Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].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>[F:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cc1cc(F)nc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(F)nc(-c2ccc(F)cc2)c1
Yield: 36.1 %

Procedure:
A mixture of 2-bromo-6-fluoro-4-methylpyridine (9.5 g, 50 mmol), 4-fluorobenzeneboronic acid (7.8 g, 56 mmol), sodium bicarbonate (12.6 g, 150 mmol), water (200 mL) and catalytic amounts of tetrakis(triphenylphosphine)palladium(0) in DME under nitrogen is heated to reflux overnight. After filtration of the reaction mixture the solvents are removed under reduced pressure. The residue is partitioned between water and ethyl acetate. The layers are separated and the aqueous layer is washed with ethyl acetate. After drying of the combined organic layers with anhydrous magnesium sulphate, the solvent is removed in vacuo. The crude product is purified by flash column chromatography (silica gel, pentane/ethyl acetate 9/1) yielding colorless crystals of 2-fluoro-6-(4'-fluorophenyl)-4-methylpyridine (3.7 g, 36.1% of th.) with mp 49° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:19])[N:3]=1.[CH2:20]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>O>[NH2:27][CH:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH:28]2[CH2:33][CH2:32][CH:31]([NH:34][C:2]3[CH:7]=[C:6]([C:8]4[C:16]5[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=5)[NH:10][CH:9]=4)[CH:5]=[C:4]([Cl:19])[N:3]=3)[CH2:30][CH2:29]2)[CH2:26][CH2:25]1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(Cl)c3)c2c1
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Solvent: O
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCC(CC5CCC(N)CC5)CC4)c3)c2c1
Yield: 58.7 %

Procedure:
A mixture of Example 149e (0.634 g, 2.16 mmol) and 4,4′-methylenedicyclohexanamine (2.267 g, 10.78 mmol) was heated at 155° C. for 90 minutes and cooled. While still warm, the slurry was treated with water and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 28 g Biotage KP-NH column using the ISCO Companion flash system eluting with MeOH/EtOAc (3:97 to 5:95) to give 593 mg of the title compound. 55 mg of this material was further purified by reverse-phase HPLC as described in Example 56 to give 17 mg of the title compound as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.02-1.45 (m, 9H), 1.57-1.92 (m, 9H), 1.99-2.18 (m, 2H), 3.02 (m, 1H), 3.70 (m, 1H), 3.95 (s, 3H), 6.72-6.92 (m, 2H), 7.80-7.91 (m, 2H), 8.06 (s, 1H). MS (DCI+) m/z 468.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:20]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:15]2[CH2:18][C:17](=[O:19])[CH2:16]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Yield: 98.8 %

Procedure:
Triethylamine (112.1 g, 1.11 mols) was added to a solution of N-diphenylmethylazetidin-3-ol (26.6 g, 0.11 mol) in DMSO (300 ml). The solution was cooled to 10° C. and a solution of sulphur trioxide-pyridine complex (112 g, 0.7 mol) in DMSO (500 ml) added, rapidly. Stirring was continued at 10° C. for 0.75h and the mixture then warmed to 25° C. and stirred for 1h. The solution was poured into ice-water (21) and extracted with EtOAc (3×1). The combined extracts were washed with water (500 ml) and brine (500 ml) and dried (Na2SO4). The crude product was purified by chromatography through silica-gel eluting with petroleum ether/EtOAc (2:1) to give the desired ketone (25.8 g), mp 74°-75° C.; δ (360 MHz, CDCl3) 4.00 (4H, s, 2 of CH2), 4.59 (1H, s, CH), 7.19-7.49 (10H, m, Ar--H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([CH3:17])[CH:11]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Br)ccc1N
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)ccc1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, 5.4 mmol) was added to a solution of 4-Bromo-2-methyl-phenylamine (1.0 g, 5.4 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (830 mg, 56% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(OC(Cl)=O)C(C)C.O[NH:33][C:34](=[NH:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:16][N:47]=[C:34]([CH2:35][O:36][C:37]3[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=3)[N:33]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(OCC(=N)NO)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.06 g, 9 mmol), NEt3 (1.2 g, 12 mmol) in toluene (150 mL) was added isobutylchloroformate (1.23 g, 9 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. N-hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine (1.5 g, 6 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.98 (2H, m), 7.14 (2H, m), 5.24 (2H, s), 4.2-4.05 (2H, m), 3.14 (1H, m), 3.03 (3H, s), 2.95 (2H, m), 2.12˜2.04 (2H, m), 1.80 (2H, m), 1.46 (9H, s).
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:12])[S:10][C:6]=2[CH:5]=[CH:4][NH:3]1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2c(=O)[nH]ccc2s1
Product: N#Cc1cc2c(Cl)nccc2s1

Procedure:
A solution of 4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-nitrile (500 mg, 2.84 mmol) prepared as in F. Eloy and A. Deryckere, Bull. Soc. Chim. Belg. 1970, 79, 301) and phosphoryl chloride (5 mL) was heated at reflux for 1 hour. The formed red solution was poured onto ice and extracted with methylene chloride (2×150 mL). The dichloromethane solution was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography with 1:10 EtOAc/hexanes to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:14][C:15]([F:31])([F:30])[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24](O)=[O:25])[N:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:18]3[N:17]=[C:16]([C:15]([F:30])([F:14])[F:31])[O:20][N:19]=3)[CH:22]=2)=[O:25])[CH2:10][CH2:9]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2ccccc2F)CC1
Yield: 28 %

Procedure:
This compound was synthesized from 1-(2-fluorophenyl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (45 mg, yield 28%). 1H NMR (400 MHz, CDCl3) δ 8.21-8.20 (m, 2H), 7.68-7.60 (m, 2H), 7.11-6.94 (m, 4H), 4.01 (m, 2H), 3.63 (m, 2H), 3.20-3.06 (m, 4H). MS (ESI) m/z: Calculated for C20H16F4N4O2: 420.12. found: 421.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7])=[O:4].CO[CH:17](OC)[N:18](C)C>>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[O:7][N:18]=[CH:17][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cnoc1-c1ccc(F)cc1
Yield: 86.3 %

Procedure:
A mixture of methyl 4′-fluorobenzoylacetate (10.02 g) and N,N-dimethylformamide dimethylacetal (8.63 g) was refluxed for 1.5 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (150 ml). To the obtained solution was added hydroxylamine hydrochloride (6.75 g) and the mixture was refluxed for 5 hr. The reaction mixture was concentrated, dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 5-(4-fluorophenyl)isoxazole-4-carboxylate (9.75 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 92–93° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>C(O)(=O)C>[Br:13][C:14]1[CH:15]=[C:10]2[CH:9]=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]2=[N:12][CH:17]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1ccnn1-c1ccccc1
Solvent: CC(=O)O
Product: Brc1cnc2c(cnn2-c2ccccc2)c1
Yield: 28.7 %

Procedure:
Dissolve 1-phenyl-5-aminopyrazole (Tokyo Kasei Kogyo Co. LTD; 1.5 g, 9.4 mmol) and 2-bromomalonaldehyde (Aldrich; 1.42 g, 9.4 mmol) in glacial acetic acid (170 mL) and reflux under nitrogen for 5 h. Concentrate under reduced pressure and purify via chromatography (silica gel, dichloromethane) to obtain 740 mg (28%) of the title compound as an off-white solid. TOF MS ES+ exact mass calculated for C12H9N3Br (p+H): m/z=273.9980, Found. 273.9965.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH:1](=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[NH2:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: NC1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCC=C1CCCCC1N
Reaction time: 1 h
Yield: 86 %

Procedure:
At 0° C., 16.3 g (20 mL, 0.23 mol) of butyraldehyde (Formula IV) was added dropwise to 21.7 g (25 mL, 0.22 mol) of cyclohexylamine (Formula III). After 1 h, 6 g of anhydrous sodium sulfate was added and the mixture stirred for 5 h. The product was decanted from the salt water slurry, dried by addition of further 10 g of anhydrous sodium sulfate, filtered and distilled. Characteristics of the product: bp 88° C. (20 mm); yield 86%; NMR (CDCl3, δ): 1.0 (3H, t) 1.1-2.1 (12H), 2.3 (2H, g), 3.0 (1H, m), 7.8 (1H, t).
Reaction SMILES: [N:1]([CH:4]([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].[Na].Cl>CS(C)=O.C(O)C>[NH2:16][C:15]1[N:1]([CH:4]([CH3:14])[CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:2]=[N:3][C:17]=1[C:18]([NH2:20])=[O:19]
Reactant: CC(CCCc1ccccc1)N=[N+]=[N-]
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 997 mg (5.28 mmol) of (4-azidopentyl)-benzene and 672 mg (8 mmol) of cyanoacetamide in 3 ml of DMSO is admixed with a solution, of a temperature of 50° C., of 127 mg (5.5 mmol) of sodium in 3 ml of ethanol. The reaction mixture is stirred at room temperature for 15 h and then poured into 25 ml of ice-water. The pH is adjusted to pH 2 using 1N HCl and the precipitated solid is filtered off with suction, washed with water and dried under reduced pressure. This gives 1.14 g (79%) of a slightly yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CC(C)=O>[F:10][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][OH:9]
Reactant: Nc1ccc(CO)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a stirred solution of (4-amino-2-fluorophenyl)methanol (100 mg, 0.709 mmol, 1 eq.) in acetone (1.0 mL) was added pyridine (0.17 mL, 2.12 mmol, 3 eq.) followed by phenyl chloroformate (0.092 mL, 0.709 mmol, 1 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated and the resulting residue was purified by CC using ethyl acetate/PE (7:13) as eluent to get phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (110 mg, 60%, off-white solid; TLC system: EtOAc/PE (1:1), Rf: 0.4).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].[NH3:12].[OH-].[Na+]>O>[NH2:12][C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11]
Reactant: N
Reactant: CC1Cc2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(N)Cc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
According to the procedure of Farnum et. al (Synthesis 1972, 191-192.), water (1.35 L) is stirred at 80° C. and de-gassed by periodic evacuating and flushing with nitrogen (3×). K3FeCN6 (202 g, 615 mmol) and 2-methyl-indan-1-one (20 g, 137 mmol) are added. The mixture is stirred rapidly under nitrogen at 80° C. while aqueous concentrated ammonia solution (105 mL) is added over 30 minutes. Stirring is continued at 80° C. for 20 hours. When cool, the solution is made alkaline by addition of sodium hydroxide (2 g) and extracted with ethyl acetate (2×200 mL). The organic extract is concentrated to a volume of 200 ml and the product is extracted into aqueous HCl (200 mL, 1M). The acidic aqueous phase is separated, basified with sodium hydroxide, and extracted with ethyl acetate (2×100 mL). The organic layer is separated, dried (Na2SO4) and the solvent removed to give an orange oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.[CH2:44]([O:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58]Br)[CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:44]([O:51][C:52]1[CH:53]=[C:54]([CH:55]=[CH:56][CH:57]=1)[CH2:58][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: BrCc1cccc(OCc2ccccc2)c1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccc(OCc3ccccc3)c2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 1-(benzyloxy)-3-(bromomethyl)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ7.43-7.14 (m, 8H), 7.06-6.99 (m, 1H), 6.97-6.87 (m, 3H), 6.81-6.75 (m, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.10-5.00 (m, 3H), 4.85-4.75 (m, 1H), 4.84 (ABq, 2H), 4.56-4.47 (m, 2H), 2.98-2.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 161.8, 161.3, 159.2, 142.1, 137.4, 136.6, 132.7, 129.9, 128.7, 128.6, 128.0, 127.5, 123.8, 123.4, 120.2, 119.9 (2C), 118.8, 114.0, 113.9, 109.3, 93.2, 80.5, 72.3, 70.0, 57.7, 44.0, 29.0; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]2[CH:27]=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[C:30]([NH2:32])[CH:31]=2)=[CH:24][CH:23]=1>CCCCCC.CCOC(C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:32][C:30]3[CH:31]=[C:26]([C:25]4[CH:37]=[CH:38][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:27]=[C:28]([C:33]([F:34])([F:35])[F:36])[CH:29]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: COc1ccc(-c2cc(N)cc(C(F)(F)F)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2cc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc(C(F)(F)F)c2)cc1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 7.1) and 4′-methoxy-5-trifluoromethyl-biphen-3-ylamine. Title compound: ES-MS: 502.9 [M+H]+; tR=5.00 min (System 1); Rf=0.21 (Hexane/EtOAc, 1:4).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][C:12]3=[CH:15][NH:16][N:17]=[C:11]3[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:18][C:19]1[N:24]=[CH:23][C:22]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:14][CH2:13]3)=[N:17]2)=[CH:21][CH:20]=1
Reactant: c1ccc(CN2CCc3c[nH]nc3CC2)cc1
Reactant: OB(O)c1ccc(Br)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1ccc(-n2cc3c(n2)CCN(Cc2ccccc2)CC3)cn1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 6-(phenylmethyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 5) (200 mg, 0.88 mmol), (6-bromo-3-pyridinyl)boronic acid (355 mg, 1.76 mmol), copper acetate (478 mg, 2.64 mmol), pyridine (0.142 ml, 1.76 mmol) and molecular sieves (600 mg) in dichloromethane (10 ml) was allowed to stir at room temperature in a flask open to the atmosphere for 240 hours. The reaction mixture was filtered through a pad of celite, washing with dichloromethane and methanol. The filtrate was evaporated, redissolved in methanol and passed down a 10 g SCX cartridge, eluting with methanol, then a 2 M solution of ammonia in methanol. The basic fractions were combined, evaporated and purified by column chromatography, eluting with a mixture of 2M ammonia in methanol and dichloromethane (0-10%). The impure product was re-purified using reverse phase chromatography, eluting with a mixture of acetonitrile and water (5-100% and 3-60%) to afford the product (D15); MS (ES+) m/e 383 & 385 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2)[CH3:2].[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:16](=[O:19])[CH2:17][CH3:18])=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2)[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCc1cc2ccc(C(=O)OC)cc2[nH]1
Product: CCC(=O)c1c(CC)[nH]c2cc(C(=O)OC)ccc12

Procedure:
Methyl 2-ethyl-3-propionylindole-6-carboxylate (435 mg) was prepared from methyl 2-ethylindole-6-carboxylate (660 mg) and propionyl chloride (0.62 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1COC1
Reactant: Brc1cnc(Br)cn1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2cnc(Br)cn2)COC1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
2,5-Dibromopyrazine (1 g, 4.2 mmol) was dissolved in toluene (20 mL) under nitrogen and cooled to −78° C. n-Butyllithium (2.5M solution in hexanes, 1.77 mL) was added slowly with stirring and allowed to stir for a further 10 minutes upon complete addition. Oxetan-3-one (270 μL, 4.62 mmol) was added, and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The residue was taken up in DCM (50 mL) and washed with saturated aqueous sodium bicarbonate solution (40 mL). The aqueous layer was re-extracted with DCM (50 mL). The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The crude brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (470 mg, 45%) as a yellow solid. Method B HPLC-MS: MH+ m/z 231, RT 1.13 minutes.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:34]([CH3:38])[CH2:35][CH2:36][OH:37])[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[CH2:27]([O:26][C:24]1[CH:23]=[C:22]([CH:34]([CH3:38])[CH2:35][CH2:36][O:37][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:21]=[C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCO)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (11.1 g., 58.1 mM) is added to a solution of 3-(3,5-dibenzyloxyphenyl)-1-butanol (20.7 g., 57 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexane. Yield: 24.63 g. (84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[C:16]([F:18])[CH:17]=1>C1C=CC=CC=1.C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:5]2[NH:4][C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[C:7](=[O:8])[CH2:6]2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CC1(C)C(=O)C=CNC1=O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC1(C)C(=O)CC(c2cc(F)cc(F)c2)NC1=O

Procedure:
To a solution of 3,3-dimethylpyridine-2,4(1H,3H)-dione (978 mg, 7.03 mmol) [U.S. Pat. No. 2,525,231] in benzene (10 mL) was added 3,5-difluorophenylmagnesium bromide (50 mL of a 0.5 M solution in THF, 25 mmol) and the resulting mixture was heated to reflux for 1.5 h. The mixture was cooled, quenched with 1 N aqueous HCl (10 mL), made basic with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with H2O (50 mL), then brine (50 mL), and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 60:40, to give the title compound. MS: m/z=254 (M+1).