Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O:11][C:12]1[CH:28]=[CH:27][CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[N+:29]([O-])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H][H]>C1COCC1.[Ni]>[S:1]([O:11][C:12]1[CH:28]=[CH:27][CH:26]=[C:14]([O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:13]=1[NH2:29])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(OS(=O)(=O)c3ccc(C)cc3)c2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cccc(OS(=O)(=O)c3ccc(C)cc3)c2N)cc1
Reaction time: 4 h

Procedure:
To 2-nitroresorcinol ditosylate (46.3 g, 0.1 mole) dissolved in THF (650 ml) was added 5 g of Raney Nickel. The reaction was then placed on the Parr-shaker apparatus and hydrogenated at 40 psi. After four hours, the reaction had consumed all of the hydrogen (12 psi, 0.3 mole). The catalyst was removed by filtration and the solvent evaporated under reduced pressure at 40° C. A white crystalline solid was recovered (42.0 g, 97.0 percent). TLC showed the product to be pure.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[S:32][C:25]2([CH2:30][CH2:29][N:28](C)[CH2:27][CH2:26]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]1=2>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[S:32][C:25]2([CH2:26][CH2:27][N:28]([C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[CH2:29][CH2:30]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]1=2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)SC(c1ccccc1Cl)c1ccccc12
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccccc1Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To 3.83 g of phenyl chloroformate in 850 ml of dichloromethane is added a solution of 6.73 g of the free base 3-(2-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 32 in 75 ml of dichloromethane over two minutes. The reaction is stirred at ambient temperature for 64 hours, then diluted with 200 ml of dichloromethane and washed with two 300 ml portions of 5% aqueous sodium hydroxide solution, two 200 ml portions of water and one 75 ml portion of brine. The solution is dried over magnesium sulfate and evaporated to an oil. The oil is chromatographed on a silca gel with dichloromethane to give an oil of 3-(-2-chlorophenyl)-1,3-dihydro-1'-phenoxy carbonylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]([O:9][CH3:10])=[CH:6][CH2:7][CH:8]=1.[Li]CCCC.[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1.CCCCCC>[CH:16]1([CH:4]2[C:3]([O:2][CH3:1])=[CH:8][CH2:7][CH:6]=[C:5]2[O:9][CH3:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC1=CCC=C(OC)C1
Reactant: BrC1CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=CCC=C(OC)C1C1CCCC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a solution of 2,5-dihydro-1,3-dimethoxybenzene (9.88 g, 70 mmol) in dry THF (150 mL) was added dropwise nBuLi solution (2.5 M, 42.4 mL) in hexane at −20° C. The orange colored reaction mixture was stirred for 0.5 hour at −20° C., then cyclopentyl bromide (20.9 g, 140 mmol) was added dropwise. The reaction mixture was stirred for 1 hour at −20° C. to 0° C. Excess nBuLi was destroyed cautiously with methanol. To the reaction mixture, 140 mL of cold water was added. The product was extracted with ethyl acetate (3×80 mL). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as light yellow liquid (14.12 g, 96.8%). 1H NMR: δ 1.0–2.4 (Complex, 9H), 2.7–2.94 (m, 3H), 3.52 (s, 6H, 2×OCH3), 4.70 (t, 2H).
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:7])=[O:6].[Cl:10]N1C(=O)CCC1=O>S(Cl)(Cl)=O>[Cl:10][CH:4]([CH2:3][C:2]([Br:9])([Br:8])[Br:1])[C:5]([Cl:7])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Cl)CCC(Br)(Br)Br
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C(Cl)CC(Br)(Br)Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
343.2 g (1.0 mol) of 4,4,4-tribromobutyric acid chloride are dissolved in 600 g of thionyl chloride, and 266.0 g (2.0 mols) of N-chlorosuccinimide are added in portions at 60° C., whilst at the same time exposing the mixture to a high-pressure mercury lamp. After all of the N-chlorosuccinimide has been added, the resulting mixture is stirred for 5 hours at 60° C., with exposure to the said lamp. The thionyl chloride is then distilled off and the residue is rectified under a high vacuum. 309.7 g (82% of theory) of 2-chloro-4,4,4-tribromobutyric acid chloride with a boiling point of 59° to 63° C./0.05 mm Hg are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[C:22]([C:23]([O:25]C)=O)=[C:21]([O:27][CH3:28])[N:20]=[CH:19][CH:18]=1.[NH3:29]>CO>[CH3:28][O:27][C:21]1[N:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[C:23](=[O:25])[NH:29][C:15]([CH2:14][CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]1=[O:11])=[CH:16]2
Reactant: N
Reactant: COC(=O)c1c(C#CCCCN2C(=O)c3ccccc3C2=O)ccnc1OC
Solvent: CO
Product: COc1nccc2cc(CCCN3C(=O)c4ccccc4C3=O)[nH]c(=O)c12
Temperature: 115 °C

Procedure:
Methyl 4-(5-(1,3-dioxoisoindolin-2-yl)pent-1-ynyl)-2-methoxynicotinate (100 mg, 0.26 mmol) is dissolved in 7% NH3 in MeOH (3 mL) and heated at 115° C. in a sealed tube for 24 hours. The reaction mixture is cooled and the solvents are removed by evaporation. The cyclized product is separated using silica gel column chromatography using hexan:ethyl acetate as solvent. MS m/z 364.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:26])[CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:9].I[CH3:28]>CN(C=O)C.O>[CH3:26][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][C:8]([N:10]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:24][CH3:25])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:28])=[O:9]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCN(C)C)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(N(C)C(=O)CCCN(C)C)ccc21
Reaction time: 5 h
Yield: 5.9 %

Procedure:
Sodium hydride (8 mg of a 60% suspension in mineral oil, 4 mg, 0.19 mmol, 1.2 equiv) was added to a solution of 4-dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-butyramide (50 mg, 0.15 mmol, 1 equiv) in DMF (0.3 mL). The resultant suspension was stirred at room temperature for 1 hour, and then iodomethane (0.012 mL, 27 mg, 0.19 mmol, 1.25 equiv) was added via syringe. After an additional 5 hours at room temperature, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water (1×10 mL) and brine (1×10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by rotary chromatography (CH2Cl2 grading to 2% ammonium hydroxide in 5% MeOH/CH2Cl2) to provide 4-dimethylamino-N-(9-ethyl-9H-carbazol-3-yl)-N-methyl-butyramide (3 mg, 5%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6]O)=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>O1CCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:5]([CH2:6][Cl:17])=[C:4]([F:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1cc(CO)c(F)cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)Oc1cc(CCl)c(F)cc1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
Then, 6.7 g of 4-chloro-2-fluoro-5-isopropoxybenzylalcohol was dissolved in 70 ml of tetrahydrofuran, to which 1 ml of pyridine was added, and the mixture was cooled to 5° C. Then, 5 ml of thionyl chloride was slowly added dropwise at 5° to 10° C., and the mixture was stirred at 5° C. for 1.5 hours. After completion of the reaction, the reaction mixture was filtered to separate the precipitated crystals, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, which afforded 7.3 g of 4-chloro-2-fluoro-5-isopropoxybenzyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18](I)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH:18]2[CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:19]2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2ccc([N+](=O)[O-])n2)C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with DMF (20 mL), 3-nitro-1H-pyrazole (1.00 g, 8.84 mmol), N-tert-butoxycarbonyl-3-iodoazetidine (3.00 g, 10.6 mmol) and potassium carbonate (2.45 g, 17.7 mmol), and the reaction mixture was stirred at 60° C. for 16 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting residue was mixed with methylene chloride (15 mL) and water (15 mL). The aqueous layer was separated and extracted with methylene chloride (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 80% yield (1.92 g) of 105a as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H, J=2.4 Hz), 6.97 (d, 1H, J=2.4 Hz), 5.13 (m, 1H), 4.44 (m, 2H), 4.33 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:18]([O:21]C(Cl)=O)(Cl)Cl.[N-]=C=O>C1(C)C=CC=CC=1>[F:16][C:3]1[C:2]([N:1]=[C:18]=[O:21])=[CH:15][C:6]2[N:7]([CH2:12][CH2:13][CH3:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: CCCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: CCCN1C(=O)COc2cc(F)c(N=C=O)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3.9 grams (0.017 mole) of 6-amino-7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one in 240 ml of toluene was added a solution of 2.06 grams (0.0104 mole) of trichloromethylchloroformate in 10 ml of toluene. This mixture was stirred at room temperature for 1.5 hours and then was heated at reflux for approximately 18 hours. The mixture was cooled, and the solvent was removed by distillation at atmospheric pressure leaving a residue. This residue was subjected to reduced pressure for two hours to yield 4.36 grams of 7-fluoro-4-propyl-2H-1,4-benzoxazin-3(4H)-one-6 yl is isocyanate as a brown solid.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[C:13]([O:17][C:18]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[CH:7]([C:6]1[C:5]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:24]=[CH:23][CH:22]=2)=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:8]
Reactant: O=Cc1cccnc1Br
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: OBO
Product: CC(C)(C)OC(=O)n1cccc1-c1ncccc1C=O

Procedure:
tert-butyl 2-(3-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (66 mg, 146.5 mg theoretical, 45.1%). LC-MS m/z 273.3 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C@@H:8]([CH2:11][Br:12])[CH2:7][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[Br:12][CH2:11][C@H:8]1[CH2:7][C:6]2[CH:5]=[C:4]([F:13])[CH:3]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[Cl:14])[C:10]=2[O:9]1
Reactant: Fc1cc(Br)c2c(c1)C[C@H](CBr)O2
Reactant: OB(O)c1ccccc1Cl
Product: Fc1cc2c(c(-c3ccccc3Cl)c1)O[C@@H](CBr)C2
Yield: 100.6 %

Procedure:
Treatment of (R)-7-bromo-2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran (0.5 g, 1.6 mmol) and 2-chlorobenzene boronic acid (0.76 g, 4.8 mmol) generally according to the procedure described for Intermediate 37 gave 0.55 g (99%) (R)-2-bromomethyl-7-(2-chloro-phenyl)-5-fluoro-2,3-dihydrobenzofuran as a colorless oil. HRMS EI M+339.9657; [α]D25=+29.6 (c 8.14 in methanol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3C(=O)C4C=CC=CC=4C3=O)[CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NN>CCO>[NH2:25][CH2:24][CH2:23][O:22][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])/[CH:12]=[CH:11]/[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCCN3C(=O)c4ccccc4C3=O)c2)cc1
Agent: NN
Solvent: CCO
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCCN)c2)cc1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added Example 27, (2E)-3-[4-(tert-butyl)phenyl]-N-{3-[2-(1,3-dioxobenzo[c]azolin-2yl)ethoxy]phenyl}prop-2-enamide, (856 mg, 1.83 mmol), EtOH (15 mL) and hydrazine (574 uL, 18.3 mmol, Aldrich). The reaction mixture was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (40 mL), washed with 10% K2CO3 (15 mL), water (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (step gradient, EtOAc followed by 1:1 EtOAc:EtOH) provided the title product as an oil. MS (ESI, pos. ion) m/z: 339 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[F:13][C:14]([F:30])([F:29])[C:15]1[N:20]=[C:19]([N:21]2[CH2:28][CH2:27][C:24]3([O:26][CH2:25]3)[CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[OH:26][C:24]1([CH2:25][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:27][CH2:28][N:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:14]([F:30])([F:29])[F:13])[N:20]=2)[CH2:22][CH2:23]1
Reactant: FC(F)(F)c1nccc(N2CCC3(CC2)CO3)n1
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCN1CC1(O)CCN(c2ccnc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 15.1 %

Procedure:
Potassium tert-butoxide (1.03 g, 9 mmol) was added to a solution of 2-pyrrolidinone (0.7 g, 7.7 mmol) in anhydrous DMF (25 mL). The mixture was stirred for 45 min at room temperature to produce a milky white precipitate. A solution of XXIX (2.0 g, 7.7 mmol) in dry DMF (6 mL) was then added and the mixture slowly turned clear as it was stirred for 18 hr. The mixture was concentrated in vacuo and the residue chromatographed on neutral alumina using ethyl acetate as the eluent to give the white solid product (0.40 g, 35%, mp: 170°-172° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[O:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH2:25][CH2:26][NH2:27])=[O:23])[N+:15]([O-:17])=[O:16]>C(O)CCC>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:27][CH2:26][CH2:25][NH:24][C:22]([NH:21][CH2:20][CH2:19][CH2:18][O:14][N+:15]([O-:17])=[O:16])=[O:23]
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Reactant: NCCNC(=O)NCCCO[N+](=O)[O-]
Solvent: CCCCO
Product: Cc1ccc(Cl)c(OCC(O)CNCCNC(=O)NCCCO[N+](=O)[O-])c1

Procedure:
3.1 g. 1-(2-Chloro-5-methylphenoxy)-2,3-epoxypropane and 8.5 g. 2-[(3-nitroxypropylamino)-carbonylamino]-ethylamine in 100 ml. n-butanol are stirred at ambient temperature for 18 hours. The solvent is distilled off at 30° C. bath temperature under oil pump vacuum, the residue is dissolved in 150 ml. ethyl acetate and this solution is washed 4 times with 60 ml. amounts of water. The organic phase is dried and evaporated and the residue is chromatographed on silica gel with methylene chloride/methanol (6:4 v/v). The appropriate fractions are evaporated and the residue is triturated with diethyl ether, filtered off with suction and dried. There are obtained 2.2 g. (35% of theory) of the desired product in the form of crystals; m.p. 109°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20]([N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 4-hydroxypiperidine (50 mg, 0.49 mmL) in anhydrous DMSO (3 mL) was heated at 100° C. under nitrogen for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-{4-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 55 mg, 89%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.C(O)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
2-(4-Methoxy-phenyl)-trans-cyclopropanecarboxylic acid ethyl ester (1.43 g, 6.51 mmol) is dissolved in dry dichloromethane (30 mL) and cooled to −78° C. Boron tribromide solution (1 M in dichloromethane, 7.81 mL, 7.81 mmol) is added dropwise then the mixture is allowed to warm to −20° C. and stirred overnight at −20° C. Ethanol (3 mL) is added and the mixture warmed to room temperature then diluted with saturated aqueous sodium bicarbonate solution. The phases are separated and the aqueous phase extracted with dichloromethane. The combined organic phases are dried through a phase seperator and the solvent removed under vacuum. The residue is purified by flash chromatography (10% ethyl acetate in cyclohexane) and then crystallised from 10% ethyl acetate in cyclohexane to give the title compound (yield 0.58 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Cl)[O:12][CH3:13]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][O:12][CH3:13])=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1
Yield: 95.1 %

Procedure:
Add sodium hydride (2.78 g of 95% dry, 0.116 mol) in portions to a 500 mL three-necked flask equipped with a nitrogen inlet, magnetic stir bar and DMF (200 mL) at −10 to −15° C. Add a solution of 4-bromophenol (20.00 g, 0.116 mol) in DMF (100 mL) over about 20 minutes, maintaining the internal temperature of the reaction below −5° C. Stir the reaction for 1 hour and then add MOMCl (8.81 mL, 0.116 mol) in portions to maintain the internal temperature below −5° C. Stir the mixture for 3 hours and then add ice until gas evolution ceases. Pour the reaction into ice-H2O (500 mL) and extract with EtOAc (2×300 mL). Wash the combined organic extracts with 1 N NaOH (500 mL), H2O (500 mL) and brine (400 mL). Dry the solution (MgSO4), filter and concentrate to obtain the title product (23.94 g, 93%) as an oil which may be used without further purification. 1H NMR (CDCl3) δ 3.46 (s, 3H), 5.14 (s, 2H), 6.92 (d, J =9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:13][CH2:14][CH2:15][CH2:16][C:17]([C:19]1[O:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:13][CH2:14][CH2:15][CH2:16][CH:17]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[C:19]1[O:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:23]=1
Reactant: COc1cccc2c1CCC2N
Reactant: O=C(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 1 h
Yield: 32.6 %

Procedure:
A solution of 1-amino-2,3-dihydro-4-methoxy-1H-indene (0.30 g), 4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butan-1-one (0.56 g) and p-toluenesulfonic acid (catalytic amount) in toluene (50 ml) was refluxed for 2 days with Dean-stark equipment. The solvent was evaporated in vacuo and the residue was dissolved in methanol (10 ml). To the methanol solution was added NaBH4 (0.20 g) at 0° C. After being stirred for 1 hour at the same temperature, the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.27 g). MS (m/z): 455 (M+ +1) NMR (CDCl3, δ): 1.60-3.20 (10H, m), 3.76 (2.5H, s), 3.84 (3.5H, s), 4.02-4.52 (2H, m), 7.59-7.69 (4H, m), 6.69-7.39 (9H, m)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.CN(C)C=O.Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH3:25])=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:17]=1>O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:18]2[N:17]=[C:16]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:25])=[CH:32][CH:31]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Temperature: 120 °C
Yield: 13.3 %

Procedure:
Sodium hydride (60% in mineral oil, 160 mg, 4.1 mmol) was added to 3,5-dimethylpyrazole (320 mg, 3.4 mmol) dissolved N,N-dimethylformamide (10 mL) and the mixture was stirred for 30 min. (2-Chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (1.0 g 3.40 mmol) was added and the reaction mixture was heated at 120° C. for 4 days, cooled down and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol/ammonia) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (160 mg, 13%) as a yellow crystalline compound.