Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]N1C(C)(C)CCCC1(C)C.N1CCCCC1.[Li]CCCC.[CH:49](=[O:52])[CH2:50][CH3:51]>C1COCC1>[NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH:49]([OH:52])[CH2:50][CH3:51])[C:13]([F:19])=[C:12]([Cl:20])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Reactant: CCC=O
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CCC(O)c1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
A −40° C. solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.274 mmol) in THF (10 mL) was treated with LTMP (1.10 mmol, freshly prepared by mixing 2,2,6,6-Tetramnethyl piperidine and n-BuLi at 0° C. for 30 min.). The mixture was then allowed to warm to 0° C. for 2 h. The reaction mixture was cooled to −30° C. and propionaldehyde (159 mg, 2.74 mmol) was added. The reaction was stiffed at −30° C. for 2 h before it was slowly quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography to afford 2-anilino-7-chloro-6-fluoro-5-(1-hydroxypropyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (120 mg, 97%) as a white solid: LCMS RT: 3.14 min, MH+: 424.2. Other electrophiles such as disulfide may be used to quench the anion.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH2:9][C:10](OC)=[O:11]>C1COCC1>[CH3:14][C:8]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:7])[CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CC(C)(C)c1cc(F)ccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CCO
Yield: 88.9 %

Procedure:
To a suspension of lithium aluminum hydride (0.75 g) in THF (20 mL) stirred under nitrogen was added dropwise a solution of methyl 3-methyl-3-(2-methoxy-5-fluorophenyl)butanoate (4.2 g) dissolved in THF (10 mL). The mixture was stirred at room temperature for 4 hours. The reaction was quenched by cautious addition of water (1 mL) and diluted with ether (100 mL). The mixture was filtered through FLORISIL® selective adsorbent and evaporated to dryness in vacuo to give 3-methyl-3-(2-methoxy-5-fluorophenyl)butan-1-ol as an oil (3.30 g, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)[CH3:22])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 18.7 g (59.7 mmol) of trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 110 ml of methanol was added 41.25 g (298.5 mmol) of potassium carbonate. The reaction mixture was then stirred for 2 hours at room temperature. The excess of potassium carbonate was removed by filtration and the methanol was removed by evaporation under reduced pressure. The crude residue was partitioned between Et2O, 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent giving 13.9 g (86%) of pure trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 272 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C1CCCCC1>ClCCl.CO>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(NC(=O)OC(C)(C)C)C4)c3n2)c2ccc(Cl)cc21
Solvent: C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(N)C4)c3n2)c2ccc(Cl)cc21
Yield: 33.7 %

Procedure:
The less polar, diastereomer B of (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester (66 mg, 126 μmol) isolated from Example 276 was dissolved in dichloromethane (5 mL) and treated with TFA (1.48 g, 1 mL, 13.0 mmol). After 18 h at room temperature the solvents were evaporated and the residue dissolved in dichloromethane/MeOH, adsorbed on silica gel and purified by chromatography (25 g column, 50 μm from Thomson, 0 to 5% MeOH containing 10% ammonium hydroxide) in dichloromethane, 20 min gradient) to give an off white residue that was dissolved in dichloromethane containing few drops of MeOH. Cyclohexane was added to promote solid formation. The precipitate was separated by decanting the mother liquor and dried under high vacuum to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide (diastereomer B) (18 mg, 33.7%) as a white solid. MS (M+H)+=424; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.42 (s, 1H), 8.37 (d, J=8.7 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.30 (d, J=10.2 Hz, 1H), 4.36 (br. s., 1H), 4.16 (s, 3H), 3.33 (br. s., 1H), 3.13 (br. s., 1H), 2.54 (br. s., 1H), 1.79 (br. s., 1H), 1.59-1.71 (m, 2H), 1.53 (d, J=9.4 Hz, 1H), 1.38 (s, 1H), 1.32 (s, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](N)[CH2:9][NH2:10].C=O>C(Cl)Cl>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:8][CH2:9][NH:10]1
Reactant: NCCN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: ClCCl
Product: c1ccc2c(c1)CCNO2
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts methylene chloride and 144 parts of ethylene diamine. The temperature of the reaction mixture is adjusted to 25° C. and 595 parts of 50% formalin is added while maintaining the temperature below 30° C. The reaction mixture is stirred for 2 hours at 30° C. after formaldehyde addition is complete. It is then heated to atmospheric reflux, refluxed for 3 hours and allowed to cool and separate into two layers. The upper water layer is withdrawn and discarded. The lower organic layer is reheated to atmospheric reflux and distilled to remove solvent. Heating is continued with the gradual reduction of pressure until a temperature of 70° C. at about 5.0 kPa pressure is reached. Cellosolve (460 parts) is added to the resin slowly, keeping the temperature near 70° C. A uniform yellow solution forms which is cooled and filtered. The product has 66% closed dihydroxybenzoxazine ring and a calculated equivalent wt. of 224. The solution has a solids content of 60.2%.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=C(N)[S:10][C:6]=2[CH:5]=1.[K]>O>[NH2:8][C:7]1[CH:12]=[CH:13][C:4]([F:3])=[CH:5][C:6]=1[SH:10]
Reactant: Nc1nc2ccc(F)cc2s1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(F)cc1S
Temperature: 40 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
In a 2,000-ml flask as a reactor were placed 166.7 g of water, 589.3 g of a 50% aqueous potassium hydroxide solution (5.25 moles as KOH) and 168.2 g (1.00 mole) of 6-fluoro-2-aminobenzothiazole. They were heated, aged for 8 hours with refluxing at 113 to 115° and then cooled to 40° C. The resulting mixture was washed with 311 g of toluene and then subjected to phase separation to obtain 904.0 g of an aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol (concentration: 20%, yield: 99.7%). This aqueous solution of a potassium salt of 2-amino-5-fluorothiophenol can be used for production of a p-toluenesulfonate of [2-(6-fluorobenzothiazolyl)]ethylamine or an aqueous solution of [2-(6-fluorobenzothiazolyl)]ethylamine hydrochloride, according to the description in Example 1 to Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11]>S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCCO
Reactant: O=Cc1sccc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: Brc1ccsc1C1OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
Pyridinium tosylate (1 g., 4 mmoles) was added to a mixture of 3-bromothiophene-2-carboxaldehyde (2) (18.7 g., 97.9 mmole), ethylene glycol (22 mL., 24.8 g., 400 mmole) and dry toluene (100 mL). The mixture was refluxed and the water removed by a Dean-Stark trap. After 1 hour, TLC (10% EtOAC/hexane) showed the reaction was complete. The mixture was cooled to room temperature and partitioned between ether (100 mL) and water (100 mL) components. The organic layer was separated and extracted with water (3×50 mL) and then with a saturated solution of sodium bicarbonate (25 mL). The resulting extract was dried (MgSO4), filtered and evaporated in vacuo to leave 21.5 g, of crude product. This product was distilled to give 17.6 g of 3 -Bromo-2-(2-dioxolanyl)thiophene (3), bp: 86°-87° C./0.5 mm.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8]1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1.O>COCCOC>[CH:7]1([CH2:10][CH2:11][O:12][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:9][CH2:8]1
Reactant: OCCC1CC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1

Procedure:
To a stirring solution of sodium tert.-butoxide (13.45 g) in DME (80 ml) was added dropwise under nitrogen a solution of 2-cyclopropylethanol (12.1 g) in DME (40 ml) over 5 min. After 30 min 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (11.84 g) was added and the stirring mixture refluxed for 20 h. After cooling the mixture was treated with water and extracted twice with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was re-evaporated twice from toluene then purified on a silica column using an ISCO Companion, eluting with methanol:ethyl acetate (0-12%) to give the title compound. Yield 6.53 gm.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH:14]=[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCCC(=O)C1
Product: CN(C)C=C1C(=O)CCCC1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
1,3-Cyclohexanedione (11.2 g, 100 mmol) was suspended in dimethylformamide dimethylacetal (28 mL) and the mixture was heated at reflux for 1 h. The mixture was cooled to room temperature and the solvent was evaporated to provide an orange solid, which was recrystalized from ethyl acetate to provide 12 g (72%) of 2-dimethylaminomethylene-1,3-cyclohexanedione as light orange needles, mp 116°-118° C.; 1H NMR (CDCl3) δ8.05 (s, 1H), 3.40 (s, 3H), 3.19 (s, 3H), 2.26 (t, 4H), 1.95 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][C:9]=2[N:10]=1.[ClH:18]>O1CCOCC1>[ClH:18].[Br:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate (4.01 g, 12.56 mmol) in dioxane (20 ml) is added 4N HCl in dioxane (20 mL, 80 mmol), and the mixture is stirred at rt overnight. The solvent is removed and the residue is washed with ether to give a white solid. MS (M+1): 218.9.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[OH:7][CH:4]1[CH2:5][CH2:6][N:2]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Temperature: 5 °C

Procedure:
Into a 500 mL 3-necked round bottom flask was placed a solution of pyrrolidin-3-ol hydrochloride (20.2 g, 163.43 mmol) in H2O (60 mL) while cooling to 5° C. Adjustment of the pH to 7 was accomplished by the NaOH (10%). This was followed by the addition of a solution of benzyl chloroformate (36.8 g, 216.47 mmol), which was added dropwise with stirring, while cooling to a temperature of 5° C. The resulting solution was allowed to react, with stirring, for 2 hours at 5° C. Then the resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting solution was extracted three times with 100 mL of ethyl acetate and the organic layers combined and dried over MgSO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 30 g (crude) of benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Br.[Br:17][C:18]1[CH:19]=[C:20]([CH2:25]Br)[C:21]([NH2:24])=[N:22][CH:23]=1>CN(C)C=O>[NH2:24][C:21]1[C:20]([CH2:25][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[CH:19][C:18]([Br:17])=[CH:23][N:22]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CN
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
Glycine ethyl ester hydrochloride (805 mg, 5.7 mmol) and triethylamine (2.6 mL, 18.46 mmol) were successively added to a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2, 5.7 mmol) in dimethylformamide (65 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (70 ml) and water (100 mL). The aqueous phase was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (10:0 to 95:5) as eluent. The title product was obtained as a yellow solid (1.1 g, 68%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:19])[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[OH-].[Na+].Cl>CO>[O:19]=[C:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: COC(=O)c1ccc2c(=O)c3ccccc3oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 25 °C

Procedure:
A solution of 9-oxo-9H-xanthene-3-carboxylic acid methyl ester (3.75 mmol) and 3 N sodium hydroxide (4.12 mmol) in MeOH (30 mL) was heated at reflux for 2 h. The solution was cooled to rt and made acidic with 2 N hydrochloric acid. The mixture was concentrated in vacuo, and then diluted with water. The resultant solid was collected by filtration, washed with water and air-dried to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[Si:13]([O:20][CH2:21][C:22]([CH3:36])([CH3:35])[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH2:23][C:22]([CH3:35])([CH3:36])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[O:11])=[CH:4][C:3]=1[F:12]
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(Br)c(F)c2)cc1C(F)(F)F
Yield: 61.4 %

Procedure:
A solution of 2-(4-bromo-3-fluorophenyl)acetic acid (50 mg, 0.215 mmol), 4-(3-((tert-butyl dimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (78 mg, 0.215 mmol), DIEA (83 mg, 0.644 mmol), HOBt (49.3 mg, 0.322 mmol) and EDC hydrochloride (61.7 mg, 0.322 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=3/1) to yield 2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (80 mg, 0.132 mmol, 61.4% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.15 (dd, J=9.7, 1.8 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 3.62 (s, 2H), 2.70 (s, 2H), 2.07 (s, 2H), 0.86 (s, 9H), 0.76-0.69 (m, 6H), 0.05-0.02 (m, 6H); ES-LCMS m/z 576.0 (M+H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]2C(=O)C3=CC=CC=C3C2=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.C(OCC)C>CO>[NH2:18][CH:16]1[CH2:17][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15]1
Reactant: O=C1c2ccccc2C(=O)N1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: NN
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Yield: 96.3 %

Procedure:
A mixture of 0.244 mol of 1-benzhydryl-3-phthalimidoazetidine in 1000 ml of anhydrous methanol is heated at reflux for 15 minutes, then, after removing the heating bath, 0.339 mol of 85% hydrazine hydrate are added thereto. The mixture is heated at reflux for 30 minutes, then a solid white product begins to precipitate from the limpid solution thus obtained. The mixture is again heated for 90 minutes, then it is cooled at 10° C. One liter of diethyl ether is added to the mixture which is then filtered. After washing with ether, the solid product (35 g) is discarded and the mother-liquor is concentrated under reduced pressure. The residue is taken up with 500 ml of water and the pH of the solution is adjusted to 11 with sodium hydroxide. After extraction with 1 liter of diethyl ether, the ethereal phase is washed with water, dried on anhydrous sodium sulfate and evaporated under reduced pressure. Thus, the 3-amino-1-benzhydrylazetidine is obtained in the form of an oil which tends to solidify Yield 96.3%. By reaction with hydrochloric acid in a isopropanol/acetone mixture, the 3-amino-1-benzhydrylazetidine dihydrochloride is obtained which, after crystallization from isopropanol, melts at 108°-110° C. 1HNMR (CDC13): δTMS (ppm): 1.65 [2H, S(b) ], 2.6 (2H,m), 3.5 (3H, m), 4.25 (1H, s) 7.0-7.5 (10H, m) (free base).
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[N+:6]([CH2:9][CH3:10])([O-])=[O:7].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>CCOCC>[CH3:10][C:9]1[C@H:3]2[CH2:2][O:1][CH2:5][C@H:4]2[O:7][N:6]=1
Reactant: CC[N+](=O)[O-]
Reactant: C1=CCOC1
Solvent: O=C=Nc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1=NO[C@@H]2COC[C@H]12
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution of 2,5-dihydrofuran (5 g, 69.9 mmol) in ether (90 ml) was treated dropwise with a solution of nitroethane (5.46 g, 71.3 mmol) in ether (15 ml) at room temperature. Thereafter, triethylamine (70.7 mg, 699 μmol) was added followed by the dropwise addition of phenyl isocyanate (17.3 g, 143 mmol). The reaction mixture was stirred for 3 days at room temperature. For the workup, the white precipitate was filtered and washed with ether. The filtrate was evaporated and the crude product was purified by chromatography using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. After a second chromatography the (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (58% yield) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9]Br.C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CNc1ccccc1
Reactant: BrBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: ClCCl
Product: CNc1ccc(Br)cc1
Temperature: 0 °C
Yield: 141.3 %

Procedure:
10.7 g N-methylaniline (XXI), 32.1 g tetrabutylammonium bromide [(C4H9)4N+Br31]and 100 ml methylene chloride (CH2Cl2) were placed in a three-necked flask and cooled down to 0° C. with iced saline. 15.8 g bromine (Br2) was dropped slowly with stirring and was stirred for 4 hours while maintaining at 0° C. The temperature was allowed to raise to room temperature and saturated sodium carbonate solution was dropped slowly till evolution of carbon dioxide is ceased. Water layer was separated and extracted with methylene chloride for three times. The organic layers were combined and dried over anhydrous sodium sulfate. Methylene chloride was evaporated to yield 26 g 4-bromo-N-methylaniline (XXII).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([NH2:7])=[O:6])[CH:17]=[CH:16][CH:15]=2
Reactant: C#CCCC(N)=O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCC(N)=O)c21

Procedure:
Using Method C above, 4-pentynamide (49 mg, 0.5 mmol) (prepared from 4-pentyonic acid according to Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (120 mg, 0.32 mmol) using (Ph3P)2PdCl2 (12 mg) and Cul (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h to yield (Z)-5-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynamide. (Yield 45 mg, 42%).