Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH:22]([C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:26])[CH2:21][CH2:20]4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)O)CC4)nc23)c1
Reactant: C1COCCN1
Product: Cc1cccc(Nc2ncnc3cnc(N4CCC(C(=O)N5CCOCC5)CC4)nc23)c1

Procedure:
Prepared from compound 46 of Example 1 by reaction with N,N'-carbonyldiimidazole and morpholine.
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:15]\[C:16](\[CH3:31])=[CH:17]\[CH:18]([CH3:30])[CH2:19][CH:20]([CH3:29])[CH2:21][CH:22]([CH3:28])[CH2:23][CH:24]([CH3:27])[CH2:25][CH3:26])/[CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:14][CH:10]([CH2:9]/[C:8](=[CH:15]/[C:16](/[CH3:31])=[CH:17]/[CH:18]([CH3:30])[CH2:19][CH:20]([CH3:29])[CH2:21][CH:22]([CH3:28])[CH2:23][CH:24]([CH3:27])[CH2:25][CH3:26])/[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]([O:13][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:12]
Reactant: CC(C)(C)OC(=O)CO
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.1 %

Procedure:
(Step 1) To Compound 8 (16 mg, 0.037 mmol), dichloromethane (1.8 mL), tert-butyl 2-hydroxyacetate (5.8 mg, 0.044 mmol), EDC.HCl (10.5 mg, 0.055 mmol), and DMAP (0.4 mg, 0.0037 mmol) were added, and the resulting mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and the resulting residue was purified by thin-layer column chromatography (ethyl acetate/n-hexane=1/9), whereby 1-(2-tert-butoxy-2-oxoethyl) 5-tert-butyl (Z)-2-methyl-4-{(E)-2,4,6,8,10-pentamethyldodec-2-enylidene}pentanedioate (14.7 mg, 73%) was obtained.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[C:13]([Cl:30])[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:30][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:8][C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)=[CH:15][C:14]=12
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C#CC1CCCN(C(=O)OC(C)(C)C)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc3c(Cl)ccnc3[nH]2)C1
Temperature: 65 °C

Procedure:
To a solution of product of Example 1E (250 mg, 0.573 mmol) in toluene (5 mL) was added potassium tert-butoxide (161 mg, 1.434 mmol) followed by 18-crown-6 (15 mg, 0.057 mmol) and the mixture was heated at 65° C. for 12 hours. The mixture was dissolved in ethyl acetate (25 mL), washed with water and brine, and dried over anhydrous sodium sulfate. Filtration followed by concentration of the filtrate afforded crude product which was purified by column chromatography (silica gel, 40% ethyl acetate in hexane) to afford the title compound. LCMS: 336.0 (M+H-Boc)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]CC2C=CC=CC=2)=[O:26])[C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:45]>[C].[Pd].CCOCC>[ClH:45].[CH2:1]([O:3][C:4]([C@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O

Procedure:
Catalytic reduction of benzyl 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) obtained in Example 21 is carried out using 10% palladium-carbon as a catalyst in a manner similar to that described in Example 17. The oily product is dissolved in ether, and 0.5 ml of hydrogen chloride-ethyl acetate solution (5N) is added dropwise to the solution to give 0.18 g of 3(S)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:18]#[C:19][CH2:20][CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: OCCCC#Cc1cc2ccn(-c3ccc(F)cc3)c2cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC#Cc1cc2ccn(-c3ccc(F)cc3)c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A solution of 87 mg (0.28 mmol) 5-[6-Fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 3 ml CH2Cl2 was treated with 0.14 ml (1 mmol) NEt3 and 80 μl (0.33 mmol) MsCl, stirred at room temperature for one hour, poured into icy 0.5 M aqueous HCl and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4 and evaporation of the solvent gave (93 mg) Methanesulfonic acid 5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as a light brown oil. 31 mg of this oil were dissolved in DMF, treated with 0.2 ml Allylmethylamine and the mixture stirred at 80° C. during 2 hours. Pouring the mixture into 0.5 M NaOH, extraction with CH2Cl2, drying of the organic layers with MgSO4, and flash chromatography with CH2Cl2/MeOH 19:1 gave 24 mg (89%) Allyl-{5-[6-fluoro-1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine as a light yellow oil, MS: 365 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[O:18])[C:6]1[N:7]([CH3:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[CH:10]=1)[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:11][C:9]1[CH:10]=[C:6]([C:5](=[O:18])[C:4]([O:3][CH2:1][CH3:2])=[O:19])[N:7]([CH3:17])[C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)c1cc(C)c(C(=O)OCC)n1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)c1cc(CBr)c(C(=O)OCC)n1C

Procedure:
Ethyl-1,4-dimethyl-5-ethoxycarbonyl-α-oxopyrrole-2-acetate (14.79 g, 55.5 mmol) is dissolved in carbon tetrachloride (300 ml) and placed in a 500 ml round bottom flask. Then N-bromosuccinimide (11.1 g, 62.5 mmol) is added, a reflux condenser is attached and the system is flushed with nitrogen. The mixture is slowly stirred. A 120 V, 150 W G.E. projection lamp is placed against the side of the flask and the lamp and the flask are enclosed in aluminum foil. The reaction mixture is then irradiated for one hour. The lamp is then removed, the solution is cooled and the succinimide is filtered off. The solvent is removed to give a yellow oil which solidifies. This material is then used immediately in the next reaction (vide infra).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:29]=[CH:28][C:24]5=[CH:25][O:26][CH:27]=[C:23]5[CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[H][H]>[Pd].CO>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:27]5[O:26][CH2:25][CH2:24][C:28]=5[CH:29]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc4cocc4c3)nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc4c(c3)CCO4)nc12
Yield: 26.7 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamide (30 mg, 0.077 mmol), 10% palladium on carbon (10 mg), and methanol (1 mL) was treated with hydrogen (50 psi) for 24 h on a parr-shaker apparatus, and then the mixture was filtered through a microfilter and washed with methanol. The filtrate was concentrated and the crude material was purified by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,3-dihydrobenzofuran-5-yl)benzoxazole-4-carboxamide (8 mg, 26%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.0 Hz, 1H), 8.15 (dd, J=7.5, 1.5 Hz, 1H), 8.05 (s, 1H), 8.04 (dd, J=8.5, 1.5 Hz, 1H), 7.66 (dd, J=8.5, 1.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.72 (t, J=8.5 Hz, 2H), 4.36-4.30 (m, 1H), 3.54 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.34 (t, J=8.5 Hz, 2H), 3.16-2.86 (m, 5H), 2.22-2.09 (m, 2H), 1.83-1.65 (m, 3H); MS (ESI+) m/z 390 (M+H); HPLC>99% (AUC), tR=12.67 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13]([OH:23])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.B(F)(F)F.CCOCC>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[O:23][C:13](=[O:22])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:7]1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1OC(COc2ccc(Cl)cc2Cl)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution containing 5.1g (0.025 mole) of 2,4-dichlorophenoxyacetaldehyde, 4.25g (0.028 mole) of mandelic acid, and 10.0g (0.07 mole) of boron trifluoride etherate in 250 ml of ether was allowed to stir for 2 hours at ambient temperature, washed with aqueous sodium carbonate and water, dried and concentrated. The residual solid was purified by silica chromatography to give 2.7g of 2-(2,4-dichloro-phenoxymethyl)-5-phenyl-1,3-dioxolan-4-one, trans isomer, having a melting point of 68°-71°.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][O:25]C(=O)C)[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@@:9]1(C)[C:32]([O-:34])=[O:33])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][OH:25])[CH2:10][C@H:9]1[C:32]([OH:34])=[O:33])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(=O)OCC(C)(C)C(=O)N(C1CCC(C)(C)CC1)[C@@H]1CN(C(=O)OC(C)(C)C)[C@](C)(C(=O)[O-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 12 h
Yield: 94.1 %

Procedure:
To a solution of 1-BOC-2-methyl-(2S,4S)-4-{[3-(acetyloxy)-2,2-dimethylpropanoyl](4,4-methylcyclohexyl)amino}pyrrolidine-2-carboxylate (1.02 g, 2.05 mmol) prepared in Step A in methanol (10 ml) and water (10 ml), was added NaOH (246 mg, 6.15 mmol), and stiffed for 12 h. After the reaction finished, the reaction solution was concentrated in vacuo, acidified with 1N HCl, and extracted with EtOAc. The organic extracts were washed with 1N HCl, dried MgSO4, and concentrated in vacuo to give the title compound (0.85 g, 95%).
Reaction SMILES: [CH3:1][CH2:2][CH2-:3].[Mg+2].[Br-].CON(C)[C:9]([C:11]1[C:12]2[N:13]([C:18]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=4[C:23]=3[CH3:32])=[C:19]([CH3:21])[N:20]=2)[N:14]=[C:15]([CH3:17])[CH:16]=1)=[O:10]>C1COCC1>[F:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([C:18]3[N:13]4[N:14]=[C:15]([CH3:17])[CH:16]=[C:11]([C:9](=[O:10])[CH2:1][CH2:2][CH3:3])[C:12]4=[N:20][C:19]=3[CH3:21])=[C:23]([CH3:32])[C:24]=2[CH:30]=1
Reactant: CON(C)C(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Reactant: [CH2-]CC
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 463.8 %

Procedure:
N-Propylmagnesium bromide (0.303 g, 2.06 mmol) is added dropwise to a solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-8-carboxylic acid methoxy-methyl-amide (0.21 g, 0.52 mmol) in THF (5 mL) at 0° C. The reaction is stirred at room temperature overnight. The mixture is quenched with H2O, extracted with CH2Cl2, dried over sodium sulfate, filtered, and concentrated to dryness. The crude is purified through an ISCO column (5-10% EtOAc/Hexane) to give the title compound (0.92 g, 42%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.4 (s, 1H), 7.2 (m, 1H), 3.6 (t, J=5.7, 2H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H), 1.9 (m, 2H), 1.1 (t, J=7.5, 3H) ppm. MS (m/e): 382 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][N:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][CH2:41][C:38]3[CH:37]=[N:36][C:35]([Br:34])=[CH:40][CH:39]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCc3ccc(Br)nc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 77.9 %

Procedure:
Using 1.4 g (3.1 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and 2-bromo-5-bromomethyl-pyridine (0.77 g, 3.1 mmol) and following the procedure of Example 42(b) afforded 1.5 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.40 (9H, s), 1.80 (4H, m), 3.2 (1H, m), 3.70 (1H, m), 5.25 (2H, s), 6.75 (1H, d), 7.0 (1H, s), 7.15 (2H, d), 7.22 (1H, s), 7.45 (1H, s), 7.7 (1H, d), 7.85 (3H, m), 8.3 (1H, d), 8.5 (1H, s).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(N(CC)CC)C>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2nccn12
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (5.02 g, 33.4 mmoles) and 1-bromo-3-chloropropane (5.26 g, 33.4 mmoles) in ethanol (100 ml) was added triethylamine (4.66 ml, 33.4 mmoles) and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 5.46 g of the desired product (72.0%, light brown oily product).
Reaction SMILES: [NH3:1].[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1.CO>[NH2:1][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:11])[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: N
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Solvent: CO
Solvent: C1COCCO1
Product: NS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Dioxane (250 mL) is saturated with ammonia and cooled down to 0° C. A solution of benzyl-4-(chlorosulfonyl)piperidine-1-carboxylate (10 g; 31.5 mmol; 1 eq) in dioxane (25 mL) is added dropwise over 10 min. The reaction mixture is stirred at room temperature for 3 h while keeping ammonia bubbling. The suspension is filtered through a short plug of silica using dioxane as eluent and the resulting solution is concentrated in vacuo to give a colourless oil. The oil is taken up in MeOH and concentrated in vacuo to give a white foam which is crystallised from EtOAc and Et2O to afford 8.1 g (86%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.40-7.29 (m, 5H), 6.79 (s, 2H), 5.08 (s, 2H), 4.10 (br d, J=13.3 Hz, 2H), 3.05 (tt, J=11.9, 3.6 Hz, 1H), 2.95-2.75 (m, 2H), 2.0 (dd, J=1.8, 11.5 Hz, 2H), 1.46 (dq, J=12.5, 4.4 Hz, 2H). HPLC (max plot) 82%; Rt 3.55 min.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C:11]1([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:22]1[CH2:23][CH2:24][CH:19]([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:20][CH2:21]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Neat DIPEA (1.54 ml, 8.86 mmol) was added dropwise to a solution of phenyl(4-piperidinyl)methanone hydrochloride (1 g, 4.43 mmol) in CH2Cl2 (20 ml) at 0° C. Then, neat MsCl (377 μL, 4.87 mmol) was slowly added and the cooling bath was removed. After 30 minutes, the reaction was quenched with water and diluted with CH2Cl2. After separation, the organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The final ketone 1 was obtained as a white solid (1.16 g, 98%).
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Cl:35]>>[ClH:35].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: Cl
Product: O=C1N(Cc2cccc(C(F)(F)F)c2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 197° C. and MS: m/e=528.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-trifluoromethylbenzylchloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pd].CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:20]([NH2:21])=[CH:19][C:18]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:17][N:16]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.03 g (2.48 mmol) of (5′-methanesulfonyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester and 0.15 g (0.14 mmol) of 10% palladium on carbon in a 1:1 mixture of ethyl acetate:methanol (50 mL) is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is filtered through diatomaceous earth and the filter pad is washed with methanol. The filtrate is concentrated under reduced pressure to provide 0.980 g (103%) of as a (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester as a brown resin.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:12]([CH2:15][CH2:16][N:17]1[C:21](=[O:22])[CH2:20][S:19][C:18]1=[S:23])(O)=[O:13]>O1CCCC1>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:12]([CH2:15][CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][C:18]2=[S:23])=[O:13])=[CH:3][CH:4]=1
Reactant: O=C(O)CCN1C(=O)CSC1=S
Reactant: Oc1ccnc2ccccc12
Solvent: C1CCOC1
Product: O=C(CCN1C(=O)CSC1=S)Oc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three g of 4-hydroxyquinoline and 2 g of 3-carboxyethylrhodanine were added to 200 ml of tetrahydrofuran. Two g of N,N-dicyclohexylcarbodiimide was added to the solution. The material was stirred at room temperature for 8 hours. The resulting insoluble matters were removed by filtration. One l of ethyl acetate was added to the filtrate. The resulting crystal was filtered off to obtain 2.2 g of 3-(4-quinolyloxycarbonylethyl)rhodanine.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH:11]O>C(O)(=O)C>[CH2:1]([S:5]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1nc[nH]n1
Reactant: OO
Solvent: CC(=O)O
Product: CCCCS(=O)c1nc[nH]n1
Reaction time: 24 h

Procedure:
To a solution of 15.7 g. 3-butylthio-1,2,4-triazole in 60 ml. glacial acetic acid was added 100 vol. hydrogen peroxide solution (11.4 ml., 1 molecular proportion). The reaction mixture was cooled occasionally during 1 hour to maintain the reaction temperature at 25° - 30°C., and then kept at room temperature for 24 hours. The resulting solution was distilled under reduced pressure to produce a solid residue which was recrystallized from ethyl acetate to give 3-n-butylsulphinyl-1,2,4-triazole, m.p. 82° - 83°C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[F:18][C:19]([F:37])([F:36])[C:20]([C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][C@@H:28]([C:33](O)=[O:34])[CH2:27][CH2:26][C:25]=2[N:24]=1)([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:33]([C@H:28]1[CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:19]([F:37])([F:36])[F:18])[CH:32]=[CH:31][C:30]=2[CH2:29]1)=[O:34])[CH3:4]
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)[C@H]2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A 2 ml, vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (51 mg, 0.18 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (47 mg, 0.16 mmol) and N,N-diisopropylethylamine (110 uL, 0.65 mmol) and N-methylpyrrolidinone (0.8 mL). A solution of N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (75 mg, 0.20 mmol) in N-methylpyrrolidinone (0.4 mL) was added and the resulting mixture was stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (72 mg, 85%). The sample was dissolved in hot 2/3 IPA/hexane (5 mL). 1.2 mL injections were separated on a ChiralPak AD-H 5 um, 250×20 mm column, eluting with 85/15/0.03 hexane/IPA/Et2NH at 20 mL/min. Peaks eluted at 7.5 and 8.7 min, with UV monitoring at 254 and 230 nm. The major isomer, eluting at 8.7 min was concentrated to afford the amide as fine plates (47 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.6 Hz, 1H), 5.09 (app pentet, J=7.2 Hz, 1H), 3.01 (s, 3H), 2.92-2.78 (m, 4H), 2.71-2.61 (m, 1H), 2.26 (s, 3H), 2.06-1.97 (m, 1H), 1.82-1.69 (m, 1H), 1.53 (s, 3H), 1.35 (d, J=7.1 Hz, 3H); m/z=516.2 (M+H)+.