Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]#[N:25])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[N-:28]=[N+:29]=[N-:30].[Na+].Cl>O>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:23][C:24]3[NH:30][N:29]=[N:28][N:25]=3)[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: c1ccc(-c2ccc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)[nH]2)cc1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
A mixture of {[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetonitrile (0.20 g, 0.62 mmol), prepared in the previous step, ammonium chloride (0.12 g, 1.85 mmol) and sodium azide (0.099 g, 1.85 mmol) in DMIF (10 mL) was heated at 100° C. under nitrogen for 5 hours. After cooling to ambient temperature, TLC analysis showed that starting material remained. An additional portion each of ammonium chloride and sodium azide was added, and the mixture was again heated at 100° C. for 4 hours, at which time no starting material remained. The mixture was cooled to ambient temperature, acidified with 1N HCl (5 mL) and diluted with water (20 mL). The precipitated solids were isolated by vacuum filtration to give the title compound as a gray solid (0.202 g, 89%), mp 237–240° C. (dec). Elemental Analysis for C22H17N5O.0.55 H2O.0.11 C3H7NO Calc'd: C, 69.60; H, 4.94; N, 18.57. Found: C, 69.71; H, 4.64; N, 18.61.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[CH2:30][C:31]([OH:33])=[O:32])=[O:19])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:36][Si](C)(C)C)=[N-]>CO>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18]([C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=2[CH2:30][C:31]([O:33][CH3:36])=[O:32])=[O:19])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2CC(=O)O)n1C[C@H]1CCCO1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Temperature: 20 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of Example 128A (400 mg, 0.856 mmol) in MeOH (3 mL) was added (diazomethyl)trimethylsilane (4.28 ml, 8.56 mmol). The mixture was stirred at 20° C. overnight then concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, gradient 20-100% solvent A in hexane; solvent A=10:1:0.5 ethyl acetate:methanol:triethylamine) to afford the title compound (250 mg, 0.519 mmol, 60.7% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 9H) 1.71-1.85 (m, 3H) 1.99-2.12 (m, 1H) 3.66 (s, 3H) 3.70-3.82 (m, 2H) 3.87 (s, 3H) 4.17-4.23 (m, 1H) 4.25-4.33 (m, 3H) 4.52-4.59 (m, 1H) 6.99 (s, 1H) 7.31 (d, J=7.80 Hz, 1H) 7.52 (dd, J=7.97, 1.53 Hz, 1H) 8.40 (d, J=1.70 Hz, 1H); MS (DCI/NH3) m/z 482 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].[CH2:18]([C@H:20]1[O:22][CH2:21]1)[Cl:19]>>[Cl:19][CH2:18][C@@H:20]([OH:22])[CH2:21][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClC[C@@H]1CO1
Agent: [Br-]
Agent: [Li+]
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium bromide (1.7 g, 20 mmol) were added to (S)-epichlorohydrin (185 g, 2 mol). The mixture was stirred at room temperature (25° C.) for 2 hours, Filtered, and the solvent was evaporated to provide 53 g of colorless Oil in 90% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:38]([S:40]([CH:43]=C)(=[O:42])=[O:41])=[CH2:39].CO>C(Cl)Cl>[CH3:43][S:40]([CH2:38][CH2:39][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:27])[F:28])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: C=CS(=O)(=O)C=C
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (90 mg, 0.22 mmol), triethylamine (150 L, and IMS (0.6 mL) was treated with vinyl sulfone (48 mL, 0.54 mmol) then diluted with DCM and stirred for 18 h at RT. The reaction mixture was concentrated in vacuo and the residue triturated in diethyl ether to provide a solid which was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) to give 152 as a white solid (96 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1 H); 7.69 (s, 1 H); 7.19-7.08 (m, 2 H); 6.92 (s, 1 H); 5.53 (q, J=8.15 Hz, 2 H); 4.54 (t, J=6.01 Hz, 2 H); 3.21-3.12 (m, 4 H); 3.21-2.92 (m, 5 H); 2.93 (t, J=6.33 Hz, 2 H); 2.63-2.54 (m, 1 H); 2.21 (t, J=11.57 Hz, 2 H); 1.94 (d, J=12.96 Hz, 2 H); 1.81-1.66 (m, 2 H). LCMS: RT=6.57 min, M+H+=525
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH2:20][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[O:11][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Reaction time: 8 h
Yield: 133.6 %

Procedure:
To a flask containing 4-bromo-3-hydroxybenzoic acid (available from Combi-Blocks Inc.) (2.40 g, 11.06 mmol) and cesium carbonate (8.287 g, 25.44 mmol) in DMF (40 mL), was added 1-bromobutane (available from Aldrich) (2.494 mL, 23.22 mmol), and the mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/Hexanes) to provide 5.1 (2.4326 g, 66.81% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][CH:12]=[N:11][C:10]=2[CH:14]=1.[Na+].[I-].Cl.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[S:13][CH:12]=[N:11][C:10]=3[CH:14]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: BrCCCOc1ccc2scnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Clc1cccc(N2CCN(CCCOc3ccc4scnc4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of intermediate 27 (218 mg, 0.8 mmol) and NaI (240 mg, 1.6 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 41 (320 mg, 1.2 mmol) and anhydrous K2CO3 (442 mg, 3.2 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 5-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propoxy)benzo[d]thiazole (compound 23) (209 mg, 62%). 1H NMR (300 MHz, CDCl3): δ 8.97 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.16-7.09 (m, 3H), 6.94 (dd, J=3.6 Hz, 6.0 Hz, 1H), J=5.7 Hz, 2H), 3.09 (m, 4H), 2.68-2.63 (m, 6H), 2.10-2.05 (m, 2H). HPLC: 99%, RT 2.607 min. MS (ESI) m/z 422.0 [M+H]+. mp: 127-129° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])=[CH:3]1.[OH-].[K+]>C(O)C.[Pd]>[O:1]=[C:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: CCOC(=O)C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h
Yield: 93.5 %

Procedure:
Ethyl 3-oxo-4,22-choladienate (2.39 g) was dissolved in 99% ethanol (170 ml) containing 0.9 g of potassium hydroxide. 10% Palladium on carbon containing 50% H2O (0.16 g) was added and the mixture was hydrogenated at room temperature and 1 atmosphere for about 3 hours (280 ml hydrogen was consumed). The catalyst was removed by filtration and water (20 ml) was added. After stirring for 3 days, acetic acid was added to pH 4, the solution was concentrated under reduced pressure to about 10 ml, and 20 ml of water was added. After stirring, the mixture crystallised. Filtration and washing with water gave 2.1 g of the title compound. 1H-NMR (CDCl3, 300 MHz), 0.67 (3H, s); 0.92 (3H, d); 1.00 (3H, s); 2.68 (1H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:32]=[C:33]3[C:47](=[CH:48][CH:49]=2)[C:36]2[NH:37][N:38]=[C:39]([C:40]4[S:44][C:43]([CH:45]=[O:46])=[CH:42][CH:41]=4)[C:35]=2[CH2:34]3)[CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:37]2[C:36]3[C:47]4[C:33]([CH2:34][C:35]=3[C:39]([C:40]3[S:44][C:43]([CH:45]=[O:46])=[CH:42][CH:41]=3)=[N:38]2)=[CH:32][C:31]([CH2:30][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:49][CH:48]=4)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: CN1CCN(Cc2ccc3c(c2)Cc2c(-c4ccc(C=O)s4)n[nH]c2-3)CC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(C=O)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 50 °C

Procedure:
To 4,4′-dimethoxybenzhydrol (5.62 g, 23.0 mmol) was carefully added thionyl chloride (20.1 mL, 276 mmol) and the mixture was heated to reflux for about 1 hour. The solution was cooled, evaporated to dryness and the residue was dissolved in tetrahydrofuran (50 mL). This solution was then added to a solution of Example 326 (5.3 g, 14.0 mmol) and triethylamine (5.9 mL, 42.0 mmol) in tetrahydrofuran (100 mL). The reaction mixture was heated to about 50° C. for about 2.5 hours, cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum, and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide the desired product. MS (ESI): m/z 605 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18](O)[CH:19]([CH2:45][CH2:46]O)[CH2:20][C:21]3[CH:22]=[C:23]([O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:24]=[CH:25][CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[S:50](Cl)(=O)=O.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:22]=4)[CH2:45][CH2:46][S:50]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CC(CCO)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1cccc(CC2CCSC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[3-(4,5-diphenyloxazol-2-yl)-3-hydroxy-2-(2-hydroxyethyl)propyl]-1-(t-butyldiphenylsilyloxy)benzene (3.0 g) and methanesulfonyl chloride (1.1 ml) and triethylamine (2.6 ml) in THF (50 ml) was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was dissolved in DMF (40 ml) and to the solution was added Na2S (600 mg). After being stirred for 30 minutes at 80° C., the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford 2-(4,5-diphenyloxazol-2-yl)-3-(3-t-butyldiphenylsilyloxybenzyl)tetrahydrothiophene (3.2 g). MS (m/z): 652 (M+ +1) IR (Neat): 1600, 1580 cm-1NMR (CDCl3, δ): 1.08 (9H, s), 2.0-2.5 (4H, m), 2.6-3.2 (3H, m), 4.10 (2/3H, d, J=7 Hz), 4.20 (1/3H, d, J=7 Hz), 6.4-6.8 (3H, m), 6.9-7.1 (1H, m), 7.2-7.8 (20H, m)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=3)[CH:5]([S:16]([NH2:19])(=[O:18])=[O:17])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[K+].[Br-]>CN(C)C=O.O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:5]1([S:16]([NH2:19])(=[O:17])=[O:18])[C:6]2[CH:7]=[C:8]([F:15])[CH:9]=[CH:10][C:11]=2[C:12]2[C:4]1=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)[CH3:28]
Reactant: NS(=O)(=O)C1c2cc(F)ccc2-c2ccc(F)cc21
Reactant: CCOC(=O)CBr
Agent: [Br-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2cc(F)ccc2-c2ccc(F)cc21
Reaction time: 0.25 h

Procedure:
Under nitrogen, (26) (2.4 g, 8.5 mmoL) was added portionwise to a stirred suspension of sodium hydride (427 mg of a 60% dispersion in mineral oil, 1.25 eq) in dry dimethylformamide (60 mL , from CaH2). After 15 min, ethyl bromoacetate (1.8 g, 10.0 mmoL, 1.25 eq) was added and the mixture was stirred for an additional hour before it was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×200 mL), dried (MgSO4), and concentrated. The residue was recrystallized from ethyl acetate/hexane to provide 1.5 g. A sample recrystallized a second time from ethyl acetate/hexane provided the following data: mp 215°-217° C.; IR (KBr) 3357, 3250, 1710, 1160, 828 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.65 (dd, 2H, J=4.8, 8.6Hz), 7.52 (ddd, 2 H, J= 2.5, 9.3Hz), 7.20 (ddd, 2H, J=2.3, 8.6, 8.6Hz), 3.97 (bs, 2H, exchangeable), 3.75 (q, 2H, J=7.1H), 0.85 (t, 3H, J=7.1Hz); MS m/z 367 (M+), 215 (base peak).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[C:25]2=[O:33])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:9][CH2:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])=[O:32])[C:25]2=[O:33])=[CH:20][CH:19]=1
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(CNC(=O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylpropan-1-amine (0.21 g, 1.00 mmol) in dichloromethane (25 mL) under nitrogen was added 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.33 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.39 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.10-7.29 (m, 14H), 6.94-7.01 (m, 4H), 5.66 (t, J=5.4 Hz, 1H), 3.95 (d, J=5.8 Hz, 2H), 3.89 (s, 2H), 3.27 (t, J=6.4 Hz, 2H), 2.55 (t, J=6.4 Hz, 2H), 1.59 (s, 3H); MS (DCI+) m/z 525 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(CCc2ccccc2)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N(CCc1ccccc1)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F

Procedure:
615 mg (1.25 mmol) of (2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-N-(2-phenylethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 1.9 ml (25 mmol) of trifluoroacetic acid in analogy to Example 38d. The title compound is obtained as oil (308 mg, 63%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.63, FD-MS: M+ =390.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[CH3:1][O:2][CH:3]([O:13][CH2:14][CH3:15])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][CH2:11][O:12]1)[C:30](=[O:31])[CH2:29][Cl:28]
Reactant: CCOC(CNCC1OCCCO1)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel eqiuipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=O)=O)=[CH:28][C:27]=1[F:36]>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[F:36]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(S)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A stirred ice-cooled solution of triphenylphosphine (23.0 g, 87.7 mmol), in CH2Cl2 (50 mL) and DMF (1.6 mL) was treated with a solution of 4-bromo-3-fluorobenzene-1-sulfonyl chloride (8.00 g, 29.2 mmol) in CH2Cl2 (50 mL) and stirred room temperature for 16 hours. The mixture was washed with 1N aqueous HCl (80 mL) and concentrated in vacuo. The resulting solid was diluted with 1N aqueous NaOH (160 mL), the solid filtered and the filtrate washed with 2-methoxy-2-methylpropane (3×150 mL) and acidified to pH 1 with 1M aqueous HCl. Extraction of the aqueous layer with 2-methoxy-2-methylpropane (3×100 mL), followed by drying over sodium sulphate and concentrating in vacuo gave the title compound as a yellow oil 66% yield, 3.97 g.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][C:11](O)=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:14][C:15]1[N:20]=[N:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl.C(O)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][C:11]3[N:19]4[N:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]4=[N:21][N:22]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)Cc1ccc2ncsc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc2nnc(Cc3ccc4ncsc4c3)n2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
Benzothiazol-6-yl-acetic acid (44 g, 228 mmoles) and (6-chloro-pyridazin-3-yl)-hydrazine (36.2 g, 251 mmoles) were dissolved in a mixture of anhydrous dimethylformamide (40 mL) and anhydrous dichloromethane (600 ml). The mixture was under nitrogen and cooled to 0° C. in an ice bath, then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (65.5 g, 342 mmoles), hydroxybenzotriazole hydrate (38.4 g, 251 mmoles) and potassium carbonate (157 g, 1.14 moles) was added into the mixture. The mixture was stirred at 5° C. for 4 h and at room temperature overnight. TLC showed that the SM disappeared. The mixture was filtered and the filtrate was washed with brine (400 mL×2). The organic phase was dried over anhydrous Na2SO4, concentrated to obtain a brown oil. The oil was dissolved in acetic acid (750 mL) and stirred at 50° C. for 4 hours. After such time the solvent was removed in vacuo and the residue was purified by a silica gel column eluting with ethyl acetate to obtain crude product (20 g). The crude product was recrystallized from ethyl acetate and petroleum ether to obtain the title compound (15 g). Analytical data presented in Table 1.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])([O:29][CH3:30])=[O:28].Cl>O1CCCC1>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:13][C:33](=[O:34])[CH2:32][CH2:31][C:27]([O:29][CH3:30])=[O:28])[CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[OH:19])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2cccc(N)c2)cc1O
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1cccc(COc2ccc(C(C)=O)c(O)c2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution of 3-[(4-acetyl-3-hydroxyphenoxy)methyl]aniline (3.4 g prepared as in Example 1B) and triethylamine (1.62 g) in tetrahydrofuran (40 ml) is cooled to -78° C. under nitrogen. To this solution is added 3-carbomethoxypropanoyl chloride (2 g, neat), dropwise. The reaction is left to warm to room temperature overnight, then poured onto 10% HCl and extracted with ether. The extracts are washed with saturated brine, and then dried over MgSO4, and concentrated on a rotary evaporator. The residue is dissolved in a minimum amount of acetone, to which several drops of ether are added and then stored at 0° C. Filtration gives 2.6 g (53% yield) of product, m.p. 121°-123° C.