 2×75 ml of ether. The combined extracts were washed with 50 ml of 5% NaOH, 2×50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent at reduced pressure yielded an amber oil which was chromatographed on 100 g of silica gel (benzene) to yield 6.7 g of an amber oil which solidified on trituration with petroleum ether, mp 70°-72.5° C.