Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][C:43]([CH3:45])=[O:44].CO>C1COCC1>[CH3:42][C:43]([OH:44])([CH3:45])[CH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: CC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 5-(2-methanesulfonyl-phenyl)-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.030 g, 0.0671 mmol) in THF (3 mL) was added lithium bis(trimethylsilyl)amide (0.20 mL, 0.201 mmol, 1.0 M solution in THF) at −78° C. After stirring for 30 min, acetone (0.2 mL) was added. The mixture was further stirred another 30 min. followed by an addition of MeOH to quench the reaction. Solvent evaporation provided a residue, which was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a white solid (0.030 g, 88%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.19 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.75-7.70 (m, 2H), 7.66-7.62 (m, 4H), 7.46 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.35 (d, 1H, J=7.6 Hz), 7.25 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 2.92 (s, 2H), 1.08 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H24F3N2O4S: 505.5 (M+H), Found 505.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[CH2:19][CH2:20]3)[CH:26]=2)[CH:3]=1
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Temperature: 15 °C
Yield: 198.2 %

Procedure:
To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was each added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The resulting mixture was heated in a microwave machine at about 15° C. for about 15 mins. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chomatograph to afford 1.98 g (99%) of the title compound. LC-MS m/z 400 (M+H)+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>CO>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CCCC(=O)O)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 4-(p-tolyl)-butyric acid (10.0 g, 56.11 mmol) in methanol (680 mL) was treated with concentrated sulfuric acid (5.4 mL). The reaction was stirred at room temperature for 18 hour. Sodium bicarbonate (˜15 g) was added and the mixture was stirred for 15 minutes, then concentrated. The residue was dissolved in ethyl acetate/water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (10.8 g, 100% crude) as an oil which was used for the next reaction.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[N:22]([CH3:23])[CH:21]=[CH:20][C:18]=2[N:19]=1>CN1C(=O)CCC1.O>[Cl:13][C:14]1[N:15]=[C:16]([O:12][C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[CH3:3])[C:17]2[N:22]([CH3:23])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cn1ccc2nc(Cl)nc(Cl)c21
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(Oc2nc(Cl)nc3ccn(C)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred suspension of NaH (8.9 mg, 0.22 mmol) in dry NMP (1.0 mL) was added 2,4,6-trimethyl phenol (30.2 mg, 0.22 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (44.6 mg, 0.22 mmol) in dry NMP (1.0 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1-2:1), to give the product as a light yellow solid (52.7 mg, 80%).
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]3[C:24]([C:30]4[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=4)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.I>O>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([C:23]3[C:24]([C:30]4[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=4)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(-c2ccccc2-c2cccc(C)c2-c2ccc(OC)cc2)cc1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCc1ccc(-c2ccccc2-c2cccc(C)c2-c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
4-decyl-3″-methyl-4′″-methoxyquaterphenyl of Intermediate 4 was mixed with 100 ml of acetic acid and 5 ml of 59% aqueous hydroiodic acid. The mixture was refluxed for twelve hours, cooled down to room temperature and poured into water. The product was twice extracted with methylene chloride. The combined organic layers were washed by diluted solution of sodium thiosulphate, water and dried over magnesium sulphate. After removing the solvent, the product was recrystallised from toluene-heptane mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].Cl>O.C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 4-nitrophenol (14.0 g., 0.10 mol), 3-chloropropionic acid (10.8 g., 0.10 mol) and potassium hydroxide (11.2 g., 0.20 mol) in water and ethanol is heated at reflux temperature for 2 hours, cooled to ambient temperature, acidified with concentrated HCl to pH˜1, and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate. The aqueous bicarbonate phase is acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The final ethyl acetate extract is washed with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized from ethyl ether and hexane to afford the title compound as an off-white crystalline solid, 5.3 g (25% yield), mp 117-118° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:21]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated with N-bromosuccinimide (0.852 g, 4.79 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (200 mL), washed with saturated aqueous sodium bisulfite (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.55 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.34 (s, 1H), 6.65 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3.55 (m, 1.3H), 3.37 (m, 0.7H), 3.2-2.9 (bm, 4H), 1.30 (m, 3H). MS calculated for C14H15BrF3NO2+H: 366, observed: 366.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:32][CH2:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:38])=[O:37]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (404 mg, 1.26 mmol) in CH2Cl2 at 0° C., triethylamine (0.7 mL, 5.04 mmol) and 3-chloropropanesulfonyl chloride (0.23 mL, 1.89 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic phase washed with brine (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified via filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the title compound (370 mg, 64%).
Reaction SMILES: [Cl-].[CH3:2][C@:3]12[C@@:20]3([CH3:21])[C@@H:11]([C@:12]4([CH3:25])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:23])([CH3:22])[C:15](=[O:24])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:6]1([NH3+:32])[CH2:5][CH2:4]2.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].Cl[CH2:52][CH2:53]Cl>C(#N)C>[N:32]1([C@:6]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:7]2[C@@H:8]2[C@@:3]([CH3:2])([CH2:4][CH2:5]3)[C@@:20]3([CH3:21])[C@@H:11]([C@:12]4([CH3:25])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:22])([CH3:23])[C:15](=[O:24])[CH2:14][CH2:13]4)[CH2:10][CH2:9]2)[CH2:53][CH2:52]1
Reactant: ClCCCl
Reactant: C=C(C)[C@@H]1CC[C@]2([NH3+])CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 130 °C

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-aminium chloride (1.09 g, 2.359 mmol) and potassium triphosphate (2.7 g, 12.72 mmol) in 1,2-dichloroethane (12 mL) and acetonitrile (24 mL) was placed in a thick-walled resealable vessel. The reaction vessel with its contents were flushed with nitrogen, sealed, and warmed to 130° C. for 36 hours. The crude reaction mixture was cooled to RT, filtered through a short bed (−1″ thick) of silica gel type-H, washed with ethyl acetate (150 mL). The filtrate was concentrated into a free flowing solid (1.1 g, quantitative) which was taken to the next step without further purification. MS: m/e 452.35 (M+H)+, 3.12 min (method 21). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.77 (d, J=2.5 Hz, 1H), 4.62 (dd, J=2.5, 1.5 Hz, 1H), 2.74-2.56 (m, 2H), 2.55-2.36 (m, 3H), 2.10-2.00 (m, 1H), 1.96-1.86 (m, 1H), 1.85-1.75 (m, 1H), 1.74-1.67 (m, 2H), 1.68 (s, 3H), 1.55-1.24 (m, 16H), 1.16-1.10 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.96 (d, J=2.8 Hz, 2H), 0.94 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>>[CH3:32][S:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][O:1][CH:2]2[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Reactant: CSc1ccc(CCl)cc1
Product: CSc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 4-methylthio-benzyl chloride [J.Org.Chem. (1988), 53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-3-(4-methylsulphanyl-benzyloxy)-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a yellowish oil; MS: 584 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25].O>CC(C)=O>[CH2:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:16]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CCOCCOCCCN
Solvent: O
Solvent: CC(C)=O
Product: CCOCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 87.3 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 3-[(2-ethoxy)ethoxy]-1-propylamine (4.41 g, 0.030 mol) was heated at 140° C. for 5 hours. The reaction mixture was dissolved in acetone (20 mL) and the solution poured into water (120 mL). The solid that formed was collected by filtration and dried under ambient conditions to give 3.0 g (87%) of material. Recrystallization from isooctane gave 2.45 g of the product; mp 65°-66° C.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8](NC#N)[NH:9][C@@H:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])=[CH:3][CH:2]=1.Cl.[O:39]1CCOCC1.N(C1C=CC(C2C=CC=CC=2)=CC=1)=C=O>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:39])[NH:9][C@@H:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: N#CNC(=Nc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCCN1CCCC1
Agent: Cl
Agent: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of [(S)-2-phenyl-1-(3-pyrrolidin-1-yl-propylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 1, step A) (0.083 g, 0.22 mmol) in CH2Cl2 (3 mL), a 4 M solution of HCl in dioxane (0.55 mL, 2.2 mmol) was added, and the mixture was stirred for 3 h at rt. The solvents were removed. The residue was treated with CH2Cl2, and the solvent was removed again under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL), and at 0° C., TEA (0.56 g, 0.55 mmol) was added followed by 4-isocyanato-biphenyl (0.052 g, 0.264 mmol). The mixture was warmed to rt over a period of 2 h and was then diluted with EtOAc (100 mL). The organic layer was washed with saturated NaHCO3 (25 mL) and brine (25 mL), and was dried (Na2SO4). The solvent was removed, and the residue was purified by flash column chromatography using 0–20% MeOH (1% NH4OH)/CH2Cl2 to afford 0.08 g (77%) of the desired product. MS (electrospray): mass calculated for C29H34N4O2, 470.27; m/z found, 471.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56–7.48 (m, 4H), 7.42–7.36 (m, 4H), 7.33–7.22 (m, 6H), 4.47 (t, J=7.1 Hz, 1H), 3.20–3.16 (m, 2H), 3.07 (dd, J=13.6, 7.1 Hz, 1H), 2.99 (dd, J=13.6, 7.1 Hz 1H), 2.51 (br m, 4H), 2.42 (m, 2H), 1.77 (br m, 4H), 1.65 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(F)cc2)=NN1
Temperature: 80 °C
Yield: 86 %

Procedure:
In a round-bottomed flask, 4-(4-fluoro-phenyl)-4-oxo-butyric acid (4.90 g, 25.0 mmol) and hydrazine hydrate (1.70 ml, 35.0 mmol) were dissolved in ethanol (50 ml), and the reaction mixture was heated to about 80° C. for about ninety minutes. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The resulting solids were suspended and stirred in ethanol (10 ml) for ten minutes and the mixture was then filtered to give pure product (4.14 g, 21.5 mmol, 86% yield). LRMS ([M+H]+)=193.2; m.p. 191-193° C.
Reaction SMILES: [Cl:1][C:2]([Cl:32])([Cl:31])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[O:14][CH:13]=[C:12]([C:27]([OH:29])=O)[C:11]2=[O:30])=[O:6].S(Cl)([Cl:35])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:31])([Cl:32])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:24])[Cl:25])=[O:20])[O:14][CH:13]=[C:12]([C:27]([Cl:35])=[O:29])[C:11]2=[O:30])=[O:6]
Reactant: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
The compound (57.3 mg) obtained in Example 5 was dissolved in 10 ml of benzene, and with stirring at room temperature, 0.5 ml of thionyl chloride was added. The mixture was refluxed for 3 hours with stirring. The reaction mixture was concentrated, and 5 ml of n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dried to afford 34.8 mg of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[N:25]([CH3:33])[C:26]4[C:31]([CH:32]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:23])=[O:22])=[C:16]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38].C(OCC)(=O)C>CCOCC>[ClH:38].[CH3:37][S:34]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[NH:20][S:21]([C:24]1[N:25]([CH3:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:23])(=[O:36])=[O:35]
Reactant: Cn1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cn1c(S(=O)(=O)Nc2ccc(C3CCNCC3)cc2S(C)(=O)=O)cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[3-methanesulfonyl-4-(1-methyl-1H-indole-2-sulfonylamino)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.038 g) was treated with 2.5 N HCl/ethyl acetate (2.5 ml). The reaction mixture was stirred at rt for 2 h, then ether (20 ml) was added. The precipitate was collected, washed with ether and dried under high vacuum over P2O5 to produce the title compound (0.032 g) as an off-white powder. MS (ISN): 446.4 (M−H)−
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:15][C:16]#[CH:17])[CH2:12][C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:18]1C=CC=C1CC(O)=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][C:13]3=[CH:14][S:18][CH:17]=[C:16]3[CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cccs1
Reactant: C#CCN(CC#C)S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2Cc3cscc3C2)cc1

Procedure:
A solution of 4-methyl-N,N-diprop-2-yn-1-ylbenzenesulfonamide obtained in Step A (700 mg), thiolacetic acid (0.267 mL), and AIBN (37 mg) in benzene (90 mL) was refluxed overnight. The solvent was removed under reduced pressure, and the residue was purified on a Biotage Horizon® system (silica, gradient 30-100% dichloromethane in hexane) to yield the title compound. LC-MS 126.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3=[N:16][S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1ccc(-c2cccnc2N)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 3-[4-(1-methylethyl)phenyl]pyridin-2-amine (700 mg) in dehydrated THF (15 mL) was added to a mixture of sodium hydride (60%, 659 mg) and 2-chloroethanesulfonyl chloride (1613 mg) in dehydrated THF (15 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (738 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@:13]([CH3:20])([CH:15]([O:18][CH3:19])[O:16][CH3:17])[C@H:12]3[O:21][C@H:11]3[C:10]=2[CH:22]=1)(=[O:4])=[O:3].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[N:33]=[N:34][N:35]([CH3:37])[N:36]=2)=[CH:26][CH:25]=1>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@:13]([CH3:20])([CH:15]([O:16][CH3:17])[O:18][CH3:19])[C@@H:12]([OH:21])[C@H:11]([N:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:10]=2[CH:22]=1)(=[O:3])=[O:4]
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Reactant: COC(OC)[C@]1(C)Oc2ccc(OS(C)(=O)=O)cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@]1(C)Oc2ccc(OS(C)(=O)=O)cc2[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 26.8 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3S,4S)-6-methane sulfonyloxy-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (231 mg, 0.70 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (187 mg, 0. 84 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:1), to give desired compound (104 mg, yield: 27%).