Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:25]([OH:34])([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccsc1-c1cccs1
Reactant: CCCCCCCCC(=O)CCCCCCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCC(O)(CCCCCCCC)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (5.00 g, 20 mmol) in dry diethylether (170 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 12.5 mL, 20 mmol) in dry diethylether (170 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Heptadecan-9-one (6.22 g, 24 mmol) was added to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 85 mL) and water (85 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by gradient column chromatography (eluent hexane/EtOAc 95:5) to afford the title compound (IIe) as a yellow oil (6.3 g, 75%). 1H-NMR (CDCl3): δ=7.34 (dd, J=5.1 Hz, J=1.3 Hz, 1H), 7.22 (d, J=5.3 Hz, 1H), 7.07 (dd, J=3.5 Hz, J=1.2 Hz, 1H), 6.99 (dd, J=5.1, J=3.5 Hz, 1H), 6.97 (d, J=5.3 Hz, 1H), 2.36 (t, J=7.7 Hz, 4H), 1.39-1.07 (m, 20H), 0.91-0.81 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[O:18])=[O:10])=[N:6][CH:7]=1.N[C:28]1[CH:33]=CC(Cl)=[CH:30][N:29]=1.C[Al](C)C.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:29]([CH3:30])[CH2:28][CH2:33][N:26]=3)=[CH:23][CH:24]=2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: N#Cc1ccc(C(=O)Nc2ccsc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: C[Al](C)C
Agent: Cl
Product: CN1CCN=C1c1ccc(C(=O)Nc2ccsc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Preparation of methyl 3-[(4-cyanophenyl)carbonylamino]thiophene-2-carboxylate A mixture of 4-cyanobenzoyl chloride (1.0500 g, 6.4 mmol), methyl 3-aminothiophenecarboxylate (1.0000 g, 6.4 mmol), and triethylamine (1 mL, 7.0 mmol) in dichloromethane was stirred at room temperature for 18 hours. The mixture was poured into a separatory funnel and washed by 1 N HCl. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 1.6588 g (91%). ES-MS 287 (M+1). Preparation of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}(4-cyanophenyl)carboxamide A portion of 2-amino-5-chloropyridine (68.6 mg, 0.5 mmol) was treated with AlMe3 (0.8 mL, 1.6 mmol), followed by adding the product from step A (160 mg, 0.5 mmol). The mixture was stirred at room temperature for 18 hours. The excess of AlMe3 was killed by 1N HCl solution. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 0.1528 g (80%). ES-MS 383 (M+1).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[N:1]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1ccc2[nH]cnc2c1
Product: O=C(Nc1ccc(-n2cnc3ccccc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from benzimidazole, 4-fluoronitrobenzene and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by using the same techniques as in Example 1.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:27][C@@H:28]1[CH2:30][O:29]1.C(N(CC)CC)C>CCO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][C@H:28]([OH:29])[CH3:30])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: C[C@@H]1CO1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)c1cccc(-c2ccc(OC[C@@H](C)O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 140 °C
Yield: 19.9 %

Procedure:
A 5 mL microwave vial was charged with Compound 157 (200 mg, 0.545 mmol), (R)-2-methyloxirane (191 μL, 2.72 mmol), triethyl amine (8 μL, 0.054 mmol) and 2 mL of EtOH. The reaction mixture was heated at 140° C. for 30 min. in microwave. Solvents were removed in vacuum and the residue was purified by preparative HPLC to yield the title compound (46 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3 H) 1.25 (d, J=6.06 Hz, 3 H) 2.27 (s, 3 H) 3.41 (q, J=7.33 Hz, 2 H) 3.94 (m, 1 H) 4.09-4.16 (m, 2 H) 4.97 (d, J=4.04 Hz, 1 H) 7.07-7.14 (m, 2 H) 7.57 (s, 1 H) 7.85 (t, J=7.71 Hz, 1 H) 7.96-8.00 (m, 2 H) 8.09 (s, 1 H) 8.28 (d, J=1.52 Hz, 1 H) 11.94 (s, 1 H); [M+H] calc'd for C23H25N2O4S, 425.2.; found, 425.3.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>CCOCC>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Br:34]
Reactant: OCc1ccccc1OC(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccccc1CBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-trifluoromethoxybenzyl alcohol (0.81 g, 4.5 mmol) from Step 1 above in ether (20 mL) at 0° C. was added triphenylphosphine (2.4 g, 9.2 mmol) and CBr4 (3.0 g, 9.2 mmol). The mixture was warmed to ambient temperature and stirred for 18 h. The ether was decanted from the gummy precipitate of triphenylphosphine oxide and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using hexanes as eluant to give 2-trifluoromethoxybenzyl bromide as a colorless liquid (TLC Rf =0.80 (hexanes)).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH:21][C:22]1([CH3:33])[CH2:30][C:29]2[C:24](=[CH:25][C:26]([CH3:32])=[C:27]([CH3:31])[CH:28]=2)[CH2:23]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:8]([O:9][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2([CH3:33])[CH2:30][C:29]3[C:24](=[CH:25][C:26]([CH3:32])=[C:27]([CH3:31])[CH:28]=3)[CH2:23]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1cc2c(cc1C)CC(C)(NCc1ccccc1)C2
Reactant: Cc1ccc(C2CO2)cc1[N+](=O)[O-]
Product: Cc1cc2c(cc1C)CC(C)(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Temperature: 110 °C

Procedure:
A mixture of 2-(4-methyl-3-nitro-phenyl)-oxirane and benzyl-(2,5,6-trimethyl-indan-2-yl)-amine is heated at 110° C. for 48 hours. The material is used without further purification. ES+ MS m/e 538 (MH+)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24].C(O)(=O)C(O)=O>C(#N)C>[CH2:21]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: CCCCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.15 g, 0.77 mmol), acetonitrile (6 mL), potassium carbonate (0.21 g, 1.55 mmol), n-butylbromid, (0.08 mL, 0.77). Flash chromatography on silica gel (Ethyl acetate/methanol, 7:1). Yield: 0.085 g. [α]D=+24.8°; The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether; M.p. 157-158° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 7), 212 (bp), 98 (52), 57 (40), 182 (37), 127 (16).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1F
Yield: 19.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 80 mg, 0.263 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 150 mg, 0.521 mmol), oxalyl chloride (98 mg, 0.78 mmol), DMF (1 drop) and DIPEA (101 mg, 0.79 mmol) in CH2Cl2 (3 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.64 (s, 1H), 10.14 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.71 (s, 1H), 8.37 (s, 2H), 8.23-8.17 (m, 2H), 7.72-7.65 (m, 2H), 7.50-7.39 (3H), 4.30 (d, 2H), 1.14 (s, 9H); MS [M+H]+: 574.14.
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28].N(CO[C@@H]1[C@@H](CO)O[C@@H](N2C=C(C#CCNC(=O)C(F)(F)F)C(=O)NC2=O)C1)=[N+]=[N-].C(=O)(O)[O-]>CN(C=O)C.[Cu]I>[F:25][C:26]([F:34])([F:33])[C:27]([NH:29][CH2:30][C:31]#[C:32][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:28]
Reactant: C#CCNC(=O)C(F)(F)F
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C#CCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 5-iodo-2′-deoxycytidine (10 g, 28.32 mmol) in DMF (200 ml) in a light protected round bottom flask under Argon atmosphere, was added CuI (1.08 g, 5.67 mmol), triethylamine (7.80 ml, 55.60 mmol), 2,2,2-trifluoro-N-prop-2-ynyl-acetamide (12.8 g, 84.76 mmol) and at last Pd(PPh)3)4 (3.27 g, 2.83 mmol). After 18 hours at room temperature, dowex bicarbonate (20 mg) was added and the mixture was stirred for a further 1 h. Filtration and evaporation of the volatiles under reduced pressure gave a residue that was purified by flash chromatography on silica gel (CH2Cl2, CH2Cl2:EtOAc 1:1, EtOAc:MeOH 9:1) The expected product (7) was obtained as a beige solid in quantitative yield. 1H NMR (D2O) δ 2.24-2.17 (m, 1H, H-2′), 2.41-2.37 (m, 1H, H-2′), 3.68 (dd, J=12.5, 5.0 Hz, 1H, H-5′), 3.77 (dd, J=12.5, 3.2 Hz, 1H, H-5′), 3.99 (m, 1H, H-4′), 4.27 (s, 2H, CH2N), 4.34 (m, 1H, H-3′), 6.11 (t, J=6.3 Hz, 1H, H-1′), 8.1 (br s, 1H, NH); MS (ES): m/z (%) (M−H) 375 (100).
Reaction SMILES: Br[C:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[C:8]([CH3:11])([CH3:10])C.[CH3:16][C:17]1[CH:22]=CC([Sn](C)(C)C)=C[CH:18]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:10][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:12]([NH:15][C:17]([CH3:16])([CH3:18])[CH3:22])(=[O:13])=[O:14])=[CH:11][CH:2]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: CC(C)(C)C1C=CC=CC1(Br)S(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 90 °C
Yield: 116.8 %

Procedure:
1-Bromo-2-t-butylbenzenesulfonamide (22.4 g, 77 mmol) (Step A) and 4-methylphenyltrimethylstannane (39.35 g, 154 mmol 2eq.) were dissolved in 221 mL of dry dimethylformamide and the resulting solution treated with 2.71 g (38.6 mmol, 0.5eq) of bis(triphenylphosphine)palladium(II) chloride. The mixture was heated at 90° C. for 6 hours. The mixture was filtered through Celite and the filter cake was washed with ether. The combined organics were washed twice with water. The aqueous washings were combined and extracted with ether. The combined organics were washed with saturated aqueous sodium chloride then dried over magnesium sulfate, filtered and concentrated to dryness to yield the product which solidified on standing. Purification by preparative HPLC on silica, eluting with 10% ethyl acetate/hexane, gave 13.63 g (44.98 mmol, 58%) of the product as a yellow powder. 1H NMR (200 MHz, CDCl3): δ 1.09 (s, 9H), 2.50 (s, 3H), 3.64 (br s, 1H), 7.3-7.7 (m,7H), 8.13 (dd; 2, 8 Hz; 1H). FAB-MS: calculated for C17H21NO2S 303; found 304 (M+H, 3%).
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]([OH:20])=O)[CH:13]=[CH:14][CH:15]=1)#[N:9].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]2=[O:41])=[C:31]([CH3:42])[CH:30]=1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]3=[O:41])=[C:31]([CH3:42])[CH:30]=2)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1cccc(NC(C(=O)O)c2ccccc2F)c1
Reactant: Cc1cc(N)ccc1N1CCCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(NC(=O)C(Nc2cccc(C#N)c2)c2ccccc2F)ccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
225 μl (2.22 mmol) of 4-methylmorpholine are added to a solution of 600 mg (2.22 mmol) of (3-cyanophenylamino)-2-fluorophenylacetic acid, 453 mg (2.22 mmol) of 1-(4-amino-2-methylphenyl)piperidin-2-one, 426 mg (2.22 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 300 mg (2.22 mmol) of hydroxybenzotriazole hydrate (HOBt) in 1 ml of DMF, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving 2-(3-cyanophenylamino)-2-(2-fluorophenyl)-N-[3-methyl-4-(2-oxopiperidin-1-yl)phenyl]acetamide as a colourless solid; ESI 456.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][O:23][CH3:24])([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>CO.O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:22][O:23][CH3:24])([S:14]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COCC1(S(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-tert-butoxycarbonyl-4-methoxymethyl-4-(3-tolylsulfanyl)piperidine (0.30 g, 0.85 mmol; Example 107, Step A) and sodium periodate (0.2 g, 0.94 mmol) in a mixture of methanol (6 mL) and water (4 mL) was stirred at room temp. overnight. The reaction mixture was diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 35% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:8][C:4]=3[CH:3]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1

Procedure:
5-Amino-1,2-diphenyl-1H-benzimidazole was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH3:21][O:19][C:18](=[O:20])[CH2:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (556 μL, 8.93 mmol) was added dropwise to a cooled (0° C.) mixture of commercially available 3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid (2.09 g, 8.12 mmol) and K2CO3 (2.81 g, 20.3 mmol) in 20 mL of DMF. The reaction mixture was permitted to warm to rt and stir overnight. The reaction mixture was diluted with ether and washed four times with water, then once with brine. The ethereal layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 40% ethyl acetate/hexanes) provided tert-butyl 4-(3-methoxy-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][NH:13][C:14]2[CH:15]=[C:16]3[C:20]4=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]4[C@H:18]4[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]34)[CH:22]=2)[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: c1ccc2ncc(CNc3cc4c5c(c3)[C@@H]3CNCC[C@@H]3N5CCSC4)cc2c1

Procedure:
Using 3-quinolinecarboxaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 164. LRMS (ES)+: 403.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][C:17]#[CH:18])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11]C)[CH:8]=2)[C:3]1=[O:15].[ClH:19].N1C=CC=CC=1>O>[Cl:19][C:17](=[CH2:18])[CH2:16][C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:15]
Reactant: C#CCC1(C)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(Cl)CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 185 °C

Procedure:
A stirred mixture of 2-methyl-2-propargyl-5-methoxy-6,7-dichloro-1-indanone (11 g., 0.039 mole) and pyridine hydrochloride (110 g.) is heated at 185° C. for one hour, then poured into water (500 ml.). The product which separates is recrystallized from ethanol-water affording 6.5 g. of 2-(2-chloroallyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 183° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[N:15]#[C:16]Br.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:13][CH:14]=1)[C:8](=[O:9])[N:10]([C:16]#[N:15])[C:11]2=[O:12])([O-:3])=[O:2]
Reactant: N#CBr
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A 25 mL round-bottomed flask was charged with 4-nitrophthalimide (0.96 g, 5.0 mmol), cyanogen bromide (0.64 g, 6.0 mmol), and 10 mL of reagent grade acetone. The resulting suspension was cooled using an ice/salt bath, and triethylamine (1.0 mL, 7.1 mmol) was added dropwise over a 4 minute period. The mixture was allowed to stir for 20 minutes before being partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and concentrated to give 0.95 g of a yellow solid. This material was recrystallized from ethyl acetate to afford 0.65 g (60%) of yellow crystals, mp 209.5°-210.5° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 215° C.): IR (nujol) 2261 (nitrile), 1811 (carbonyl), 1769 (carbonyl), 1533 (nitro), 1343 (nitro) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.34 (d, 1, J=8.9 Hz), 8.70-8.78 (m, 2); 13C NMR (50 MHz, DMSO) δ 161.15, 160.92, 152.34, 135.19, 132.10, 131.16, 126.48, 119.76, 102.26; GC/MS (relative intensity) 217 (77.8), 149 (71.7), 103 (64.4), 75 (100), 74 (52.7).
Reaction SMILES: [C:1]([O:13]CC)(=O)[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[OH:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:1]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:13])[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCc1ccc(O)c(O)c1
Product: O=C(CCc1ccc(O)c(O)c1)N1CCOCC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
' 3 g of ethyl dihydrocaffeate was mixed with 3 g of morpholine, and the mixture was then heated with stirring at 150° C. for 2 hours. After cooling, the reaction solution was concentrated, and the resultant residue was then purified through a silica gel column chromatography. Elution was then carried out with a mixture of chloroform:methanol=20:1, thereby obtaining 3.7 g of N-[3-(3,4-dihydroxyphenyl)propionyl]morpholine having a melting point of from 211° to 213° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[CH3:30]I>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:12]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH3:30])[CH2:9][C@H:8]1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N(C)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (0.97 g) in N,N-dimethylformamide (5.0 ml) was added sodium hydride (0.099 g) at 0° C. After stirring at ambient temperature for 1 hour, the mixture was cooled to 0° C. To the mixture was added methyl iodide (0.31 ml) and the resulting mixture was stirred for additional 4 hours at 0° C. The reaction mixture was diluted with water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give (2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (1.01 g). IR (Neat): 1700 cm-1