Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[CH:12]=O.C([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20]
Reactant: C#CCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 775.3 %

Procedure:
Piperidine (85.0 mL, 85.6 mmol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (163 g, 85.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (182 g, 81.5 mmol) in toluene (1.0 L) and treated according to Procedure 2, acidifying with 50% AcOH. The crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cold EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (222 g, 77%) as a yellow crystalline solid; mp 191-193° C.; δH (400 MHz, DMSO-d6) 3.59 (t, J=2.4 Hz, 1H, HC≡C), 3.84 (s, 3H, OCH3), 4.84 (d, J=2.4 Hz, 2H, OCH2), 6.81 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6=8.4 Hz, 1H, H6′), 7.41 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br S, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C2OH17NO5 [M+H]+ 352.1179. found 352.1187; vmax 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm−1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].Cl.[CH3:19][NH:20]OC.Cl.[CH3:24]N(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][O:10][C:9](=[O:11])[CH:8]([NH:20][CH3:19])[NH:7][C:5](=[O:6])[C:4]1[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=1[C:2]([F:16])([F:17])[F:1]
Reactant: CNOC
Reactant: O=C(O)CNC(=O)c1ccccc1C(F)(F)F
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(NC(=O)c1ccccc1C(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To 45.2 g of 2-[2-(trifluoromethyl)benzoylamino]acetic acid in 609 ml of dichloromethane, 21.4 g of N,O-dimethylhydroxylamine hydrochloride, 42.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 73.8 g of triethylamine and 2.2 g of 4-(dimethylamino)pyridine were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was washed with 500 ml of saturated anhydrous sodium hydrogen carbonate, 500 ml of 1N aqueous hydrochloric acid twice and 500 ml of water in this order, the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 200 ml of hexane to obtain 31.4 g of the desired product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CBr)c1ccoc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccoc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (587 mg) and crude 3-bromoacetylfuran (2.00 g, ca. 4.5 mmol, based on purity ca. 40% by 1H n.m.r; contaminated with 3-dibromoacetylfuran and diethyl ether) in triethylamine (0.95 ml) and ethanol (25 ml) was stirred at room temperature. After 45 min with solvent was removed and the residue triturated with ethyl acetate. The resulting solid was collected and retriturated with water. This gave a buff solid which was crystallised from ethyl acetate to give the title pyrimidinone (335 mg), m.p. 195°-197° C. (dec), λmax (EtOH) 333 nm (ε 2,530).
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][CH2:6][OH:7].[Br:8][C:9]1[CH:10]=[CH:11][C:12](Cl)=[N:13][CH:14]=1>>[F:3][CH2:4][CH2:5][CH2:6][O:7][C:12]1[CH:11]=[CH:10][C:9]([Br:8])=[CH:14][N:13]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OCCCF
Agent: [H-]
Agent: [Na+]
Product: FCCCOc1ccc(Br)cn1
Yield: 98.6 %

Procedure:
2-(3-Fluoropropoxy)-5-bromopyridine (97c, 600 mg, 98%) was prepared in the same manner as in Preparation Example 13 using sodium hydride (94 mg, 3.90 mmol), 3-fluoropropanol (305 mg, 3.90 mmol) and 5-bromo-2-chloropyridine (96, 500 mg, 2.60 mmol).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H].C[OH:42]>[Pd]>[C:21]([OH:42])(=[O:22])[CH3:23].[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CO
Reactant: [H][H]
Agent: [Pd]
Product: CC(=O)O
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of intermediate (7) (0.025 mole) in methanol (250 ml) was hydrogenated at 50° C. overnight with Pd/C 10% (2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried. A part (0.2 g) of this fraction was purified by high performance liquid chromatography over RP-18 (eluent: (NH4OAc 0.5%/CH3CN 90/10)/CH3OH/CH3CN 75/25/0, 0/50/50, 0/0/100 and 75/25/0; column: Hyperprep RP 100 Å 8 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.119 g of N-[4-(4-piperidinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide acetate (1:2) (intermediate 8, melting point 150° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-])=O)=O.N12CCCN=C1CCCCC2.C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:35][C:36]2[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[CH:38][CH:37]=2)=CC=1.[Br-]>C1(C)C=CC=CC=1>[NH2:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[CH2:1][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:42]#[N:43])[CH:41]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: N#Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CCc2cccc(C#N)c2)c(N)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 136 %

Procedure:
Ethyl 4-formyl-3-nitrobenzoate (5.81 g) was dissolved in 70 ml of toluene, then 2.1 ml of 1,8-diazabicyclo[5.4.0]-undec-7-ene and the mixture was stirred at 80° C. for one hour. To the reaction solution, 2.69 g of 3-[(1,1,1-triphenylphosphonio)methyl]benzonitrile bromide was added, and the mixture was stirred at 80° C. for 24 hours. Insoluble matters were filtered out and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (10:1) as an eluting solvent. The resulting intermediate (3.1 g) was dissolved in a mixed solvent of 50 ml of ethanol and 10 ml of tetrahydrofuran, then 1 g of a palladium oxide-barium sulfate complex was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 3 days. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluting solvent to give 2.35 g of ethyl 3-amino-4-[2-(3-cyanophenyl)ethyl]benzoate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.Br[C:37](C)(C)[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([N:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:37][C:38]([OH:40])=[O:39])=[CH:35][CH:34]=2)=[O:11])[C@@H:13]([CH3:33])[CH2:14]1)(=[O:25])[CH3:24].[CH2:41]([O:40][C:38](=[O:39])[CH2:37][NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:23](=[O:25])[CH3:24])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:34][CH:35]=1)[CH3:42]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCNCC(=O)O)cc2)c2ccccc21
Product: CCOC(=O)CNCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 50 °C
Yield: 12 %

Procedure:
{[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic acid was prepared from (2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide. (2S,4R)-N-{1-[4-(3-amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (0.032 g, 0.065 mmol) was dissolved in dimethylformamide, ethyl bromoisobutyrate (0.05 mL, 0.26 mmol) and potassium carbonate (0.018 g, 0.13 mmol) were added. The reaction was heated to 50° C. for 17 h. The reaction was concentrated down and purified using 50% ethyl acetate/50% hexane to 100% ethyl acetate to give 0.007 g, 12% yield of {[3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)propyl]amino}acetic ethyl ester.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Li]C[CH2:12][CH2:13][CH3:14].C1(C(Cl)=O)CC1.O>C1COCC1>[CH:12]1([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:14]1
Reactant: [Li]CCCC
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(Cl)C1CC1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CC1
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 36.6 %

Procedure:
To a cooled (-70° C.) solution of monoethyl malonate (33.97 g, 257.10 mmol) in THF (639 mL) was added n-BuLi (1.6M in hexanes, 319 mL, 514.19 mmol) and the mixture was stirred under an argon atmosphere for 15 min. The resulting solution was cooled to -65° C. and cyclopropanecarbonyl chloride (15.55 g, 148.77 mmol) was added. The reaction mixture was stirred for 1 h and then allowed to warm up to room temperature. Some drops of water were added and THF was removed. The residue was taken up in 1N HCl/Et2O and extracted with Et2O. The organic phase was washed with saturated NaHCO3, dried and concentrated to a residue. This was purified by chromatography on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a yellow oil (14.7 g, 63%).
Reaction SMILES: [Na].[CH2:2]([O:9][P:10]([O-:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].C(OP([O-])OCC1C=CC=CC=1)C1C=CC=CC=1.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CCOCC.C(O)C>[CH2:43]([O:42][C:40]([P:10](=[O:19])([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:41])[CH3:44]
Reactant: CCOC(=O)Cl
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)P(=O)(OCc1ccccc1)OCc1ccccc1

Procedure:
Ethanol (4.6 g) was added to a fine suspension of sodium metal (2.25 g) in dry ether (200 ml) under an atmosphere of nitrogen. The mixture was heated for 8 hours, after which dibenzylphosphite (25.7 g) in dry ether (50 ml) was added. After standing over-night the dibenzylphosphite sodium salt was added over a period of 2 hours to a cold solution of ethyl chloroformate (10.8 g) in ether, under an atmosphere of nitrogen. The reaction was heated at reflux for 1 hour, cooled, washed with water, a NaCl solution and dried over Na2SO4. The ether was evaporated. After evaporating and discarding components volatile at 0.01 mm and 150° C. the residue was collected (13 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C([Sn](CCCC)(CCCC)[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:35](/[C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)=[CH:36]\[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
Under inert atmosphere (Ar) a mixture of palladium(II)-acetate (0.45 g , 2 mmol) and triphenylphosphine (0.95 g, 3.6 mmol) in DMF (50 ml) was stirred for 0.5 hr at rt. Then 2-chloro-5-nitropyridine (3.2 g, 20 mmol) and tributyl-styryl-stannane (15.7 g, 40 mmol) was added and the mixture was stirred at 130° C. for 15 hr. The solvent was evaporated and the residue partitioned between AcOEt and 1N HCl. The aqueous phase was neutralized with 6N NaOH and extracted with AcOEt. The organic phase was dried with Na2SO4, concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH=97/3) to (give the title compound (0.90 g, 23%) as a yellow solid. Mp. 159-160° C. (AcOEt), MS: 196 (M+).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([F:35])([C:31]([F:34])([F:33])[F:32])[C:7]([F:30])([F:29])[C:8]([F:28])([F:27])[C:9]([F:26])([F:25])[C:10]([F:24])([F:23])[C:11]([F:22])([F:21])[C:12]([F:20])([F:19])[C:13]([F:18])([F:17])[C:14](Cl)=[O:15]>C(OC(C)C)(C)C>[CH2:1]([NH:4][C:14](=[O:15])[C:13]([F:17])([F:18])[C:12]([F:19])([F:20])[C:11]([F:21])([F:22])[C:10]([F:23])([F:24])[C:9]([F:25])([F:26])[C:8]([F:28])([F:27])[C:7]([F:30])([F:29])[C:6]([F:35])([F:5])[C:31]([F:34])([F:33])[F:32])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C=CCNC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 30 °C

Procedure:
Allyl amine (6.03 milliliters, 3.0 molar equivalent) and isopropyl ether (35.0 milliliters) were added to a 3-neck 100-milliliter round bottom flask equipped with water cooled condenser (to a nitrogen inlet), dropping funnel and thermometer adapter (to a Thermowatch device) at room temperature under a nitrogen blanket. A solution of nonadecafluoro-1-decanoyl chloride (14.27 grams, 1.0 molar equivalent) in 5.0 milliliters isopropyl ether was added by the dropping funnel over 2 hours while maintaining the temperature below 30° C. After the addition was completed, the reaction mixture was heated for 2 hours at 30° C., followed by additional treating for 2 hours at 40° C. After cooling the mixture to room temperature, the mixture was diluted with 100 milliliters isopropyl ether and washed with 9% aqueous hydrochloric acid solution (75 milliliters). The aqueous layer was extracted with 50 milliliters isopropyl ether. The combined organic layers were evaporated in vacuo to give a red solid. High vacuum distillation produced 13.03 grams (88% isolated yield) of a light yellow solid (boiling point 100° C., 0.1 millimeters Hg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Li+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28](/[CH:35]=[CH:36]/[CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: C/C=C/[C@H](CC(=O)OCC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C=C/[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 22 h
Yield: 93.9 %

Procedure:
To a stirred solution of 1.1 (0.050 g, 0.099 mmol) in THF (2.00 mL, 24 mmol) and EtOH (2.00 mL, 34 mmol) at 23° C. was added 1N lithium hydroxide (1.00 mL, 1.0 mmol). Stirring was continued for 22 hours. The reaction was concentrated in vacuo. 1N HCl was added to reach pH 1, and the resulting mixture was extracted with EtOAc (3×10 mL), dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes) to give a clear oil (0.0443 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.58 (1H, d, J=8.6 Hz), 7.40 (1H, dd, J=8.2, 2.0 Hz), 7.13 (2H, d, J=8.6 Hz), 7.08 (1H, d, J=1.5 Hz), 7.00 (1H, t, J=8.8 Hz), 6.92 (2H, d, J=8.6 Hz), 6.86 (1H, m), 6.79 (1H, m), 5.57 (1H, m), 5.50 (1H, m), 4.99 (2H, s), 3.79 (3H, s), 3.76 (1H, dd, J=14.5, 7.6 Hz), 2.71 (2H, dd, J=7.6, 2.5 Hz), 1.66 (3H, d, J=5.9 Hz), 1.23 (9H, m). MS ESI (neg.) m/e: 951.4.1 (2M−H)+, 475.1 (M−H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:37]
Reactant: O=C(N[C@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide (example A148) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([CH:7]([K])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [K]C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 5.01 g (24.3 mmol) of diphenylmethyl potassium in 25 mL of THF was added about 10 mL (about 8.6 g, 80 mmol) of chlorotrimethylsilane. The dark orange color instantly faded. The solvent was removed under reduced pressure. The residue was extracted with hexane and filtered and the solvent was removed under pressure to give the product as a pale yellowish liquid. The yield was 4.63 g, 79.3 percent. 1H NMR (C6D6) δ 7.08-7.23 (m, 8H), 6.98-7.06 (m, 2H), 3.41 (s, 1H), 0.00 (s, 9H). 13C NMR (C6D6) δ 143.2, 129.1, 128.6, 125.4, 46.5, -1.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH3:12])(=[O:10])=[O:9].O[Li].O>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH3:12])(=[O:9])=[O:10]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)S(=O)(=O)c1ccccc1Cl)CC2
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN([C@@H]1CCc2ccc(C(=O)O)cc21)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 3-(2-chloro-N-methylphenylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-16) (840 mg, 2.216 mmol, 1.0 eq.) in MeOH:THF (1:1, 20 ml) was added dropwise a solution of LiOH.H2O (185 mg, 4.433 mmol, 2.0 eq.) in water (10 ml) and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness and diluted with water (20 ml) and washed with ethyl acetate (20 ml). The aqueous layer was acidified to pH≈3 using 1N HCl and then extracted with methylene chloride (2×50 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford the desired product as an off-white solid. Yield: 58% (470 mg, 1.2876 mmol).
Reaction SMILES: C1(C)C=CC(S([C:10]([OH:31])([OH:30])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])[CH3:13])(=O)=O)=CC=1.[N-:33]=[N+:34]=[N-:35].[Na+].[N-]=[N+]=[N-]>CN(C)C=O>[N:33]([C:10]([OH:31])([OH:30])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])[CH3:13])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)C(O)(O)CC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(O)(O)N=[N+]=[N-]
Yield: 81.6 %

Procedure:
The yielded phytandiol derivative (0.48 g) was dissolved in 25 ml of dimethyl formamide and 0.06 g (1.00 mmol) of sodium azide (Sigma-Aldrich) was added, followed by reflux for 5 hr in order to substitute azide for para-toluene sulfonyl group. The reaction mixture was extracted with 50 ml of methylene chloride solution and washed with saline. Following drying over anhydrous magnesium sulfate, filtration and concentration, 0.29 g of azido phytandiol derivative was yielded.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=O)O[CH2:10][CH2:9]1>>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][O:6][C:1]1=[O:7])[CH:9]=[CH2:8]
Reactant: O=C1CCCCO1
Reactant: O=C1CCO1
Product: C=CCC1CCCOC1=O

Procedure:
9.81 g of tetrahydro-3-(2-propenyl)-2H-pyrane-2-one of interest were prepared in the same manner as in Preparation Example 2Z-5 except that 10.01 g (100.0 mmol) of δ-valerolactone were used instead of β-propiolactone described in Preparation Example 2Z-5.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:1]1([S:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: BrCCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: N#CC1(S(=O)(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
629 mg (2.8 mmol) of benzyltriethylammonium chloride is added to 5 g (27.6 mmol) of benzenesulfonylacetonitrile and 6.55 g (30.3 mmol) of 1,4-dibromobutane in 50 ml of a 50% aqueous soda solution. The reaction mixture is stirred at room temperature for 3 h. It is then diluted with water and extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over magnesium sulfate, filtered and the solvents are evaporated. The residue is purified on silica gel (heptane/ethyl acetate, 50/50, v/v). 6.35 g of 1-benzenesulfonyl-cyclopentanecarbonitrile is obtained in the form of a beige powder. (Yield=98%).