Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[N:29]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[N:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)n1

Procedure:
Example 88 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methyl propanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.08 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.67 (t, 1H, J=7.6 Hz), 7.33–7.27 (m, 4H), 6.88 (d, 1H, J=7.2 Hz), 6.57 (brs, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.58–2.53 (m, 2H), 2.37 (t, 2H, J=6.4 Hz), 1.97 (t, 2H, J=11.2 Hz), 1.87 (d, 2H, J=13.2 Hz), 1.67–1.58 (m, 4H), 1.57 (s, 6H), 1.28 (d, 6H, J=7.2 Hz); ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](OC2C=CC=CC=2)=[O:12])[N:7]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:48]=[CH:47][C:35]([O:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]([NH:45][CH3:46])=[O:44])[CH:38]=2)=[CH:34][C:33]=1[F:49].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:12])[NH:31][C:32]2[CH:48]=[CH:47][C:35]([O:36][C:37]3[CH:42]=[CH:41][N:40]=[C:39]([C:43](=[O:44])[NH:45][CH3:46])[CH:38]=3)=[CH:34][C:33]=2[F:49])[N:7]([C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C(=O)NC)c3)cc2F)c1
Yield: 57.6 %

Procedure:
A solution of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}benzoate (9.36 g, 22.0 mmol), 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (5.0 g, 19.1 mmol; prepared as described in Dumas et al., PCT Int. Appl. WO 2004078748 (2004)) and triethyl amine (3.87 g, 38.3 mmol) in anhydrous THF (100 mL) was stirred at room temperature overnight. The crude product was purified by column chromatography (CH2Cl2 plus 1% to 3% of 2M NH3 in MeOH), followed by recrystallization from EtOAc/hexanes to give the desired product as an off-white crystalline solid (6.32 g, 57%). MS m/z 575.1 (M+H)+; calcd. mass 574. Retention time (LC-MS): 3.75 min. 1H-NMR (DMSO-d6): δ 8.97 (m, 1H); 8.89 (m, 1H); 8.80 (m, 1H); 8.52 (d, J=5.6 Hz, 1H); 8.16 (t, 1H); 8.06 (m, 1H); 7.99 (m, 1H); 7.85 (m, 1H); 7.71 (t, 1H); 7.39 (m, 1H); 7.33 (m, 1H); 7.17 (m, 1H); 7.06 (m, 1H); 6.42 (s, 1H); 4.36 (q, 2H); 2.78 (d, J=5.2 Hz, 3H); 1.31 (m, 12H).
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][O:7][C:8]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([O-:19])=O)[CH2:12]1.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:6][O:7][C:8]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([N:28]([O:27][CH3:26])[CH3:29])=[O:19])[CH2:12]1
Reactant: COc1ccc(CN2CC(C(=O)[O-])CC2=O)c(OC)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C(=O)N(C)OC)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (15.3 mL, 30.6 mmol) was added to a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (3.0 g, 10 mmol) and O,N-dimethyl-hydroxylamine (1.5 g, 15 mmol) in THF (100 mL) at −10° C. The mixture was stirred at 0° C. for 1 hour then the mixture was added to water and concentrated under reduced pressure to afford 1-(2,4-dimethoxybenzyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide. 1H NMR (400 MHz, CDCl3) δ 7.13-7.15 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.67 (s, 3H), 3.46-3.49 (m, 3H), 3.18 (s, 3H), 2.70-2.77 (m, 1H), 2.57-2.63 (m, 1H). MS ESI calc'd. for C16H23N2O5 [M+H]+ 323. found 323.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: COC(=O)CCC(=O)c1cc(OC)ccc1OCC1CO1
Product: COC(=O)CCC(=O)c1cc(OC)ccc1OCC(O)CNC(C)(C)C

Procedure:
Methyl 3-[2-(2,3-epoxypropoxy)-5-methoxybenzoyl]-propionate was reacted with t-butylamine in a similar manner to that described in Example 2 (i) to give methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-5-methoxybenzoyl]-propionate, which recrystallised from ether, had m.p. 70° - 72° C. (Found: C, 62.22; H, 8.22; N, 3.65; C19H29NO6 requires: C, 62.10; H, 7.96; N, 3.81%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][NH:49][CH:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][N:49]([C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH:50]([CH3:52])[CH3:51]
Reactant: COc1cc(Cl)cc(C(=O)O)c1
Reactant: COC(=O)CCNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-benzoic acid (0.932 g), TBTU (3.21 g) and in DMF (10 ml) was added DIPEA (1.73 ml) followed by 3-isopropylamino propionic acid methyl ester (0.871 g) after 10 min. The reaction mixture was stirred at room temperature for 48 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 2M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (1.6 g).
Reaction SMILES: [C:1]([C:3](=[C:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][CH:14]([OH:28])[C@@H:15]2/[CH:18]=[CH:19]/[C@@H:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[O:11]1)[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8])#[N:2].[CH2:29]([CH2:31][NH2:32])O>>[OH:28][CH:14]1[CH2:13][C@H:12]2[C@H:16]([CH2:17]/[C:10](=[C:3](/[CH2:4][CH2:5][CH2:6][C:7]3[O:8][CH2:29][CH2:31][N:32]=3)\[C:1]#[N:2])/[O:11]2)[C@H:15]1/[CH:18]=[CH:19]/[C@@H:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: NCCO
Reactant: CCCCC(C)[C@H](O)/C=C/[C@H]1C(O)C[C@@H]2OC(=C(C#N)CCCC(=O)O)C[C@@H]21
Product: CCCCC(C)[C@H](O)/C=C/[C@H]1C(O)C[C@@H]2O/C(=C(/C#N)CCCC3=NCCO3)C[C@@H]21

Procedure:
Analogously to Example 4 from 78 mg (0.2 mmol) of 5-cyano-5-{(1S,5R,6R)-7-hydroxy-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octenyl]-2-oxabicyclo[3.3.0]octan-3-ylidene}-pentanoic acid and ethanolamine. Yield: 60 mg (72% of theory).
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:29][NH2:30]>CCO>[N:15]1([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:16][CH2:17][C:12]2([C:3]3[CH:2]=[N:30][NH:29][C:4]=3[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11]2)[CH2:13][CH2:14]1
Reactant: NN
Reactant: O=C1C(=CO)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)Oc1ccccc1-c1[nH]ncc12
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.95 g, 5.10 mmol) and hydrazine (161 μL, 5.10 mmol) in EtOH (39 mL) was stirred at room temperature for 1 hour and then at 50° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (10-100% ethyl acetate in hexane) to afford benzyl 1H-spiro[chromeno-[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.11 g, 58%). ESI-MS m/z calc. 375.2, found 376.3 (M+1)+; Retention time: 1.71 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12]Br)=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:20].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1COCC1.C(=O)(O)[O-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:20]
Reactant: O=c1c(-c2ccccc2)c(CBr)oc2ccc(Br)cc12
Reactant: C1COCCN1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccc(Br)cc12
Yield: 131.3 %

Procedure:
To a solution of Intermediate 3 (0.30 g, 0.761 mmoles) in THF (2 ml), was added morpholine (0.066 g, 0.761 mmoles) at RT and refluxed for 12 h. The reaction mixture was cooled, diluted with aqueous bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.40 g, 79% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.12 (d, J=2.2 Hz, 1H), 7.98 (dd, J=8.8, 2.3 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.45-7.39 (m, 3H), 7.29 (d, J=7.0 Hz, 2H), 3.50 (t, J=4.2 Hz, 4H), 3.40 (s, 2H), 2.32 (br S, 4H).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]([OH:11])CO)=[C:6]([C:12]2[N:16]=[CH:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:13]=2)[S:5][C:4]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1)#[N:2].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[C:1]([C:3]1[C:7]([CH:8]=[O:11])=[C:6]([C:12]2[N:16]=[CH:15][N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:13]=2)[S:5][C:4]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1)#[N:2]
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C(O)CO)c2C#N)ccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(C=O)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
Methyl (4-{3-cyano-4-(1,2-dihydroxyethyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (0.362 g, 0.769 mmol) was dissolved in acetone (40 mL) and water (10 mL). Sodium metaperiodate (0.494 g, 2.31 mmol) was added and the mixture was stirred at room temperature for 6 hours. Sodium metaperiodate (0.329 g, 1.54 mmol) was added and the mixture was stirred for 16 more hours. The mixture was concentrated in rotavapor. The residue was triturated with water, filtered and washed thoroughly with water, then dried in lyophilizer to give a dry solid product (0.320 g, yield 94.8%). LC/MS: (FA) ES+ 439. 1H NMR (400 MHz, d6-dmso) δ 10.67 (s, 1H), 10.57 (s, 1H), 9.05 (s, 1H), 8.49 (m, 1H), 8.28 (s, 1H), 7.50 (m, 1H), 5.69-5.73 (m, 1H), 3.94-3.98 (m, 1H), 3.73 (s, 3H), 3.66-3.71 (m, 1H), 1.93-2.12 (m, 3H), 1.58-1.71 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(C3CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (55 mg, 0.12 mmol) in 1,2-dichloroethane (1.0 mL) was added cyclohexanone (0.014 mL, 0.14 mmol) and sodiumtriacetoxyborohydride (33 mg, 0.16 mmol). The mixture was stirred for 14 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 2-[5-(1-cyclohexyl-piperidin-4-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.3 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 530.2 (ethyl ester).
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][N:29]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:7])[CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:15][CH2:16]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)N1CCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N3CCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 1-pyrrolidinecarbonyl chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=422.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[CH3:28][C:29]1([CH3:36])[O:34][CH2:33][CH:32](O)[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:36])[O:34][CH2:33][CH:32]([O:22][C:18]2[C:19]([CH3:21])=[CH:20][C:15]([C:12]3[N:11]=[C:10]([C:8]4[CH:7]=[C:6]([CH3:25])[N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:26][CH3:27])[CH:9]=4)[O:14][N:13]=3)=[CH:16][C:17]=2[CH2:23][CH3:24])[CH2:31][O:30]1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Reactant: CC1(C)OCC(O)CO1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC1COC(C)(C)OC1
Yield: 49.5 %

Procedure:
4-[5-(2-Diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (100 mg, 0.273 mmol, Example 12) is reacted with 2,2-dimethyl-[1,3]dioxan-5-ol (54 mg, 0.409 mmol) under Mitsunobu conditions as described in Example 18, step a) to give (4-{3-[4-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-methyl-pyridin-2-yl)-diethyl-amine (65 mg) as yellow oil; LC-MS: tR=0.97 min; [M+1]+=481.27. This material (65 mg, 0.135 mmol) is dissolved in 25% aq. HCl (3 mL) and the resulting mixture is stirred at rt for 2 h. The solvent is evaporated and the crude product is purified by prep. HPLC to give the title compound (23 mg) as yellow solid; LC-MS: tR=0.80 min; [M+1]+=441.24; 1H NMR (CD3OD): δ 1.22 (t, J=7.0 Hz, 6H), 1.28 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.44 (s, 3H), 2.82 (q, J=7.5 Hz, 2H), 3.61 (q, J=7.0 Hz, 4H), 3.78 (dd, J=11.3, 4.8 Hz, 2H), 3.84 (dd, J=11.5, 5.0 Hz, 2H), 4.11-4.18 (m, 1H), 7.02 (s, 2H), 7.77 (s, 1H), 7.82 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: C/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[(E)-3-chloro-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 3, 36 g, 0.17 mol) in dichloromethane (50 ml) was added rhodium (II) acetate dimer (1 g, 2.3 mmol). To the mixture was added dropwise at room temperature over 8 h a solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture was stirred at room temperature for 16 h. To the mixture was added dropwise at room temperature over 7 h a further solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture was stirred at room temperature for a further 16 h. The mixture was concentrated in vacuo and the residue purified by silica column (1 kg) chromatography, eluting with 1:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then concentrated under a stream of nitrogen for 16 h. The residue was purified further by silica column (2 kg) chromatography, eluting with 1:1 hexane/dichloromethane then dichloromethane. Product containing fractions were combined and concentrated in vacuo, to give the title compound as a very pale yellow oil (14.2 g, 29%).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:34](O)[CH3:35]>O1CCCC1>[CH2:34]([CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([OH:21])=[O:20])[CH3:35]
Reactant: CCO
Reactant: CCOC(=O)COc1ccc(CC(NS(=O)(=O)c2ccccc2)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(CC(NS(=O)(=O)c2ccccc2)c2cccnc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-[2-benzenesulfonamido-2-(3-pyridyl)ethyl]phenoxyacetate (70 mg) was dissolved in 2 ml of ethanol and 2 ml of tetrahydrofuran, followed by addition of 0.30 ml of aqueous 2N sodium hydroxide solution, and stirred at room temperature for one hour. The solvent was concentrated under reduced pressure, and neutralized with 2N hydrogen chloride. Then, the crystalline deposited was taken out by filtration and recrystallized in aqueous ethanol, to yield 15 mg of ethyl 4-[2-benzenesulfonamido-2-(3-pyridyl)ethyl]phenoxyacetic acid. The spectrometric data thereof supports the structure of [21] as follows.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: OC(Cc1ccccc1Br)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OC(Cc1ccccc1-c1ccccc1)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
1-(4-Benzyl-morpholin-2-yl)-2-(2-bromo-phenyl)-1-phenyl-ethanol (0.50 g, 1.0 equiv. prepared according to Example 15a below) and phenylboronic acid (0.402 g, 3.0 equiv., available from Aldrich Chemical Company) were suspended in a mixture ethanol/water (2/1, 7.5 mL) and Pd(Ph3)4 (0.022 g, 0.04 equiv.), then K2CO3 (0.654 g, 4.30 equiv.) were added. The mixture was heated to 80° C. under nitrogen atmosphere. After 16 hours, the reaction was cooled down to room temperature and filtered through Celite, then extracted with ethyl acetate. The organic layers were combined, dried with MgSO4, filtered and concentrated in vacuo yielding a yellow oil, which was purified by column chromatography on silica gel (10% EtOAc:Hexane) to give 0.491 g (98%) of the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].I[C:22]1C=C(C=C(I)[C:30]=1OC1C=CC(OC)=CC=1)C(Cl)=O>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([O:7][CH2:22][CH3:30])=[O:6]
Reactant: COc1ccc(Oc2c(I)cc(C(=O)O)cc2I)cc1
Reactant: COc1ccc(Oc2c(I)cc(C(=O)Cl)cc2I)cc1
Product: CCOC(=O)c1cc(I)c(Oc2ccc(OC)cc2)c(I)c1
Temperature: 70 °C

Procedure:
Ethyl 3,5-diiodo-4-(4′-methoxyphenoxy)benzoate (Compound 5) was synthesized by way of 3,5-diiodo-4-(4′-20 methoxyphenoxy) benzoyl chloride, the latter having been described in Borrows et al., supra. Thus, in a 10 ml flask 3,5-diiodo-4-(4′methoxyphenoxy)benzoic acid (99.2 mg, 0.200 mmole) was converted to 3,5-diiodo-4-(4′-methoxyphenoxy) benzoyl chloride. After removal of excess thionyl chloride under vacuum, anhydrous ethanol (5.0 ml) was added with stirring and the mixture heated to 70° C. for 5 minutes. Excess ethanol was removed and the dry residue dissolved in hot 95% ethanol (4.0 ml), from which the product ester crystallized in the refrigerator (3° C.). Yield: 55.8 mg (53%) of buff-colored crystals. Melting point: 96-98° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[Cl:15])(=[O:5])[CH3:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:3](=[O:5])[CH3:4])=[C:7]1[Cl:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 72 h

Procedure:
To a slurry of 400 mg of NaH in 20 ml THF was added 1 g of (75), and then 770 μl of benzyl bromide. The reaction was left with stirring for 3 days. Water was added, and the product extracted with diethylether, dried, and the solvent evaporated off to give 1.52 g of a redbrown powder, which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C.N1C=CC=CC=1>[O:17]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH:4]=[C:3]([NH:2][C:20](=[O:21])[CH2:19][Cl:18])[CH:16]=[CH:15][C:14]=2[NH:13]1
Reactant: Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 828.4 %

Procedure:
To a supension of HCl salt of 2-amino-6(5H)-phenanthridinone (100 mg, 0.04 mmol) in DMF (5 mL), pyridine (0.5 mL) was added, followed by the addition of chloroacetyl chloride (0.2 mL, 0.002 mol) at 0° C. The reaction mixture was stirred at room temperature for 1 to 2 hrs. It was then poured over crushed ice, and the solid obtained was washed thoroughly with cold water. The solid was then dried under vacuum to give N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-choroacetamide (95 mg, 84%).