Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].B(F)(F)F.CCOCC.[CH:19]([O:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([N:29]2[CH2:34][CH2:33][C:32](=[CH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][C:24]=1[CH3:41])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]1[CH:9]=[C:6]([CH:7]([OH:8])[CH2:37][C:36](=[O:38])[CH:35]=[C:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:26]3[CH:39]=[CH:40][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[C:24]([CH3:41])[CH:25]=3)[CH2:30][CH2:31]2)[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(F)c1
Reactant: CC(=O)C=C1CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC(=CC(=O)CC(O)c3cncc(F)c3)CC2)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-fluoronicotinaldehyde (51 mg, 0.41 mmol) in dichloromethane (1.7 mL) was cooled to −78° C. and boron trifluoride diethyl etherate (164 μL, 0.82 mmol) was added. The mixture was stirred at −78° C. for 5 min. The solution from step 1 was added. The mixture was stirred at −78° C. for 5 min, quenched with a buffer solution of pH=7. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to afford 4-(5-fluoro-3-pyridyl)-4-hydroxy-1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butan-2-one (105 mg). 1H NMR (400 MHz, CDCl3) δ 8.46-8.31 (m, 2H), 7.53-7.49 (m, 1H), 7.24-7.22 (m, 2H), 6.83 (d, J=8.1 Hz, 1H), 6.09 (s, 1H), 5.26 (dd, J=8.9, 5.9 Hz, 1H), 4.62-4.53 (m, 1H), 4.13-4.12 (m, 1H), 3.69 (br d, 4H), 3.00 (br s, 2H), 2.88 (d, J=6.2 Hz, 2H), 2.37 (br s, 2H), 2.21 (s, 3H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 440.21, found 441.4 (M+1)+; Retention time: 1.65 minutes (3 min run).
Reaction SMILES: C[O-].[Na+].Cl.[Cl:5][CH:6]=[CH:7][CH2:8][O:9][NH2:10].[C:11]([CH:16]1[C:21](=[O:22])[CH2:20][CH:19]([CH2:23][CH:24]([S:26][CH2:27][CH3:28])[CH3:25])[CH2:18][C:17]1=[O:29])(=O)[CH2:12][CH2:13][CH3:14]>CO>[Cl:5][CH:6]=[CH:7][CH2:8][O:9][N:10]=[C:11]([C@H:16]1[C:21](=[O:22])[CH2:20][C@H:19]([CH2:23][CH:24]([S:26][CH2:27][CH3:28])[CH3:25])[CH2:18][C:17]1=[O:29])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)C1C(=O)CC(CC(C)SCC)CC1=O
Reactant: NOCC=CCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCC(=NOCC=CCl)[C@H]1C(=O)C[C@H](CC(C)SCC)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.38 g of sodium methoxide, 10 ml of methanol, and 1.0 g of 3-chloroallyloxyamine hydrochloride (H2NOCH2CH=CHCl) were admixed together and then stirred for 10 minutes at room temperature. 2 g of 2-butyryl-5-(2-ethylthiopropyl)cyclohexane-1,3-dione was added and the resulting mixture stirred for about two days at room temperature. The mixture was then concentrated by evaporation and the concentrate mixed with 60 ml of diethyl ether and 40 ml of water. The ether layer was extracted with 40 ml of aqueous 2 wt. % sodium hydroxide solution, washed with 20 ml of water, dried over anhydrous magnesium sulfate and evaporated affording a minor amount of the title compound as the trans isomer.
Reaction SMILES: [C:1](OCC)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.C(O[CH:25]=[CH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])C.Cl>C(#N)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:8])[O:32][C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=1)=[O:4])[CH3:7]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(F)(F)F)oc1=O
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Diethyl malonate (33.7 g, 0.2 mol) was dissolved in acetonitrile (200 mL), and magnesium chloride (21.4 g, 0.22 mol) was slowly added thereto at 0 to 5° C. After 10 minutes, triethylamine (44.5 g, 0.44 mol) was added dropwise thereto at 0 to 5° C., and the mixture was allowed to react for 1 hour at room temperature. To the reaction mixture, 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (37.0 g, 0.22 mol) was added dropwise at 0 to 5° C., and the mixture was allowed to react for 1 hour at room temperature. The reaction mixture was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. Thus obtained oily product was dissolved in toluene (100 mL), p-toluenesulfonic acid (5 g) was added thereto, and the mixture was allowed to react for 3 hours under heating. After cooling, the solvent was distilled off, and thus obtained crystal was recrystallized from ethyl acetate, to obtain 31.8 g of a desired product (yield: 67%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14].CS([C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)(=O)=O.C(=O)([O-])[O-]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[C:8]([O:14][C:19]2[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=2)=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: Cc1ncoc1-c1c(O)cccc1Cl
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2-c2ocnc2C)n1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
5 ml DMF solution containing 0.25 g 2-(4-methyloxazole-5-yl)-3-chlorophenol, 0.19 g 2-methanesulfonyl-4,6-dimethoxypyrimidine and 0.42 g pottasium carbonate was stirred for 14 hours at 50° C. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and then dried by using anhydrous magnesium sulfate. After filtration, the solvent used was removed by distillation under reduced pressure, affording the objective substance in an amount of 0.34 g.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:13]#[N:14])=[CH:5][C:6]=1[CH:7]=[N:8][NH:9][C:10](=[O:12])[CH3:11].C([O-])(=O)C.[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.[Cu]>[C:10]([N:9]1[C:2]2[S:3][C:4]([C:13]#[N:14])=[CH:5][C:6]=2[CH:7]=[N:8]1)(=[O:12])[CH3:11]
Reactant: CC(=O)NN=Cc1cc(C#N)sc1Cl
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)n1ncc2cc(C#N)sc21
Temperature: 200 °C
Reaction time: 6 h
Yield: 10.1 %

Procedure:
To a solution of 2.53 g of acetic acid (2-chloro-5-cyanothiophen-3-ylmethylene)hydrazide in 22 mL of diphenyl ether were added copper powder and potassium acetate at room temperature, and stirred at 200° C. for 6 hours. Following filtration through Celite, the filtrate was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:5), to afford 215 mg of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:22]([C:23]=2[CH2:24][CH:25]=1)[CH2:21][CH2:20][C@@:18]1([CH3:19])[C@H:9]3[CH2:10][CH2:11][C:12]21[CH2:16][CH:15]([OH:17])[CH2:14][O:13]2.C(O)(=O)C>O>[OH:17][CH:15]1[CH2:14][O:13][C:12]2([CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:22]([CH2:21][CH2:20][C@:18]23[CH3:19])[C:23]2[CH2:24][CH2:25][C:3](=[O:2])[CH2:4][C:5]=2[CH2:6][CH2:7]4)[CH2:16]1
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23CC(O)CO3)C1
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC21CC(O)CO1)CC(=O)CC4
Reaction time: 4 h

Procedure:
A suspension of 1 part of 4',5'-dihydro-3-methoxyspiro[estra-2,5(10)-diene-17,2'(3'H)-furan]-4'-ol in 20 parts of aqueous 90% acetic acid is stirred for 13/4 hours, during which solution occurs. Approximately 100 parts of cold water is thereupon introduced, whereupon the precipitate which forms is filtered off, washed with water, dried in air, and recrystallized from ethyl acetate to give 4',5'-dihydro-4'-hydroxyspiro[estr-5(10)-ene-17,2'(3'H)-furan] -3-one melting at 118°- 123°.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][CH2:29][CH2:30][NH2:31]>O>[CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16]([NH:31][CH2:30][CH2:29][OH:28])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: NCCO
Solvent: O
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(NCCO)nc12

Procedure:
8.1 gm (0.02 mol) of 8-(N-benzyl-methylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 158°-160° C.) were heated at about 90° C. for one hour with 12.2 gm (0.2 mol) of 2-hydroxyethyl-amine. The mixture thus obtained was taken up in about 250 ml of water, whereby the reaction product separated out as a precipitate which soon solidified. It was filtered off, washed with water and dried at about 60° C. Yield: 8.2 gm (96% of theory).
Reaction SMILES: [I:1][C:2]1[C:10](C)=CC=C[C:3]=1[C:4](O)=O.B.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[I:1][C:2]1[CH:10]=[C:16]([CH2:17][OH:13])[CH:15]=[CH:14][C:3]=1[CH3:4]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: C1CCOC1
Agent: B
Product: Cc1ccc(CO)cc1I

Procedure:
To a solution of 5.0 g (19.1 mmol) of 2-iodo-3-methyl benzoic acid in 50 mL of anhydrous tetrahydrofuran, was slowly added 22 mL of a 1M borane solution in tetrahydrofuran. The resultant reaction mixture was reacted for approximately ninety minutes and then was quenched with ethanol resulting in the evolution of hydrogen gas. The mixture was diluted with ethyl acetate. The resulting layers were separated and the organic layer was washed sequentially with sodium bicarbonate and brine, dried over sodium sulfate, filtered and crystallized from a hexane/ethyl acetate mixture to provide 120 mg of the desired subtitled compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[S:22][C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH3:29])CCC.O1CCOCC1>ClCCl.[OH-].[Na+].C([O-])(O)=O.[Na+]>[CH3:29][C:19]1[N:20]=[C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[S:22][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1
Reactant: O=C1CCCc2ccc(Cl)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2cccnc2)nc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Yield: 92 %

Procedure:
In a MW vial, 2-chloro-6,7-dihydro-5H-quinolin-8-one (0.215 g, 1.18 mmol) and tributyl-[4-methyl-2-(3-pyridyl)thiazol-5-yl]stannane (0.500 g, 1.07 mmol) were stirred in 1,4-dioxane (3.6 mL, 1.07 mmol) at ambient temperature. This yellow solution was degassed with an argon flux for 10 min and Tetrakis(PPh3)Pd(O) (0.124 g, 0.107 mmol) was added. The solution was irradiated in MW at 160° C. for 40 min. The crude was diluted with dichloromethane, NaOH (1 M) and NaHCO3 sat aq were added and aqueous layer was extracted 3 times with dichloromethane. The organic phase was then washed with brine, dried over Na2SO4 anhydrous, filtered and concentrated. Purification by column with a gradient of dichloromethane+0-10% methanol gave the title compound as a beige solid, yield: 92%. LCMS: 0.81 Min, 322 (M+1).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CC(O)C.[C]=O.[C:16]([O:19][CH:20]([CH2:27][CH2:28][S:29][CH3:30])[C:21]([O:23][CH:24](C)C)=O)(=[O:18])[CH3:17]>O1CCCC1.C1(C)C=CC=CC=1>[C:16]([O:19][CH:20]([CH2:27][CH2:28][S:29][CH3:30])[C:21]([O:23][CH3:24])=[S:8])(=[O:18])[CH3:17]
Reactant: CSCC=COC(C)=O
Reactant: CSCCC(OC(C)=O)C(=O)OC(C)C
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene (Z:E ratio 43:57) and 2.5 mmoles 2-propanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. No catalyst was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that no 2-acetoxy-4-(methylthio)butanoic acid, 2-propyl ester was produced and that no 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced. 0.0515 mmoles of acrolein and 0.0456 mmoles of methyl acetate were the only products detectable.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([CH3:10])([CH3:9])[C:3]1=[O:11].C1C=CC=CC=1.[CH2:18](O)[CH:19]([CH3:21])[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][C:7]=1[O:8][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CO
Reactant: CC1C(=O)C=CC(C)(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=C(OCC(C)C)CCC(C)(C)C1=O
Temperature: 25 °C

Procedure:
The compound 2,6,6-trimethylcyclohexen-1,3-dione (43.6 g) was added to a mixture of benzene (250 ml), isobutanol (50 ml) and PTSA (500 mg) and heated under reflux for 3 hr in conjunction with a Dean and Stark water separator. The reaction was then cooled to room temperature, washed with aqueous sodium carbonate solution and brine and taken to dryness "in vacuo". Distillation of residue through a 6" vacuum jacketed vigreaux column yielded pure 2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1 one (54.6 g) bp 104°-107°.
Reaction SMILES: [CH2:1]([N:4]([CH:8]=[N:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[OH:16])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O1CCCC1>[CH3:24][N:25]([CH3:29])[C:26]([O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[N:9]=[CH:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:27]
Reactant: CN(C)C(=O)Cl
Reactant: CCCN(C=Nc1ccncc1O)CCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(C=Nc1ccncc1OC(=O)N(C)C)CCC

Procedure:
A mixture prepared from 4-[[(dipropylamino)methylene]amino]-3-pyridinol (3.22 g), triethylamine (3.15 g), dimethylcarbamyl chloride (2.01 mL) and tetrahydrofuran (100 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. The eluate was concentrated and the solid was recrystallized from diethyl ether to yield 2.99 g of product, m.p. 84°-85° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([OH:15])=[CH:12]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:15][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: COC(=O)CBr
Reactant: C=CCOc1ccc2ccc(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2ccc(OCC(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7.9 g of 7-(2-propenyloxy)-2-naphthalenol and 8.3 g of potassium carbonate in 50 ml of anhydrous acetone was stirred at room temperature for 1.5 hours. Methyl bromoacetate (4.7 ml), was added and stirring was continued for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield (8.4 g) of [[7-(2-propenyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester, mp 69°-70° after recrystallization from ether-hexane.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)S[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:20].O[O:22][S:23]([O-:25])=O.[K+]>CO.O>[CH3:1][C:2]1[C:15]2[N:14]([CH2:16][CH2:17][CH2:18][NH2:19])[C:13]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:23](=[O:25])(=[O:22])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1C)N(CCCN)c1ccccc1S2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To 20 ml of a solution of 870 mg of 1,2-dimethyl-10-(3-aminopropyl)phenothiazine obtained in Example 1 in methanol was added an aqueous solution of 3.7 g of oxone in 20 ml of water and the resulting mixture was stirred at room temperature for 30 min. After evaporating the solvent, the residue was purified by silica gel column chromatography to give 200 mg of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[C:5]([CH2:10]O)=[N:6][CH:7]=[CH:8][CH:9]=1.S(Cl)(Cl)=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:30]3[CH:31]=[CH:32][C:33]4[O:34][CH2:35][CH2:36][O:37][C:38]=4[C:29]=3[O:28][CH2:27]2)[C:19]1=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>ClCCl.CN(C)C=O>[F:2][C:3]([F:13])([F:12])[C:4]1[C:5]([CH2:10][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([C:30]4[CH:31]=[CH:32][C:33]5[O:34][CH2:35][CH2:36][O:37][C:38]=5[C:29]=4[O:28][CH2:27]3)[C:19]2=[O:39])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCc1ncccc1C(F)(F)F
Reactant: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1c2ccc2c1OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
A mixture of (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride (0.324 g, 1.52 mmol) and thionyl chloride (0.174 mL, 2.39 mmol) in anhydrous dichloromethane (10 mL) was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and anhydrous N,N-dimethylformamide (10 mL) was added. To this mixture was added 2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one (0.300 g, 1.01 mmol), cesium carbonate (0.926 g, 2.84 mmol), potassium iodide (0.094 g, 0.57 mmol) and anhydrous N,N-dimethylformamide (15 mL) and the mixture was heated at 90° C. for 1 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo, and the resulting residue was taken up in water (50 mL), sonicated and filtered. The solid was purified by column chromatography and eluted with a 0% to 40% gradient of ethyl acetate in dichloromethane followed by recrystallization from methanol to afford 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihyrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one (0.123 g, 27%) as a colorless solid: mp 206-207° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J=4.4 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.55 (dd, J=7.8, 5.0 Hz, 1H), 7.26-7.20 (m, 2H), 7.01 (dd, J=11.3, 3.8 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.36 (s, 2H), 5.22 (ABq, 2H), 4.83 (ABq, 2H), 4.27 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 152.6, 152.4, 148.7, 144.6, 142.9, 134.9, 131.7, 129.1, 128.6, 123.5, 123.0, 122.8, 122.6, 122.5, 122.0, 114.8, 110.0, 108.9, 80.1, 64.1, 63.9, 57.3, 41.8; MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH3:7])[C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Si:21]([O:1][C@H:2]1[CH2:6][N:5]([CH3:7])[C@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C
Reaction time: 12 h

Procedure:
Methyl (2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-carboxylate 3b (6 g, 37 mmol) was dissolved in 100 mL of dichloromethane, followed by addition of imidazole (7.70 g, 113 mmol) and tert-butyl dimethylchlorosilane (6.80 g, 45 mmol) successively. After stirring for 12 hours, the reaction mixture was diluted with 100 mL of dichloromethane, washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound methyl (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carboxylate 3c crude product as a colourless oi, which was directly used in the next step without purification.
Reaction SMILES: [CH3:1][Li].[OH:3][C@@H:4]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:21]2[C:20](=[O:26])[CH2:19][C@@:18]2([CH3:27])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:14](=[O:17])[CH:15]=[CH2:16])[CH2:5]1.[Cl-].[NH4+]>CCOCC>[CH2:16]([CH2:15][C:14](=[O:17])[C@@H:13]1[C@:18]2([CH3:27])[C@H:10]([C@H:9]3[C@H:21]([C:20](=[O:26])[CH2:19]2)[C@:22]2([CH3:25])[C@H:6]([CH2:5][C@H:4]([OH:3])[CH2:24][CH2:23]2)[CH2:7][CH2:8]3)[CH2:11][CH2:12]1)[CH3:1]
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
Methyl lithium in ether (≈1.3M: 7.5 ml) was added slowly to a slurry of cuprous iodide (950 mg) in dry ether (40 ml) under nitrogen at -20°, the initial yellow precipitate just redissolving. 3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) in dry ether (10 ml) was added rapidly to the solution forming a yellow precipitate. After 3/4 hr. at ≈0° the mixture was poured into saturated ammonium chloride solution and the oily precipitate extracted with ether. The extracts were washed with saturated ammonium chloride solution, then water, and dried over anhydrous sodium sulphate. The dried solution was evaporated to an off white foam (430 mg) which was purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band (Rf ≈ 0.4) gave a white foam which on trituration with petrol, containing a small quantity of ether, gave title compound (320 mg.) as a white solid, m.p. 112°-113°, [α]D + 105° (c = 1.01).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10].Cl>CCOCC>[CH:1]1([C:4]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCOCC
Product: CCCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice:4 N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, bp-102°-104° C. (80 mm), pmr spectrum (CDCl3): δ2.55 (triplet, --CH2CO--).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[N:12]#[C:13]Br.[NH4+].[OH-]>CO.O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=2[N:11]=[C:13]1[NH2:12])[CH3:2]
Reactant: CCNc1ccc(F)cc1N
Reactant: N#CBr
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(N)nc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of N1-ethyl-4-fluoro-benzene-1,2-diamine (1.54 g, 10.0 mmol) in MeOH (20 mL) and H2O (20 mL) was added cyanogen bromide (2.1 mL, 10.5 mmol, 5.0 M in acetonitrile). The resulting mixture was stirred at room temperature over night. The resulting mixture was then adjusted to pH>9 with concd NH4OH and the resulting solid was collected by filtration, washed with H2O and hexanes to yield 1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine MS 180 (M+1)+