Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C1(CN[CH2:10][C:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])=[O:12])C=CC=CC=1.C[C@@H](C1C=CC=CC=1)NCC1C=CC=CC=1.[C:45](=[O:48])([O-:47])[NH2:46]>>[ClH:1].[O:12]=[C:11]([N:13]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:10][NH:46][C:45](=[O:47])[OH:48]
Reactant: NC(=O)[O-]
Reactant: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNCc1ccccc1
Agent: C[C@H](NCc1ccccc1)c1ccccc1
Agent: Cl
Product: C[C@@H](c1ccccc1)N(Cc1ccccc1)C(=O)CNC(=O)O

Procedure:
2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride: By following the procedure of Example 1(a) but replacing dibenzylamine with α(S)-methyl-N-(phenylmethyl)benzene methanamine, ((S)-N-benzyl-α-methylbenzylamine, Oxford Asymmetry Ltd., Abingdon Oxon, UK), tert-butyl N-{2-oxo-2-{(phenylmethyl)1(S)-phenylethyl}amino}ethyl}carbamate was made. The Boc group was removed following the procedure of Example 1(b) to give N-{2-oxo-2-{(phenylmethyl)(1(S)-phenylethyl}amino}ethyl}carbamate hydrochloride, which was subjected to reductive amination with benzaldehyde according the procedure of R. F. Borch, Org. Synth., 1972, 52, 124, to give 2-(phenylmethyl)amino-N-phenylmethyl-N-{1(S)-phenylethyl}acetamide hydrochloride.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([B:14]([CH:16]([O:23][CH:24]([B:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([Cl:40])[CH:34]=2)[OH:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH:10]=[CH:11][C:12]=1[CH3:13]>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([B:14]([CH:16]([O:23][CH:24]([B:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([Cl:40])[CH:34]=2)[O:32][CH2:4][CH2:3][NH:2][CH3:1])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:5][CH2:4][CH2:3][NH:2][CH3:1])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CNCCO
Reactant: Cc1ccc(B(O)C(OC(B(O)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl
Solvent: CCO
Product: CNCCOB(c1ccc(C)c(Cl)c1)C(OC(B(OCCNC)c1ccc(C)c(Cl)c1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (31 mg) was obtained by allowing 32 mg of N-methylethanolamine to act on 99 mg of bis(4,4′-(3-chloro-4-methylphenyl-hydroxyboryl)benzyl) ether in 0.5 mL of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1.CCN(C(C)C)C(C)C.[C:26]12([CH2:36][NH2:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:26]12([CH2:36][NH:37][C:8]([C:7]3[C:3]([O:2][CH3:1])=[N:4][N:5]([C:11]4[N:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[CH:6]=3)=[O:10])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: COc1nn(-c2ncccn2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1nn(-c2ncccn2)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-methoxy-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (40 mg, 0.18 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.063 mL, 0.36 mmol), 1-adamantan-1-ylmethan-amine (30 mg, 0.18 mmol) and BOP (97 mg, 0.22 mmol). The resulting mixture is stirred at RT for 18 h. Water (3 mL) is added, and the mixture is extracted with EtOAc (5 mL). The EtOAc layer is dried (Na2SO4), filtered, and evaporated in vacuo to give a brown solid. Purification by column chromatography (gradient from 80% EtOAc/Hex to EtOAc) affords the title compound as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 9.02 (1H, s), 8.74 (2H, d, J 4.8), 7.19 (1H, t, J 4.8), 6.88 (1H, bs), 4.24 (3H, s), 3.12 (2H, d, J 6.4), 2.00 (3H, bs), 1.60 (12H, m). MS (M+1)=368.07; RT=1.65 min. *IC50.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].[S:25](Cl)([CH3:28])(=[O:27])=[O:26].Cl>O1CCCC1.CO.[Pd].C(N(CC)CC)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(ccn2Cc2ccc(F)cc2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
1-(4-fluoro-benzyl)-5-nitro-1H-indole (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and ammonium formate of an excess amount and palladium/carbon (10%) of a catalytic amount were added. The solution was stirred at around 30° C. for 1 hour to complete the reduction, filtered through celite, concentrated under reduced pressure, dissolved again in dichloromethane (10 ml), and then washed with water and brine. After drying the resulting solution over anhydrous magnesium sulfate, dichloromethane solution containing amine compound (1-(4-fluoro-benzyl)-5-amino-1H-indole) was obtained. Mesyl chloride (0.012 ml, 0.16 mmol) and triethylamine (0.022 ml, 0.16 mm) were added to the above obtained solution and stirred at room temperature for 2 hours to complete the reaction. After adding 2N-hydrochloric acid solution (10 ml) to separate layers, dichloromethane solution was induced, washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then triturated with isooctane and isopropyleter. As a result, the present compound (30 mg, productive yield 51%) was obtained as a solid.
Reaction SMILES: [CH:1]([C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)=[CH2:2].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[CH2:1]([C:3]1([C:6]2([CH3:11])[O:7][CH2:8][CH2:9][O:10]2)[CH2:4][CH2:5]1)[CH3:2]
Reactant: C=CC1(C2(C)OCCO2)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCC1(C2(C)OCCO2)CC1
Yield: 78.6 %

Procedure:
500 mg of olefin 8 is dissolved in 15 ml of ethyl acetate, 150 mg of platinum(IV) oxide is added and hydrogenated in a hydrogenating apparatus until no more hydrogen is taken up. After filtration, it is concentrated by evaporation, whereby 398 mg of title compound 195 is obtained as a colorless oil, which is immediately further reacted.
Reaction SMILES: [OH:1][C:2]1([CH2:16][SH:17])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[C:18]1(=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]1=[O:28]>>[O:28]=[C:19]1[C:20]2[S:17][CH2:16][C:2]3([CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6][CH2:7]3)[O:1][C:21]=2[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]1=[O:29]
Reactant: CC(C)(C)OC(=O)NC1CCC(O)(CS)CC1
Reactant: O=C1C=Cc2ccccc2C1=O
Product: CC(C)(C)OC(=O)NC1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
The crude tert-butyl [4-hydroxy-4-(mercaptomethyl)cyclohexyl]carbamate was reacted with naphthalene-1,2-dione as outlined in procedure G [both step (i) (ii) and (iii)] to afford crude tert-butyl (5′,6′-dioxo-5′,6′-dihydrospiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiin]-4-yl)carbamate. The crude product was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product as a purple solid. M.p.=224-225° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (dd, J=7.6 Hz, 0.8 Hz, 1H), 7.83 (d, J=6.8 Hz, 1H), 7.75 (td, J=7.6 Hz, 1.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.34 (br, 1H), 3.02 (s, 2H), 2.05 (d, J=10.8 Hz, 2H), 1.76-1.53 (m, 6H), 1.39 (s, 9H); LCMS: 416 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])/[CH:7]=[CH:8]\[C:9]1[NH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)/C=C/C1NC(C(OC)=O)=CC=1)(C)(C)C>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[NH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(/C=C\C(=O)OC(C)(C)C)[nH]1
Agent: [Pd]
Agent: COC(=O)c1ccc(/C=C/C(=O)OC(C)(C)C)[nH]1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)OC(C)(C)C)[nH]1
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of (z)-methyl 5-(3-tert-butoxy-3-oxoprop-1-enyl)-1H-pyrrole-2-carboxylate or (E)-methyl 5-(3-tert-butoxy-3-oxoprop-1-enyl)-1H-pyrrole-2-carboxylate (13.6 g, 54.1 mmol, 2 equal batches) in EtOAc (200 mL) under nitrogen was added 10% Pd/C. The flask was flushed with hydrogen three times before allowing the reaction to stir under hydrogen for about 18 h. The catalyst was filtered off using Celite and the filtrate was concentrated to give 27.4 g methyl 5-(3-tert-butoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate as a white solid (100%) for each stereoisomer. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H), 2.54-2.59 (m, 2H), 2.90 (t, J=6.83 Hz, 2H), 3.83 (s, 3H), 5.97 (dd, J=3.49, 2.86 Hz, 1H), 6.81 (dd, J=3.61, 2.59 Hz, 1H), 9.30 (br s, 1H); LCMS-MS (ESI+) 197.86 (M-isobutylene).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][O:14][C:15](=[O:22])[C@@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH2:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:17][C@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([O:14][CH3:13])=[O:22])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(OC)c(F)c1

Procedure:
Prepared in a similar manner to example 4 using 3-fluoro-4-methoxybenzoic acid and D-leucine methyl ester. MS (M+H, 298).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH:11]([O:19][N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][CH:23]([OH:28])[CH2:22][C:21]2([CH3:30])[CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:32])([CH3:31])[CH2:3]1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([O:28][CH:23]1[CH2:22][C:21]([CH3:30])([CH3:29])[N:20]([O:19][CH:11]([O:10][N:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][C:2](=[O:1])[CH:3]=[CH2:4])[CH2:3][C:4]2([CH3:31])[CH3:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:25]([CH3:27])([CH3:26])[CH2:24]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCC(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C
Product: C=CC(=O)OC1CC(C)(C)N(OC(CCCCCCC)ON2C(C)(C)CC(OC(=O)C=C)CC2(C)C)C(C)(C)C1

Procedure:
The title compound is prepared by the reaction of the compound prepared in Example 4 with acryloyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14]([C:17]1[CH:21]=[C:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:19][N:18]=1)([CH3:16])[CH3:15]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:19]2[C:20]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:21][C:17]([CH:14]([CH3:16])[CH3:15])=[N:18]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1F
Reactant: CC(C)c1cc(C(=O)OC(C)(C)C)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(F)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 168 h
Yield: 43.2 %

Procedure:
4-Fluoro-3-nitrophenylboronic acid (0.9 g, 4.9 mmol) was dissolved in CH2Cl2 (10 mL) and pyridine (1 mL) with MS (activated 4A) and dried for 6 hours. A mixture of 4-fluoro-3-nitrophenylboronic acid, tert-butyl 3-isopropyl-1H-pyrazole-5-carboxylate (1.0 g, 4.9 mmol), copper(II) acetate (0.88 g, 4.9 mmol) and molecular sieves (4A activated, powder) was stirred at RT for 7 days open to the air. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 1-(4-fluoro-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.74 g, 44% yield). MS (ESI) m/z: 350.3 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C1O[C:30]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)([CH2:31][CH2:32][CH2:33][Cl:34])[O:29]C1.O>C(O)CCC>[ClH:34].[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:30]([CH2:31][CH2:32][CH2:33][N:2]2[CH2:3][CH2:4][C:5]3([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[O:14][C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:6][CH2:7]2)=[O:29])=[CH:40][CH:39]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: c1ccc2c(c1)Oc1ccccc1C21CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: O=C(CCCN1CCC2(CC1)c1ccccc1Oc1ccccc12)c1ccc(F)cc1
Yield: 32.5 %

Procedure:
A mixture of xanthene-9-spiro-4'-piperidine hydrochloride (1 g.), potassium carbonate (1.2 g.) and γ-chloro-p-fluorobutyrophenone ethylene ketal (1.03 g.) in n-butanol is heated under reflux for 48 hours. The mixture is poured into water, extracted with ether, the ether solution evaporated and the residue warmed with 3 N hydrochloric acid for 1 hour to hydrolyse the ketal. The acidic solution is extracted with ethyl acetate, the solvent evaporated and the residue recrystallised from ethyl acetate to give 1'-[3-(p-fluorobenzoyl)propyl]xanthene-9-spiro-4'-piperidine hydrochloride (0.51 g.), m.p. 219°-222° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1OC(C)(C)[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH:24]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]([C:35](=O)[CH:36]([CH3:38])[CH3:37])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])=[CH:19][CH:18]=1.C(OCC)C.[Cl-].[NH4+]>CS(C)=O.O>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:1]([CH2:2][CH2:3][C@H:4]3[CH2:5][C@H:6]([OH:7])[CH2:12][C:13](=[O:14])[O:15]3)[C:35]([CH:36]([CH3:38])[CH3:37])=[C:25]([C:26]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[C:24]=2[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)O)O1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@H]1C[C@H](O)CC(=O)O1
Temperature: 105 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of (±)4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 mL of dimethyl sulfoxide is heated at 105° C. for 15 hours. The solution is cooled and poured into 100 mL of diethyl ether and 50 mL of saturated ammonium chloride in water. The layers are separated and the organic layer washed with water (2×50 mL) and 5% sodium hydroxide solution (2×100 mL--to extract the intermediate from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 30 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 6 mL of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two crops.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[O:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[O:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2occc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2occc2C1)C(=O)O
Yield: 53.4 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.5 g, 1.16 mmol) was added to a mixture of ethanol (20 mL) and sodium hydroxide (0.32 g, 8.0 mmol) in water (6.6 mL). The mixture was heated to reflux for 6.5 hours. Evaporated solvent under reduced pressure and water (20 mL) was added to the residue. The aqueous solution was washed with a mixture of ethyl acetate/heptane 1/10 (10 mL), and the extract was discarded. The aqueous fraction was acidified with concentrated hydrochloric acid to pH=6 and the product was extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid (0.25 g, 46.9%) as a yellow oil. The material was dissolved in diethyl ether (5 mL) and added to hydrochloric acid solution (2N HCl in diethyl ether, 0.34 mL). Water (12 mL) was added and after mixing the aqueous portion was separated and freeze dried to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid, hydrochloride salt (Compound Io hydrochloride, 0.16 g, light yellow powder, 59.3% yield). 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.77 (br s, 1H), 7.63-7.48 (m, 5H), 6.37 (br s, 1H), 5.05 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.02 (m, 2H), 2.36-2.24 (m, 2H), 1.42-1.40 (m, 2H), 1.32 (m, 2H), 1.20-1.18 (m, 4H), 1.11 (s, 6H), 1.08-0.92 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CD3OD/TMS) δ (ppm): 181.70, 147.11, 144.55, 137.40, 132.15, 131.89, 130.08, 128.21, 129.87, 112.37, 109.71, 66.34, 52.10, 50.05, 43.07, 41.60, 35.10, 31.67, 30.56, 26.64, 25.85, 22.31. HRMS (HR, DIP-CI): Calculated for C23H30ClNO3 (M+H)+: 404.1987, found 404.2009. CHN analysis: Calculated; 62.73 C, 7.09 H, 3.18 N, 16.10 Cl, found; 59.13 C, 7.04 H, 3.03 N, 13.58 Cl.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[Cl:33].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:28]2[C:27]([Cl:33])=[C:26]([O:25][CH2:24][O:23][CH3:22])[CH:31]=[CH:30][C:29]=2[O:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][O:23][CH3:22])=[C:27]([Cl:33])[C:28]=2[CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COCOc1ccc(O)cc1Cl
Reactant: CCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(Cc2c(Oc3ccc(OCOC)c(Cl)c3Cc3ccc(OCCCCCCCCCCCC)cc3)ccc(OCOC)c2Cl)cc1
Yield: 58.7 %

Procedure:
In dimethylformamide, 2 g of 4-dodecyloxybenzyl bromide synthesized in the same manner as described in Referential Example 17 was reacted with 1.5 g of 4-methoxymethyloxy-3-chlorophenol synthesized in the same manner as described in Example 11 in the presence of NaH to obtain 1.5 g of 4-dodecyloxybenzyl(4-methoxymethyloxy-3-chlorophenyl) ether. According to customary procedures, the methoxymethyl group was removed from the so-obtained compound in the presence of zinc in acetic acid to obtain 1.2 g of 4-dodecyloxybenzyl(4-hydroxy-3-chlorophenyl) ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6](=[O:26])[N:7]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:8](=[O:18])[N:9]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:10]=1.O[C:28]1[CH:42]=[CH:41][C:31]([O:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=1>>[O:18]=[C:8]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:6](=[O:26])[C:5]([NH:4][CH2:3][CH2:2][O:1][C:28]2[CH:42]=[CH:41][C:31]([O:32][C:33]([CH3:39])([CH3:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=2)=[N:10][N:9]1[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: O=c1c(NCCO)nn(CCCC(F)(F)F)c(=O)n1CCCC(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCNc2nn(CCCC(F)(F)F)c(=O)n(CCCC(F)(F)F)c2=O)cc1

Procedure:
Compound 41 (oil) is prepared from triazine 9a and from intermediate 10c according to synthesis method 2.
Reaction SMILES: F.F.F.[CH2:4](N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@:40](C)([N:42]2[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:57][N:55]([CH3:56])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:4])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: CCN(CC)CC
Reactant: CN(C)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@@]1(C)n1ccc(=O)[nH]c1=O
Agent: F
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).