Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:24]#[N:25].C(OCC)C.[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[C:18]([C:24]#[N:25])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1[C@H]1CN(Cc2ccccc2)CCO1
Reactant: N#C[Cu]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc(C#N)cc1[C@H]1CN(Cc2ccccc2)CCO1
Yield: 0.1 %

Procedure:
A solution of (2S)-4-benzyl-2-(5-bromo-2-methoxyphenyl)-morpholine (17.1 g, 47.2 mmol) and copper cyanide (6.35 g, 70.9 mmol) in 1-methyl-2-pyrrolidinone (140 ml) was stirred at 160° C. for 9 hours. Diethyl ether and 1N aqueous sodium hydroxide were added to the reaction mixture, and the solution was passed through Celite column. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (2S)-4-benzyl-2-(5-cyano-2-methoxyphenyl)-morpholine (10.1 mg, 69%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#N)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.Cl.NNC(N)=[O:16].C([O-])(=O)C.[Na+]>[Ni].O.CO>[Cl:1][C:2]1[C:7]([CH:8]=[O:16])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: NNC(N)=O
Reactant: Cc1cc(C#N)c(Cl)nc1C
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C=O)c(Cl)nc1C
Yield: 60.5 %

Procedure:
A mixture of 2-chloro-3-cyano-5,6-dimethylpyridine (21.5 g), semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) was hydrogenated at 344 kPa at 50° using Raney nickel catalyst (5 g). The mixture was added to water (750 ml) and filtered. The solid filtered off was suspended in water (130 ml) and concentrated hydrochloric acid (70 ml) was added and the mixture was heated at 100° for 1 hour; formalin (40% w/w, 120 ml) was added and the mixture was heated at 100° for a further 0.5 hour and allowed to cool. Sodium acetate (95 g) and water (250 ml) were added and the mixture was extracted with ether and the extracts were washed with 5% aqueous potassium carbonate and evaporated to give 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, 60%), m.p. 69°-70°.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C(N(C(C)C)CC)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([CH2:2][CH2:3][O:4][CH2:5][CH:6]=[CH2:7])(=[O:20])=[O:19]
Reactant: C=CCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOCCS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
Combine allyl hydroxyethyl ether (1.02 g, 10 mmol), and diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain allyl methanesulfonylethyl ether: Rf=0.80 (silica gel, 20% ethyl acetate/dichloromethane).
Reaction SMILES: [Na].C[O-].[Na+].[F:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH:23]=1)[CH:21]=O>CO>[F:5][C:6]1[CH:14]=[CH:13][C:9](/[C:10](=[CH:21]/[C:20]2[CH:23]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=2[N+:24]([O-:26])=[O:25])/[C:11]#[N:12])=[CH:8][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: N#CCc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(/C=C(\C#N)c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
Sodium metal (0.836 g, 0.0363 mol) was dissolved in MeOH (40 mL), and the resulting sodium methoxide solution was cooled to 0° C. To this was added 4-fluorobenzyl cyanide (4.9 g, 0.0363 mol), and the mixture stirred for 30 min. at 0° C. 5-Methyl-2-nitrobenzaldehyde (3.0 g, 0.0181 mol) was added at the same temperature, and the reaction mixture was stirred for a further 1 h at 0° C. After completion of reaction (monitored by TLC), the precipitated solid was isolated by filtration to give the desired compound as a light yellow colored solid (3.0 g, 58% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][CH:10]([CH:17]([C:23]([O:25]CC)=[O:24])[C:18]([O:20]CC)=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:28])[CH2:9][CH:10]([CH:17]([C:23]([OH:25])=[O:24])[C:18]([OH:20])=[O:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CC(c1ccccc1)C(C(=O)O)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
The solution of diethyl 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonate (0.9 g) and 3M NaOH (7.5 ml) in ethanol (30 ml) was heated to reflux for 4 h. The mixture was cooled to rt, poured into water (30 ml), and acidified with 10% HCl. The aqueous layer was extracted three times with ethyl acetate (20 ml) and the combined organic layers were washed with brine and dried (magnesium sulfate). After evaporation of the solvent the residue was recrystallised from benzene to give 2-[3-(4-chlorophenyl)-3-oxo-1-phenylpropyl]malonic acid (0.5 g) as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[CH:19]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:22]([C:21]4[CH:25]=[CH:26][C:18]([F:17])=[CH:19][C:20]=4[N:27]4[N:31]=[CH:30][CH:29]=[N:28]4)=[O:23])[CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and Intermediate 4. MS (ESI): mass calculated for C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (400 MHz, CDCl3) 7.83-7.72 (m, 4H), 7.42 (dd, J=8.5, 5.8, 1H), 7.14 (ddd, J=8.5, 7.8, 2.5, 1H), 3.94-3.86 (m, 1H), 3.82-3.74 (m, 1H), 3.73-3.60 (m, 2H), 3.56-3.47 (m, 1H), 3.42-3.31 (m, 2H), 3.10-2.82 (m, 3H), 2.50 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
An ice-cold solution of 4-bromo-2-methylphenol (5.6 g, 30 mmol) and pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane was treated with a solution of acetyl chloride (2.8 mL, 26 mmol) in 5 mL of anhydrous dichloromethane. After 2 hours, the reaction mixture was concentrated in vacuo. The resulting residue was treated with crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.9 g of 4-bromo-2-methylphenyl acetate as a light brown oil (quantitative yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Product: Cc1cnc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-5-methyl-3-nitropyridine and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[CH:37]=[C:36]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:35]=[CH:34][C:33]=1[F:42].CC12CC3(C)P(C4C=CC=CC=4)C(C)(CC(C)(O3)O1)O2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:42][C:33]1[CH:32]=[CH:37][C:36]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][C:34]=1[C:6]1[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=3)(=[O:22])=[O:21])[C:4]=2[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(S(C)(=O)=O)ccc4F)cn(C)c(=O)c32)cc1
Temperature: 60 °C
Yield: 88.5 %

Procedure:
A mixture of Example 6a (0.642 g, 1.5 mmol), 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.380 g, 1.500 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.051 g, 0.176 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.041 g, 0.045 mmol), and potassium phosphate (0.796 g, 3.75 mmol) in dioxane (10 mL) and water (2.500 mL) was degassed and back-filled with nitrogen several times. The reaction was heated at 60° C. for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes to give the title compound (0.63 g, 1.328 mmol, 89% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.CC1C=CC(S(O[CH2:20][C@@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].O1CCOCCOCCOCCOCCOCC1.CN(C=O)C>>[CH3:26][C:23]1([CH3:27])[O:22][C@H:21]([CH2:20][N:3]2[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]2)[CH2:25][O:24]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: Cc1n[nH]c(C)c1I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C[C@@H]2COC(C)(C)O2)c(C)c1I
Temperature: 70 °C

Procedure:
A mixture of 3,5-dimethyl-4-iodopyrazole (200.0 mg, 0.9008 mmol), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (515.9 mg, 1.802 mmol), K2CO3 (136.9 mg, 0.9909 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (23.81 mg, 0.09008 mmol) and DMF (4 mL, 50 mmol) was heated to 70° C. overnight. The material was extracted in EtOAc, and washed with water (3×). The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 20-30% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1>>[CH3:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[C:27](=[O:32])[C:26]12[C:44]2[C:35](=[CH:36][C:37]3[O:42][CH2:41][CH2:40][O:39][C:38]=3[CH:43]=2)[O:34][CH2:33]1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Reactant: FC(F)(F)c1cccnc1CCl
Agent: BrCC1CCCCO1
Agent: Cl
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ncccc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 137-139° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=4.6 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 7.57-7.50 (m, 1H), 7.02-6.94 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.40 (s, 1H), 5.29-5.03 (ABq, 2H), 4.76-4.64 (ABq, 2H), 4.18-4.06 (m, 4H), 2.18 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 153.0, 152.9, 144.5, 140.9, 138.2, 135.5 (q, 4J=5.31 Hz), 132.5, 132.5, 129.3, 124.5, 124.4 (q, 1J=273.6 Hz), 123.5 (q, 2J=32.3 Hz), 123.5, 122.2, 112.3, 109.3, 99.1, 79.7, 64.7, 64.1, 57.8, 42.4 (q, J=3.1 Hz), 21.0; MS (ES+) m/z 469.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](Br)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(OCC)(=O)C.[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:33]#[N:34])=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
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
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2C#N)CC1

Procedure:
Under argon atmosphere 47 mg (0.4 mmol) of Zn(CN)2 and 23 mg of (0.02 eq) Pd(PPh3)4 were added to a solution 62 mg (0.4 mmol) of 4-(5-bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (11) in DMF. The reaction was heated for 5 minutes to 150° C. in a microwave reactor (CEM Discovery). After cooling to room temperature water and ethyl acetate were added. The mixture was filtered through celite, washed with ethyl acetate and concentrated to yield 176 mg of compound 15.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>O1CCCC1>[CH3:21][Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4-oxocyclohexanecarboxylate (5.95 g) (Example B) in 200 ml of anhydrous tetrahydrofuran is added dropwise under nitrogen to a solution of lithium diisopropylamide (prepared from 4.40 g of diisopropylamine and 26.2 ml of 1.6 M n-butyllithium hexane solution) in 200 ml of tetrahydrofuran at -78° C. The mixture is stirred at this temperature for one hour and trimethylsilyl chloride (4.71 g) is added dropwise via syringe. The reaction mixture is allowed to warm to room temperature overnight and the solvent evaporated in vacuo. The residue is triturated with 100 ml of diethyl ether and filtered to remove inorganic salts. Evaporation of the volatile components of the mixture gives ethyl 4-[(trimethylsilyl)oxy]-3-cyclohexene-1-carboxylate as a colorless oil which is reacted with N-bromosuccinimide and thiourea by following the procedure of Example 1 (Method A) to yield the title compound as a white solid; mp 170°-173° C.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=O)[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=[CH2:1])[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Butyl lithium (3.56 mL, 1.58 M, toluene solution) was added dropwise under cooling with ice to a suspension of methyltriphenylphosphonium bromide (2.15 g, 6.03 mmol) in tetrahydrofuran (20 mL), followed by stirring at room temperature for 20 minutes, and further at 40° C. for 5 minutes. Subsequently, a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine [an isomer mixture of (4S)-form: (4R)-form (1:3)] (700 mg, 2.01 mmol) in tetrahydrofuran (7.0 mL) was added under cooling with ice to the resultant mixture, followed by stirring at room temperature for 10 hours. The reaction mixture was poured to a 10% aqueous citric acid solution (20 mL), and the resultant mixture was diluted with ethyl acetate (100 mL). The obtained aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed sequentially by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:4), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (250 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH:7]=[CH:8][CH:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl.[Co](Cl)Cl>[C:1]([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=CC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)OC(C)(C)C)COc1ccccc1-3

Procedure:
Cobalt chloride hexahydrate (cat.; 0.12 eq) was added to a solution of methyl 7-[3-tert-butoxy-3-oxoprop-1-en-1-yl]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH (0.02 M). Once the cobalt chloride was in solution, NaBH4 (5.4 eq) was introduced. Vigorous effervescence was noted, along with a darkening of the solution to grey/black. After circa 5 min, effervescence had subsided and the dark colour in the reaction began to dissipate with the reaction returning to yellow within 10 min. The reaction mixture was partitioned between EtOAc and 1N HCl (aq). The organics were washed with sat. aq. NaHCO3, water and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The product was taken on without further purification (97%). (ES+) m/z 518 (M+H)+; 540 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C1C(=O)N([Br:28])C(=O)C1>ClCCl>[Br:28][C:17]1[CH:18]=[CH:19][C:20]2[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOCCn1c2ccccc2c2ccccc21
Solvent: ClCCl
Product: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 1a (2 g, 7.4 mmol) in dichloromethane (60 mL) was added NBS (1.3 g, 7.4 mmol) portionwise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:5) as eluent to afford 2a (1.75 g) in 68% yield as an oil that can turn into solid after standing. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.44 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.22 (m, 1H), 4.46 (t, J=6.0 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.48 (m, 2H), 3.39 (m, 2H), 3.28 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.7, 139.2, 128.2, 126.3, 124.5, 122.8, 121.8, 120.4, 119.3, 111.7, 110.4, 109.0, 71.8, 70.7, 69.1, 59.0, 43.2. MS (FAB) m/z Calcd for C17H18BrNO2 347.0 Found 347.3 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([N:21]([CH3:20])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: CNc1ccccc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: CN(c1ccccc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with N-methylaniline following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21].Cl>>[C:20]([O:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1cccc(Oc2ccc(O)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(Oc2cccc(C(=O)O)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
An amount of 3-(4'-hydroxyphenoxy)benzoic acid (9.772 g, 42.45 millimoles (mmoles)) was dissolved in 6 M NaOH (18 ml, 108 mmoles) and cooled in an ice bath. Acetic anhydride (8.0 ml, 11.1 g, 109 mmoles) was added cautiously to the basic solution at such a rate as to maintain 0° to 5° C. and then stirred vigorously for an additional 15 minutes (min) at 0° C. The reaction mixture was then allowed to warm to room temperature over 1 hour. The aqueous solution was acidified with 6 M HCl (18 ml, 108 mmoles) and extracted with 75 ml of ethyl acetate. The organic solution was washed three times with a 50 ml saturated solution of NaCl, dried with MgSO4, filtered, and solvent evaporated. The crude product was taken up in methanol, treated with activated carbon, filtered through a celite pad, and evaporated. Recrystallization of the product gave 9.83 g of 3-(4'-acetoxyphenoxy)benzoic acid as an off-white powder with a m.p. 141° C. to 143° C.