Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]2[O:15][CH2:16][C:17]([O:20][CH3:21])([O:18][CH3:19])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]=[O:14])[CH:10]2[O:15][CH2:16][C:17]([O:20][CH3:21])([O:18][CH3:19])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1(OC)COC2C(CO)CN(C(=O)OC(C)(C)C)C21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC1(OC)COC2C(C=O)CN(C(=O)OC(C)(C)C)C21
Reaction time: 0.67 h
Yield: 78.9 %

Procedure:
To a solution of the alcohol 1g (370 mg, 1.22 mmol) dissolved in dry DCM (10 mL) was added Dess Martin periodinane (673 mg, 1.59 mmol). The reaction was stirred for 40 minutes and then quenched by addition of 10 mL of 10% Na2S2O3:NaHCO3(sat) 1:1. The solution was diluted with DCM (50 mL) and extracted with a 1:1 mixture of 10% Na2S2O3:NaHCO3(sat) (50 mL). The organic phase was dried with Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (heptane: ethyl acetate (2:1) which gave the title compound (290 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1cccc(F)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccc(F)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 12.8 %

Procedure:
A mixture of 1-(3-fluorophenyl)-2-phenylethanone (100 mg, 0.47 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (82 mg, 0.39 mmol), urea (70 mg, 1.17 mmol), and concentrated HCl solution (0.03 mL, 0.39 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo and purified by preparative HPLC to give Compound 32 (22.35 mg, yield 13%) as a yellow solid. 1H NMR (DMSO-d6 400 MHz): δ 10.28 (s, 1H), 8.79 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.30-7.25 (m, 1H), 7.16 (s, 1H), 7.12-6.99 (m, 6H), 6.86 (d, J=7.6 Hz, 2H), 5.23 (d, J=2.4 Hz, 1H), 4.04 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); MS (ESI): m/z 450.0 [M+1]+.
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([NH:33][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)[NH:30][N:29]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1cc(-c2ccc(Cl)cc2)n[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCNc2cc(-c3ccc(Cl)cc3)n[nH]2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-(4-chlorophenyl)-1H-pyrazole-5-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (The objective compound was extracted in the saturated aqueous sodium hydrogen carbonate solution layer). Aqueous 10% citric acid solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromo-N-isobutyl-benzenesulfonamide (0.25 g, 856 μmol) in anhydrous dimethylacetamide (5 mL) was added NaH (60% dispersion in mineral oil, 37.7 mg, 942 μmol) and the mixture was stirred at room temperature for 15 minutes. 4-Fluorobenzyl bromide (117 μL, 942 μmol) was added and reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water added and then extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give 4-bromo-N-(4-fluoro-benzyl)-N-isobutyl-benzenesulfonamide (267 mg, 78%) 1H NMR (300 MHz, CDCl3): δ 7.65-7.66 (m, 4H), 7.23 (m, 2H), 6.99 (t, 2H), 4.27 (s, 2H), 2.89 (d, 2H), 1.64 (dt, 1H), 0.74 (d, 6H).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9](CC1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.N[C:60]1C=CC=C[CH:61]=1>>[CH:8]12[N:7]([C:13]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:56][C:55]5[CH:57]=[CH:58][C:52]([N:49]6[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]6)=[CH:53][CH:54]=5)=[O:27])=[CH:23][CH:24]=4)[N:16]=[C:15]4[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=34)[CH:6]([CH2:60][CH2:61]1)[CH2:5][O:12][CH2:9]2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Nc1ccccc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Product: CCn1ncc2c(N3C4CCC3COC4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCN(C)CC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(4-methylpiperazin-1-yl)aniline as the aniline component. (53%, MS=568.5 (M+H))
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][CH:18]1[CH2:19][CH2:20][CH:21]2/[CH:26]=[N:27]/[OH:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].CCN(C(C)C)C(C)C>N1C=CC=CC=1.C(Cl)Cl>[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26]1[CH:30]=[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N2CC(CCC2/C=N/O)N1OCc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39.6 %

Procedure:
NCS (290 mg, 2.17 mmol) and pyridine (2 drops) were added to a solution of (E)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde oxime (560 mg, 2.04 mmol) in dry DCM (15 mL). The reaction mixture was stirred at rt for about 3-4 hrs. Ethynyltrimethylsilane (240 mg, 2.44 mmol) was added, then a solution of DIPEA (290 mg, 2.24 mmol) in dry DCM (5 mL) was added slowly over a 0.5 h period. After addition, the reaction mixture was stirred at rt overnight. The reaction mixture was then washed with 10% citric acid, water, saturated sodium chloride (10 mL), dried and concentrated. The residue was purified by silica gel column chromatography (10:1 petroleum ether/EtOAc) to afford (2S,5R)-6-(benzyloxy)-2-(5-(trimethylsilyl)isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (300 mg, 41%) as a colorless oil. ESI-MS (EI+, m/z): 372 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CCCC)[C:13]([CH3:28])=[C:12]2[CH2:29][C:30]([NH2:32])=[O:31])C.[OH-].[Na+].O.Cl>CO>[NH2:32][C:30](=[O:31])[CH2:29][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:33])[CH:10]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]=1[CH3:28]
Reactant: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1C1CCCCC1
Yield: 28 %

Procedure:
A mixture of 190 mg (0.46 mmol) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 2 mL of 5N NaOH in 20 mL of MeOH was heated to maintain reflux for 2.5 hours, cooled, poured into water and made strongly acidic with 5N HCl. The precipitate was filtered and recrystallized from MeOH. There was obtained 50 mg (28% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid. mp, 212-214° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].CN(C)C=O.S(Cl)([Cl:25])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([Cl:25])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(C(=O)O)C(C)C)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(C(=O)Cl)C(C)C)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Into a solution of 0.15 g (0.62 mM) of 2-(3-fluoro-4-ethoxyphenyl)isovaleric acid in 3.0 ml of anhydrous methylene chloride, a catalytic amount of dimethylformamide and 0.16 g (1.37 mM) of thionyl chloride were added, and the mixture was stirred for 2 hours in an oil bath at 40° C. Thereafter, an excess of thionyl chloride and methylene chloride were distilled off from the reaction mixture under a reduced pressure to obtain 2-(3-fluoro-4-ethoxyphenyl)isovaleric chloride as an oily substance.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C(O[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C.[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][C:20]1([CH3:26])[C:21]([CH3:24])([CH3:23])[O:22][B:18]([C:2]2[C:10]3[O:9][C:8]([F:12])([F:11])[O:7][C:6]=3[C:5]([F:13])=[CH:4][CH:3]=2)[O:19]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Br)c2c1OC(F)(F)O2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(F)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -5 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
4-Bromo-2,2,7-trifluorobenzo[d][1,3]dioxole (2.0 g, 7.8 mmol) was dissolved in dry tetrahydrofuran (12 ml), cooled to −5° C. and treated in portions with isopropylmagnesium lithium chloride complex (1.3 M; 6.3 mL, 8.2 mmol). The mixture was stirred for 2 h at 5 to 15° C., treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 8.4 mmol) and stirred for 2 h at 10 to 20° C. The mixture was treated with saturated NH4Cl (5 mL), stirred for 10 min and then shaken with 1 M HCl (10 mL) and ethyl acetate (75 mL). The organic phase was washed with saturated NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (2.3 g, 98%): 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J=8.7, 5.3 Hz, 1H), 6.88 (dd, J=9.5, 8.8 Hz, 1H), 1.36 (s, 12H); 19F NMR (376 MHz, CDCl3) δ −49.07, −131.31; EIMS m/z 302.
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37]C1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Cl:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Product: Cl

Procedure:
Intermediate 25a was used in the method of Example 39 instead of Intermediate 26 to obtain the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[C:27]([NH:29][C:30](=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[N:44]=[C:45]([NH:48][C:49]([NH2:51])=[NH:50])[S:46][CH:47]=1)OC1C=CC=CC=1)#[N:28]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30]([NH:29][C:27]#[N:28])=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[N:44]=[C:45]([NH:48][C:49]([NH2:51])=[NH:50])[S:46][CH:47]=2)[CH3:20])=[CH:4][CH:3]=1
Reactant: CN(CCCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (1.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and 0.7 g (1.9 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=655 ([M+H]+ 2), 230 (18), 154 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 150° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]([C:7]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[O:8])[C@@H:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][C:3]1=[O:26].[Li+].[BH4-].O>C1COCC1>[OH:8][C@@H:7]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[C@@H:6]1[N:2]([CH3:1])[C:3](=[O:26])[CH2:4][C@@H:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C(=O)c1ccc(-c2ccccc2)s1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@@H](O)c1ccc(-c2ccccc2)s1
Temperature: 50 °C
Yield: 69.6 %

Procedure:
To a solution of (4R,5R)-1-methyl-4-phenyl-5-[(5-phenyl(2-thienyl))-carbonyl]pyrrolidin-2-one (60 mg, 0.17 mmol) in THF (2 mL) was added a solution of LiBH4 (2M in THF, 0.1 mL, 0.2 mmol) and the reaction mixture was heated at 50° C. for 2 h. The resulting pale yellow suspension was treated with water and a saturated NH4Cl solution, extracted with EtOAc, dried (Na2SO4), concentrated onto silica gel and purified by flash chromatography to give (4R,5R)-5-[(1R)-hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-phenylpyrrolidin-2-one (43 mg, 71%) as a yellow solid: TLC (EtOAc) Rf 0.36; HPLC ES-MS m/z 364 (MH+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=O)[NH:13][CH:14]=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([Cl:24])=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(-c2cnc[nH]c2=O)cc1OC(C)=O
Product: CC(=O)Oc1ccc(-c2cncnc2Cl)cc1OC(C)=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4-(3,4-Dihydro-4-oxo-5-pyrimidinyl)-o-phenylene diacetate (194 mg) (0.67 mmol) are added to 5 ml of phosphorus oxychloride. After stirring at 100° C. for 6 hours the mixture is concentrated in a vacuum at 40° C. The residue is dissolved in dichloromethane/methanol (99:1 v/v) and the solution is washed with water. The solution is dried over sodium sulphate and concentrated. The residue is crystallized using ethanol. The beige crystals are filtered off under suction, washed with petroleum ether and dried in a high vacuum at room temperature. There are obtained 90 mg of 4-(4-chloro-5-pyrimidinyl)-o-phenylene diacetate of m.p. 108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: O=C(Cl)c1ccccn1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccccn3)CC2)C1

Procedure:
Compound 762 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and pyridine-2-carbonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%-20%-30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0476 g, 39% yield). HRMS (M+H) calcd for C25H28N4Cl2O5: 532.15184. found: 532.1514.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:46]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:47].CCOCC>C(Cl)Cl>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:46]([O:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:47])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.5 g, 0.93 mmole) and triethylamine (0.16 g, 1.6 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of phenyl chloroformate (0.16 g, 1.02 mmole) in methylene chloride (2 ml). After 1 hour at 0°, an additional portion of phenyl chloroformate (0.05 g, 0.32 mmole) was added and stirring continued for a further 0.5 hour. The reaction was subsequently quenched by the addition of 2N sodium hydroxide solution, methylene chloride added, the organic phase separated, washed with water, dried over magnesium sulphate and concentrated under reduced pressure to yield a foam. Trituration of this foam with ether yielded the desired product as a buff solid, (0.42 g, 68%), which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N3CCCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with pyrrolidine (9 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane and allowed to react overnight. The reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 26 mg of the title compound as a colorless solid.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:27]CCC.[F:31][C:32]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[CH:47]=[CH:46][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([CH:44]=O)[S:43][C:36]=12.O>C1COCC1>[F:31][C:32]1[CH:49]=[C:48]([N+:50]([O-:52])=[O:51])[CH:47]=[CH:46][C:33]=1[O:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]2[CH:41]=[C:42]([CH:44]=[CH:27][CH2:5][CH2:4][N:3]([CH3:25])[CH3:2])[S:43][C:36]=12
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Reactant: O=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC=Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of (2-(dimethylamino)ethyl)triphenylphosphonium bromide (680 mg, 1.54 mmol) in THF (7.7 mL) was added n-BuLi (2.5M in hexanes, 0.65 mL, 1.62 mmol) dropwise at 0° C., the resulting mixture was warmed to room temperature and stirred for 30 min. 7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carbaldehyde 233 (500 mg, 1.17 mmol) was added in one portion and the mixture was stirred for 2 h. The mixture was poured into water, extracted with EtOAc; the organic phase was extracted with 3% citric acid, the combined aqueous phase was basified to pH˜11 by the addition of 1N NaOH. It was then extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure affording title compound 234 (360 mg, 0.929 mmol, 78% yield) as a crude mixture that was used in the next step without further purification. MS (m/z): (M+1) 388.1 (100%).