Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:5]([O:18][CH:19]1[CH2:23][CH:22]2[CH:21]([CH:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Reaction time: 12 h
Yield: 538 %

Procedure:
To a stirred solution of tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane (0.100 kg, 310 mmol) and rhodium acetate dimer (1.37 g, 3.10 mmol) in anhydrous dichloromethane (1.2 L) at room temperature was added a solution of ethyl 2-diazoacetate (63.68 mmol) in dichloromethane (300 mL) over 8 h. After an additional 12 h. The reaction mixture was filtered through Celite. Concentration of the filtrate afforded crude ethyl 3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexane-6-carboxylate (140 g) which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
A mixture of 2,2-diphenylacetyl chloride (0.300 mmol, 69.2 mg), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.250 mmol, 75.8 mg) and triethylamine (0.500 mmol, 50.5 mg) was dissolved in THF (2.00 mL) and the mixture was shaken on an Orbital J-KEM Shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC [silica, CH2Cl2: ammonia (2.0 M in methanol) 100:5] to afford the desired product (83.3 mg, 62% yield): 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.33–7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (t, 2H, J=5.6 Hz), 2.93 (d, 2H, J=11.3 Hz), 2.52–2.36 (m, 4H), 1.97 (t, 2H, J=11.3 Hz), 1.83–1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); Anal. Calcd for C32H39N3O2+HCl+0.19CHCl3: C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 97.8 %

Procedure:
5 g (24.5 mmol) of 2-chloro-3,5-dinitropyridine, 40 ml of THF and 50 mmol of morpholine were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 6.09 g of yellow powder were obtained.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(C(C)(C)C)(C)C.[F-]>C1COCC1>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2c(O)cccc21
Reaction time: 7 h

Procedure:
To a solution of ethyl (4-{[tert-butyl(dimethyl)silyl]oxy}-1H-indol-1-yl)acetate (3.7 g) in THF (74 mL) was added tetra n-butylammomium fluoride (3.5 g) at ambient temperature. The reaction mixture was stirred at the same temperature for 7 hours. The resulting mixture was evaporated in vacuo and diluted with EtOAc. The organic solution was washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-60:40) to give ethyl (4-hydroxy-1H-indol-1-yl)acetate.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9](OCC)=[O:10])=[CH:5][N:6]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>O1CCCC1.CCCCCCC.O1CCCC1.O>[Br:1][C:2]1[S:3][C:4]([CH:7]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][CH2:9][OH:10])=[CH:5][N:6]=1
Reactant: CCOC(=O)CC(c1cnc(Br)s1)c1c[nH]c2c(CSC)cccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CSCc1cccc2c(C(CCO)c3cnc(Br)s3)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.19 g (2.71 mmol) of the compound from Example 50A in 25 ml of tetrahydrofuran was added dropwise to 8.13 ml (8.13 mmol) of a 1N solution of diisobutylaluminum hydride in heptane/tetrahydrofuran and 25 ml of tetrahydrofuran at RT. The mixture was stirred at RT for 1 h, and the solution was mixed with ethyl acetate, water and 1N hydrochloric acid. The phases were separated, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution. This was followed by drying over sodium sulfate, removal of the solid by filtration and removal of the solvents from the crude product in vacuo. Purification of the residue by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 0.73 g (68% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH2:32]([NH:36][C:37](=[O:69])[CH2:38][C@H:39]([O:61][Si](C(C)(C)C)(C)C)[C@@H:40]([NH:48][C:49](=O)[O:50]C1C=CC([N+]([O-])=O)=CC=1)[CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:33][CH2:34][CH3:35]>C(Cl)Cl.CCOCC>[CH2:32]([NH:36][C:37](=[O:69])[CH2:38][C@H:39]([OH:61])[C@@H:40]([NH:48][C:49]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH2:18]1)=[O:50])[CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCNC(=O)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A solution of methyl 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (40 mg, 0.12 mmol) and DIEA (0.10 mL, 0.55 mmol) in CH2Cl2 (1 mL) was added to 4-nitrophenyl (2S,3S)-5-(butylamino)-3-(tert-butyldimethylsilyloxy)-1-cyclohexyl-5-oxopentan-2-ylcarbamate (39 mg, 0.07 mmol). The mixture was stirred at rt for 3 h, diluted with ether (100 mL), washed with 5% aq HCl (20 mL) and 1 M aq NaOH (20 mL) and dried over MgSO4. Removal of the solvent left an oil (43 mg) which was dissolved in MeCN (2 mL) and treated with Et4N+F− (25 mg, 0.18 mmol). The solution was stirred at rt for 3 h and submitted directly to preparative HPLC to afford Methyl 2-((R)-((R)-1-((2S,3S)-5-(butylamino)-1-cyclohexyl-3-hydroxy-5-oxopentan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate (30 mg, 38%) as an oil. 1H NMR (CD3OD) 0.92 (t, 3H), 1.0-1.9 (22H), 2.26 (m, 1H), 2.35 (m, 1H), 2.92 (m, 2H), 3.17 (m, 2H), 3.23 (m, 2H), 3.30 (2H), 3.61 (s, 3H), 3.80 (br d, 1H), 3.88 (br d, 1H), 3.94 (m, 1H), 4.03 (d, 1H), 4.15 (br d, 1H), 7.21 (d, 1H), 7.34 (3H); LC-MS (16 min) tR=9.89 min, m/z=623. It is noted that although the compound described in this example was the only compound prepared, the other compounds of the invention described herein could be prepared in accordance with the methods taught herein.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]([N:15](CC)[CH:16](C)[CH3:17])(C)[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NCC)C>C(Cl)Cl.CN(C=O)C>[CH2:12]([N:15]([CH2:16][CH3:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])[CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 71.4 %

Procedure:
To a stirred solution of 2,3-dimethyl-benzoic acid (1.52 g, 10.1 mmol) in CH2Cl2/DMF (118 mL/12 mL) was added N,N-diisopropylethylamine (1.76 mL, 10.1 mmol) and TBTU (3.25 g, 10.1 mmol) and the reaction mixture stirred at RT for 50 min. N,N-diethylamine (1.58 mL, 15.2 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was washed with 10% Na2CO3 solution (2×100 mL) and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 30% EtOAc/isohexane to obtain N,N-diethyl-2,3-dimethyl-benzamide as a colourless liquid (1.48 g, 72%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17](O)=[O:18].[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Br:20][C:21]1[C:22]([C:27]2[NH:31][N:30]=[CH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:18])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:13])[F:14])=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)CN1C(=O)CCc2cc(C(F)(F)F)ccc21
Product: O=C(CN1C(=O)CCc2cc(C(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was synthesized from 2-(2-oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.373, method [7], MS(ESI) 500.0 (M+H); 1H NMR (300 MHz, CD3Cl) δ 7.90 (s, 1H), 7.50 (s, 1H), 7.48 (d, J=6.6 Hz, 1H), 7.03 (d, J=9.34, 1H), 6.90 (s, 1H), 4.92 (s, 2H), 3.20-3.14 (m, 2H), 2.93-2.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH2:21][CH:22]=[CH2:23])=[C:19]=[O:20]>>[CH2:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1)=[O:20])[CH:22]=[CH2:23]
Reactant: C=CCN=C=O
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: C=CCNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1

Procedure:
Example 10 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 3-isocyanatoprop-1-ene (12.0 μl) to give the title compound (0.027 g). LC-MS (System A): Rt 1.93 mins, Mass Spectrum m/z 358 [MH+].
Reaction SMILES: C(Cl)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1>C1(C)C=CC=CC=1>[C:7]1([O:8][CH3:9])[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=1)[O:5][CH3:6]
Reactant: COc1ccc(CCl)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccccc1OC

Procedure:
1650 parts of a solution of crude veratryl chloride in toluene, containing 510 parts of veratryl chloride and obtained by chloromethylation of veratrol, were added, in the course of 15 minutes, to a mixture of 305 parts of toluene, 140 parts of acetone, 197 parts of NaCN, 3.1 parts of NaI, 25 parts of H2 and 5.2 parts of triethylamine, the mixture having been preheated to 65° C. After the addition, stirring was continued for a further 1.5 hours at 85° C., after which 700 parts of H2O were added to the mixture, the lower aqueous phase was separated off and the organic phase was washed a second time with 200 parts of H2O. The organic phase was freed from the toluene, and the residue was distilled over a column under 6 mbar and at 162°-164° C. 445 parts (92%) of VCN were obtained. 1.6% of veratryl alcohol were present in the distillate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[O:3]=[C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)=[CH:31][CH:32]=1)(=[O:26])=[O:25])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: O=C=NCCCCN=C=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Yield: 64.9 %

Procedure:
Compound 248 was prepared following the procedure outlined in Example 208 using 1,4-diisocyanatobutane (7.64 mg, 0.545 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82, 84.4 mg, 0.109 mmol). Purification by preparative HPLC gave the title compound (43.6 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.89 (d, 4H), 7.54 (s, 2H), 7.45 (d, 4H), 6.84 (s, 2H), 4.79-4.71 (m, 4H), 3.89-3.85 (dd, 2H), 3.59-3.56 (m, 17H), 3.49-3.43 (m, 14H), 3.28-3.23 (m, 5H), 3.14 (s, 7H), 3.09-3.04 (m, 9H), 1.42 (s, 4H). MS (m/z): 1233.03 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccoc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccoc2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(3-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (335 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 220 mg, 76%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:10][CH3:11])=[N:5][O:6][C:7]=1[CH2:8][CH3:9].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([C:4]1[C:3]([CH2:2][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)=[C:7]([CH2:8][CH3:9])[O:6][N:5]=1)[CH3:11]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1noc(CC)c1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1noc(CC)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-diethyl-1,2-oxazole (4.6 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (440 mg, 3.3 mmol), and triethylamine (1.3 mL, 9.3 mmol) in absolute ethanol (35 mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was treated with water (50 mL). The solid material was removed by filtration. The solid was washed with diethyl ether (3×25 mL). The filtrate was recovered, extracted with water (2×75 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording the title compound (220 mg, 30% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.18 (m, 6H), 2.21 (s, 3H), 2.65 (m, 2H), 2.83 (m, 2H), 4.22 (s, 2H), 6.02 (s, 1H); M+280.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:35][CH:36]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)cc1
Yield: 44 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (3-cyclohex-1-enyl-4′-methanesulfonylamino-biphenyl-4-yl)-amide (as prepared in the previous step, 29.5 mg, 0.0498 mmol). Silica gel chromatography (5-10% EtOAc/DCM) afforded the title compound (10.1 mg, 44%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.29 (d, 1H, J=8.6 Hz), 8.01 (s, 1H), 7.60 (d, 2H, J=8.6 Hz), 7.53 (dd, 1H, J=8.4, 2.0 Hz), 7.42 (d, 1H, J=2.0 Hz), 7.33 (d, 2H, J=8.6 Hz), 5.89 (m, 1H), 2.98 (s, 3H), 2.23-2.38 (m, 4H), 1.77-1.93 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C24H23N5O3S, 462.2 (M+H), found 461.9.
Reaction SMILES: Cl.[Cl:2]C1C=CC(C2C3C4CCNCCC=4NC=3C=CC=2)=CC=1.C([N:31]1[CH2:44][CH2:43][C:42]2[C:41]3[C:40]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=4)=[CH:39][CH:38]=[CH:37][C:36]=3[NH:35][C:34]=2[CH2:33][CH2:32]1)(=O)C1C=CC=CC=1>>[ClH:2].[ClH:51].[Cl:51][C:47]1[CH:46]=[C:45]([C:40]2[C:41]3[C:42]4[CH2:43][CH2:44][NH:31][CH2:32][CH2:33][C:34]=4[NH:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)[CH:50]=[CH:49][CH:48]=1
Reactant: Clc1ccc(-c2cccc3[nH]c4c(c23)CCNCC4)cc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4cccc(Cl)c4)c3c2CC1
Agent: Cl
Product: Clc1cccc(-c2cccc3[nH]c4c(c23)CCNCC4)c1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride, making non-critical variations, starting with 3-benzoyl-10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, the title compound was obtained. 1H NMR (DMSO-d6) δ 3.05, 3.21, 3.31, 4.51, 6.85, 7.1-7.5, 11.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][N:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CN(C)CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B2) Rt 3.07 [M+H]+ 325.99. 1H NMR (Me-d3-OD) δ 2.5 (6H, s), 2.98 (2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2OC(C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=[O:37])C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[C:15]([OH:37])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1oc(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c1OCc1ccccc1
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Product: O=C(O)c1oc(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c1OCc1ccccc1
Yield: 89.25 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-05) (2.04 g, 89.25%) was synthesized as a white solid from N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-3-chloro-benzenesulfonamide (11-05) (2.2 g, 5.08 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>>[N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:10]=1[CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Product: O=C1CCN(Cc2nc3ccccc3[nH]2)CC1

Procedure:
1-(2-Benzimidazolyl)methyl-4-piperidone is prepared from 4-piperidone and 2-(chloromethyl)benzimidazole essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O.[Na+].[Cl-].C(O[Ti](OCC)(OCC)OCC)C>[C:14]([S@@:17]([N:19]=[C:4]([C:3]([CH3:12])([CH3:11])[CH2:2][F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CCOC(=O)C(=O)C(C)(C)CF
Reactant: CC(C)(C)[S@@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)C(C)(C)CF
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
To a solution of ethyl 4-fluoro-3,3-dimethyl-2-oxobutanoate (2.3 g, 13.05 mmol) in THF (20 mL) was added (S)-2-methylpropane-2-sulfinamide (1.899 g, 15.67 mmol) and tetraethoxytitanium (5.91 mL, 26.1 mmol). The reaction mixture was heated at 65° C. for 6 h. The reaction mixture was cooled down, diluted with EtOAc and sat. NaCl (40 mL) and stirred at rt for 0.5 h. The solid was filtered and washed with water and EtOAc. The filtrate was separated and the organic layer was washed with water, sat. NaCl, dried (MgSO4) and purified by flash chromatography (EtOAc/hexane) to afford (S)-ethyl 2-(tert-butylsulfinylimino)-4-fluoro-3,3-dimethylbutanoate (1.1 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.46-4.53 (1H, m), 4.28-4.42 (3H, m), 1.59 (3H, s), 1.21-1.31 (15H, m).