Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[N+:39]=[N-:40]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(-c2ccc(N3CCC(C)CC3)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(-c2ccc(N3CCC(C)CC3)cc2)c1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (250 mg, 0.532 mmol) in hydrochloric acid, (12 mL, 37% aqueous solution) was cooled in an ice bath and a solution of sodium nitrite (220 mg, 3.19 mmol) in water (2 mL) was added slowly. The orange-red solution was stirred for 30 min and a solution of sodium azide (208 mg, 3.19 mmol) in water (2 mL) was added dropwise. After 30 min this was partitioned between DCM and water. The organic phase washed with water and the combined organic phases were basified with 10 N aq. NaOH solution. This was extracted with DCM and the organic phases were washed with sat. NaHCO3 solution, brine, and dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (step gradient elution with DCM containing 0 to 2% MeOH) afford methyl 4′-azido-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (128 mg, 0.26 mmol, 49% yield) as a solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.02 (1H, d, J=2.44 Hz), 7.85 (1H, s), 7.79 (1H, d, J=7.63 Hz), 7.68 (1H, d, J=2.44 Hz), 7.64 (1H, d, J=7.63 Hz), 7.59 (1H, d, J=7.63 Hz), 7.42 (2H, d, J=8.55 Hz), 7.04 (2H, d, J=8.85 Hz), 4.03 (3H, s), 3.26-3.39 (4H, m), 2.57-2.69 (4H, m), 2.38 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[NH:23][C:24](=[O:30])OC(C)(C)C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][C:16]3[C:17](=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=3)[NH:23][C:24]2=[O:30])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Product: O=C1Nc2c(F)cccc2CN1C1CCN(Cc2ccccc2)CC1

Procedure:
tert-Butyl 2-((1-benzylpiperidin-4-ylamino)methyl)-6-fluorophenylcarbamate (83.0 g, 201 mmol) was dissolved in pyridine (600 mL) and heated at reflux for 12 h. The reaction was concentrated, triturated with hot diethyl ether and placed in the freezer overnight. The resulting solid was filtered to give 68.1 g (64%) as a white solid. 1H-NMR (CDCl3, 500 MHz) δ 1.68 (m, 2H), 1.86 (dddd, J=11.9, 11.9, 11.9, 3.4 Hz, 2H), 2.14 (dd, J=11.6, 10.1 Hz, 2H), 2.98 (d, J=11.6 Hz, 2H), 3.51 (s, 2H), 4.34-4.44 (m, 3H), 6.71 (bs, 1H), 6.79-6.89 (m, 2H), 6.94 (dd, J=9.2, 9.2 Hz, 1H), 7.21-7.34 (m, 5H). Mass spec.: 340.30 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:16]1[CH2:23][CH:22]2[C:24]([CH3:26])([CH3:25])[CH:18]([CH2:19][NH:20][CH2:21]2)[CH2:17]1)[CH2:13][CH2:14][CH3:15]>ClCCl>[CH2:12]([N:16]1[CH2:17][CH:18]2[C:24]([CH3:25])([CH3:26])[CH:22]([CH2:21][N:20]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:19]2)[CH2:23]1)[CH2:13][CH2:14][CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Solvent: ClCCl
Product: CCCCN1CC2CN(S(=O)(=O)c3ccc(F)cc3)CC(C1)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A solution of 7.2 g of 4-fluorobenzenesulfonyl chloride in 10 ml of dichloromethane was added dropwise with ice-cooling to a solution of 7.8 g of 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane in 40 ml of dichloromethane. The ice-cooling was then removed, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was worked up by adding aqueous sodium bicarbonate solution and extracting twice with dichloromethane. The combined dichloromethane extracts were dried with magnesium sulfate and concentrated. 12.9 g of 7-(n-butyl)-3-[(4-fluorophenyl)sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane were obtained.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:41]O>>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:41])=[O:34])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 62 %

Procedure:
The title compound (1.03 g, 62%) was prepared from 3,4,5-triphenyl-lH-pyrazole-1-decanoic acid (1.60 g) by esterification in methanol using a catalytic amount of conc. sulfuric acid. MS(CI): m/e =481 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[O:13][C:12]2=[O:28])=[CH:7][CH:6]=1)=[O:4].[ClH:29]>O1CCOCC1>[ClH:29].[O:28]=[C:12]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:15][C:14]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:13]1
Reactant: COC(=O)c1ccc(N2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1

Procedure:
A solution of tert-butyl 3-[4-(methoxycarbonyl)phenyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (1.68 g, 4.3 mmol) in 4 N HCl in dioxane (20 mL) was stirred at room temperature for 1 hour to give a white suspension. Upon removal of the volatiles, the title compound was collected as its HCl salt as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>C(O)(=O)C>[O:16]=[C:7]1[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5](=[O:22])[C:4]2[C:9](=[CH:10][C:11]([C:12]([F:13])([F:15])[F:14])=[C:2]([N:1]3[CH:25]=[CH:29][CH:28]=[CH:27]3)[CH:3]=2)[NH:8]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cccc3)cc2c1=O
Yield: 59 %

Procedure:
The solution of 80 mg (0.236 mmol) ) N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.092 ml (0.709 mmol) 2,5-dimethoxy-tetrahydrofuran in 1.5 ml acetic acid is refluxed for 2 hours. After rotavapor evaporation of the solvent the residue is purified by reversed phase chromatography (C18) with an acetonitril-water gradient and the product is lyophilized to give 54 mg (59%) of N-(2,4-dioxo-6-pyrrol-1-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide as a brown solid. MS (ES+): m/e =389 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>CN(C1C=CN=CC=1)C>[C:21]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=2[N+:11]([O-:13])=[O:12])[CH:5]=[C:6]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20]
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: Cc1cc([N+](=O)[O-])c2c(c1)cc(-c1ccccc1)n2C(=O)OC(C)(C)C

Procedure:
5-Methyl-7-nitro-2-phenyl-1H-indole prepared in Preparation 24, (BOC)2O and DMAP were reacted according to the same procedure as Preparation 23 to give the title compound.
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].[H-].[Na+].S(OC)(O[CH3:39])=O.O>CN(C)C=O>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:39])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2[N+](=O)[O-])C1=N
Reactant: COS(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2[N+](=O)[O-])C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(o-nitrophenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.62 g.; 0.01 mol) in dimethyl formamide (40 ml.) there is added 57% sodium hydride (0.42 g.; 0.01 mol) (oil dispersion). The mixture is stirred at room temperature for one hour and to it there is added dimethyl sulfite (1.1 g.; 0.01 mol). The mixture is stirred at room temperature for 11/2 hours and is poured into an excess of water. The suspension formed is vacuum filtered and the filter caked dried to afford 3-imino-(o-nitrophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=O)(=O)[CH2:2][CH2:3][CH3:4].[NH2:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[OH:19][C:18]1[C:13]2=[N:12][C:1]([CH2:2][CH2:3][CH3:4])=[CH:6][C:7](=[O:9])[N:14]2[CH:15]=[CH:16][CH:17]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1ncccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1cc(=O)n2cccc(O)c2n1
Yield: 49.5 %

Procedure:
A mixture of 31.5 g of ethyl butyrylacetate, 11.0 g of 2-amino-3-pyridinol, 125 ml of ethyleneglycol monomethyl ether, and 1.0 g of p-toluenesulfonic acid is stirred and heated under reflux for 21 hours and then allowed to cool. The product that crystallizes is filtered and dried to give 10.1 g of 9-hydroxy-2-propyl-4H-pyrido[1,2-a]pyrimidin-4-one, m.p. 95°-96°. The filtrate is concentrated to one-half volume to give 5.8 g of solid, m.p. 92°-94°. This is extracted with two 50 ml portions of boiling diisopropyl ether to leave behind 1.0 g of an insoluble solid. From the diisopropyl ether extracts there is obtained 3.8 g of additional product, m.p. 95°-96°. The 1.0 g of solid insoluble in diisopropyl ether is recrystallized from acetonitrile to give 0.60 g of 9-hydroxy-2-propyl-4 H-pyrido[1,2-a]pyrimidin-4-one, salt with p-toluenesulfonic acid, m.p. 202° -204°. The same salt is prepared by mixing rapidly hot solutions of 1.40 g of the product, m.p. 95°-96° in 15 ml of acetonitrile and 1.30 g of p-toluenesulfonic acid in 15 ml of acetonitrile. A clear solution forms briefly and then the salt crystallizes. The yield of salt, m.p. 202°-204°, is 2.16 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22]O)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][CH2:22][O:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCC3(CC2)OCCc2ccccc23)cc1
Yield: 20.7 %

Procedure:
To a solution of 1-benzyl-4-[2-(2-hydroxy-ethyl)-phenyl]-piperidin-4-ol (2.0 g, 6.6 mmol) and triethylamine (1.9 ml, 14 mmol) dry tetrahydrofuran (50 ml) was added methanesulfonyl chloride (0.48 ml, 6.2 mmol) at room temperature. The reaction mixture was heated at reflux for 4 h. Quenching with water and basification with 1 M aqueous sodium hydroxide solution was followed by extraction with three portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography of the crude product with n-heptane/ethyl acetate as eluent gave the title compound (0.40 g, 21%) as yellow oil. MS m/e: 294 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][NH:25][CH:24]([C:27]([O:29]C)=[O:28])[CH2:23][CH2:22]2)[C:3]=1[Br:31].C1COCC1.[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH:21]2[CH2:26][NH:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]2)[C:3]=1[Br:31]
Reactant: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Br)c(C2CCC(C(=O)O)NC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
Methyl 5-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-2-carboxylate (11 mg, 0.023 mmol) in 2:1 THF:H2O (1.5 mL) was treated with 2N NaOH(aq) (0.25 mL). The resulting solution was stirred at room temperature for 18 hours. This solution is reduced in vacuo and purified by prep-LC to afford the title compound (8.9 mg): LC/MS RT=2.16 min. Mass calculated for, M+H 467.08, observed 467.08.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:7][C:8](=[O:11])[O:9][CH3:10])[CH3:6])=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:7][C:8](=[O:11])[O:9][CH3:10])[CH3:6]
Reactant: COC(=O)N[C@@H](C)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)N[C@@H](C)CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate (S)-methyl 1-azidopropan-2-ylcarbamate (2.86 g, 18.2 mmol) in ethyl acetate (200 ml) was added 10% palladium on carbon (wet, 286 mg). The flask was degassed and refilled with hydrogen gas (balloon, 1 atmosphere), and the mixture was stirred at rt for 16 hours. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give crude (S)-methyl 1-aminopropan-2-ylcarbamate, which was used without further purification. 1H NMR 400 MHz (CDCl3) δ 4.79 (s, 1H), 3.71-3.65 (m, 1H), 3.66 (s, 3H), 2.75 (dd, 1H), 2.65 (dd, 1H), 1.14 (d, 3H); MS m/z 133.1 (M+1).
Reaction SMILES: Br[CH:2]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.[Mg].[CH:11](=[O:13])[CH3:12].Cl>C(OCC)C>[CH:2]1([C:11](=[O:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: CC=O
Reactant: BrC1CCC=CCCC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(=O)C1CCC=CCCC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
A solution of 5-bromo-cyclooctene (5 g, 26 mmol; prepared by treatment of 1,5-cyclooctadiene with HBr in AcOH) in diethyl ether was added to magnesium (0.7 g, 29 mmol, 1.1 eq.). The resulting solution was cooled to 5° C. and treated dropwise with a solution of acetaldehyde (5 ml, 89 mmol, 3.4 eq.) in diethyl ether (10 ml). The resulting mixture was stirred 3 h at 20° C., treated with 2M HCl, and extracted with diethyl ether. The organic phases were washed successively with NaHCO3, NH4Cl and NaCl solutions, and dried (Na2SO4) and the solvent evaporated under vacuum. The crude product was purified by flash chromatography (hexane/Et2O 10:1) to give 1.2 g of 1-cyclooct-4-enylethanone (30%).
Reaction SMILES: [CH2:1]([C@@H:7]([C@@H:18]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:19][C@H:20]([OH:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([C@@H:7]([C@@H:18]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:19][C@H:20]([O:32][CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46][O:41]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCC[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCC[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCCCC)C(=O)OCc1ccccc1)OC1CCCCO1
Temperature: -15 °C

Procedure:
M)f) 350 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]-5-hydroxyhexadecanoate and 0.5 ml of freshly distilled 3,4-dihydro-2H-pyran were dissolved in 10 ml of methylene chloride and cooled to -15° C. A crystal of p-toluenesulfonic acid monohydrate was added thereto. The mixture was stirred until the reaction has finished. Thereupon, the solution was evaporated and the residue was chromatographed on silica gel. There were obtained 330 mg of benzyl (2S,3S,5R)-2-hexyl-3-[(t-butyldimethylsilyl)oxy]5-[(tetrahydro-2 H-pyran-2-yl)oxy]hexadecanoate, MS: 603 (M+ -t-butyl).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I:18]Cl>C(O)(=O)C.O>[CH3:17][C:2]([CH3:1])([C:8]1[CH:13]=[CH:12][C:11]([I:18])=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cccc(OCC)c1
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(I)c(OCC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a cooled solution (5° C.) of ethyl dimethyl-3-ethoxyphenylacetate (5.0 g, 21.1 mmol) in acetic acid (40 mL) was added dropwise a solution of iodine monochloride (5.0 g, 30.9 mmol) in acetic acid. The reaction was stirred at room temperature for 18 h and diluted with water and extracted with methylene chloride. The combined organic layers were washed with aqueous sodium thiosulfate, aqueous sodium bicarbonate and brine. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate (6.25 g, 82%) as a yellow oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:8]2[C:9]([O:20][CH3:21])=[CH:10][CH:11]=[C:12]([C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[C:7]=2[O:6][C:5]=1[C:22]([O:24]CC)=[O:23].CO>O>[CH3:3][C:4]1[C:8]2[C:9]([O:20][CH3:21])=[CH:10][CH:11]=[C:12]([C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[C:7]=2[O:6][C:5]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1oc2c(C(=O)c3cccs3)ccc(OC)c2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)c2cccs2)c2oc(C(=O)O)c(C)c12

Procedure:
To a solution of potassium hydroxide (1.96 g, 34.86 mmol) in water (75 mL) was added compound 1 (4.00 g, 11.62 mmol) and the resulting suspension was heated to reflux for two hours. During the reflux a small portion of methanol was rinsed into the reaction mixture. After cooling, the reaction mixture was diluted with water (225 mL) and acidified with 2N HCl (25 mL). The resulting suspension was cooled in an ice bath, and the product collected by filtration. After vacuum drying, 3-methyl-4-methoxy-7-(2-thienoyl)-benzofuran-2-carboxylic acid, compound 2, was obtained. mp 252°-255° C.; 1H NMR d 2.80 (3H, s), 2.80 (1H, br s), 4.06 (3H, s), 6.76 (1H, d, J=8 Hz), 7.19 (1H, m), 7.70 (1H, dd, J=4 Hz, 1 Hz), 7.76 (1H, dd, J=4 Hz, 1 Hz), 7.90 (1H, d, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[N+:9]([O-])([O-:11])=[O:10].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
1-Bromo-4-fluorobenzene (50.0 g) was added to concentrated sulfuric acid (200 mL) slowly at 0° C., followed by slow addition of KNO3 (43.3 g). The resulting mixture was stirred at 0° C. for 1 hour. TLC indicated the reaction was complete. The reaction mixture was poured onto ice slowly, and extracted with EtOAc (3×200 mL). The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated to afford 1-bromo-4-fluoro-2-nitrobenzene (D39) (52.0 g) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]2[CH2:15][CH2:14][Si:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.O1CCCC1.[Cl-].[F:33][C:34]1[CH:35]=[C:36]([Zn+])[CH:37]=[CH:38][C:39]=1[F:40].[Cl-].[NH4+]>C(O)C.[Pt]=O>[CH2:22]([Si:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:37]2[CH:36]=[CH:35][C:34]([F:33])=[C:39]([F:40])[CH:38]=2)[CH2:11][CH2:12]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Fc1ccc([Zn+])cc1F
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(Br)cc2)CC1
Agent: O=[Pt]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCC[Si]1(c2ccccc2)CCC(CCc2ccccc2-c2ccc(F)c(F)c2)CC1
Yield: 86 %

Procedure:
42.8 g of 4-(2-(4-bromophenyl)ethenyl)-1-n-pentyl-1-phenyl-1-silacyclohexane was dissolved in 200 ml of ethanol at room temperature and then hydrogenated at normal pressures in the presence of a catalyst made of 200 mg of platinum oxide. After consumption of a theoretical amount of hydrogen, the catalyst was removed by filtration and the resultant flitrate was concentrated. 200 ml of tetrahydrofuran and 180 mg of tetrakis(triphenylphosphine) palladium (0) were added to the resulting residue. Thereafter, 120 ml of a tetrahydrofuran solution of 1.0 mole of 3,4-difluorophenylzinc chloride, followed by agitation at 40° C. for 12 hours. The reaction mixture was poured into an ammonium chloride aqueous solution and extracted with ethyl acetate. After ordinary washing, drying and concentrating operations, the resultant product was purified through silica gel column chromatography to obtain 39.6 g (yield: 86%) of 4-(2-(4-n-pentyl-4-phenyl-4-silacyclohexyl)ethyl-3',4'-difluorobiphenyl.
Reaction SMILES: [CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:5]2[CH2:4][CH2:3]1.[C:27](I)([F:30])([F:29])[F:28].OO>CS(C)=O>[CH3:1][N:2]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2=[CH:7][C:8]([C:27]([F:30])([F:29])[F:28])=[C:9]([C:10]([F:11])([F:13])[F:12])[N:5]2[CH2:4][CH2:3]1
Reactant: FC(F)(F)I
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: OO
Solvent: CS(C)=O
Product: CN1CCn2c(cc(C(F)(F)F)c2C(F)(F)F)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ferrous sulfate heptahydrate (803 μL of 1.00 M, 0.803 mmol) was added to a mixture of tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.00 g, 2.68 mmol) and DMSO (15 mL) at room temperature. The vessel was then charged with CF3I (gas) before H2O2 (304 μL of 30% w/v, 2.68 mmol) was added dropwise. The mixture was allowed to stir overnight at room temperature before it was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The reside was purified by column chromatography (0-100% ethyl acetate/hexanes) to give tert-butyl 2-methyl-6,7-bis(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate. ESI-MS m/z calc. 441.2, found 442.5 (M+1)+; Retention time: 1.36 minutes (3 min run).