Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.[ClH:45]>C1COCC1>[ClH:41].[ClH:45].[ClH:41].[Cl:41][C:39]1[CH:40]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)[CH:36]=[C:37]([Cl:43])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 65 °C
Yield: 257 %

Procedure:
To a solution of tert-butyl (1-(5-((3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (94 mg, 0.15 mmol) in THF (5 mL) was added water (3 mL) and HCl (6 M in water, 2 mL, 12 mmol). The reaction mixture was heated at 65° C. for 4 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TEA). The residue was dissolved in methanol (5 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (81.2 mg, 85%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.32 (s, 1H), 8.32-8.25 (m, 2H), 8.13-8.05 (m, 2H), 8.03-7.97 (m, 1H), 7.37 (s, 2H), 7.22 (d, J=9.1 Hz, 1H), 4.17-4.07 (m, 2H), 4.00-3.90 (m, 2H), 3.86-3.77 (m, 1H), 2.84 (s, 3H), 2.79 (s, 3H), 2.71-2.60 (m, 1H), 2.48-2.38 (m, 1H). ESI MS m/z 522 [C27H25Cl2N5O2+H]+; HPLC 97.5% (AUC), tR=10.00 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:22][CH2:23][CH3:24])([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:22][CH2:23][CH3:24])([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)OCC
Yield: 99.7 %

Procedure:
3-(4-Benzyloxyphenyl)-2-ethoxy-2-methyl propanoic acid ethyl ester (0.34 g; 0.99 mmole) was hydrogenated for 18 hours at atmospheric pressure in ethyl acetate using Pd/C (0.05 g) as catalyst and then filtered through hyflo. The solvent was evaporated and 0.249 g (98% yield) of 2-ethoxy-3-(4-hydroxyphenyl)-2-methyl propanoic acid ethyl ester was obtained.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[Br:17][C:18]1[CH:19]=[C:20]([CH:21]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[OH:22])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOc1ccc(Br)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A 2.6 M n-butylithium hexane solution (5.8 mL) was added to a mixture of 4-bromophenetole (2.87 g, 0.0143 mol) and tetrahydrofuran (30 mL) at −78° C. After the mixture was stirred for 0.5 hours, a tetrahydrofuran (15 mL) solution of 3-bromobenzaldehyde (2.65 g, 0.0143 mol) was added, and further stirred for 15 minutes to warm the reaction mixture to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=7:1 to 5:1) to obtain colorless oily (3-bromophenyl)(4-ethoxyphenyl)methanol (3.94 g, 90%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[O:6]1[C:10]2([CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[O:9][CH2:8][CH2:7]1>>[S:1]1[C:5]([C:13]2([OH:16])[CH2:14][CH2:15][C:10]3([O:9][CH2:8][CH2:7][O:6]3)[CH2:11][CH2:12]2)=[CH:4][CH:3]=[N:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1cnsc1
Product: OC1(c2ccns2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from isothiazole (Focus Synthesis) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: C([O:5][CH2:6][CH:7]1[CH2:12][N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9][N:8]1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][N:8]2[CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:12][CH:7]2[CH2:6][OH:5])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: CC(C)(C)OCC1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(CO)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butoxymethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine (30 mg) in DCM (2 mL) was added TFA (2 mL). The reaction was allowed to stir at 25° C. for 2 hours. LC showed complete removal of the tert-butyl group. The solvents were removed under reduced pressure, and the residue was collected without further purification. LC-MS (IE, m/z): 415 [M+1]+. (0.26 μM)
Reaction SMILES: CC1C=CC(S(O[C@@H:12]2[C@H:16]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])OC(C)(C)[O:13]2)(=O)=O)=CC=1>O1CCCC1>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([O:17][CH2:16][C@@H:12]([OH:13])[C@H:12]([OH:13])[CH2:16][O:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])(=[O:19])=[O:20])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2OC(C)(C)O[C@H]2OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 221.1 %

Procedure:
A solution of (4R,5S)-2,2-dimethyl-5-[(4-methylphenyl)sulfonyl]oxy-1,3-dioxolan-4-yl 4-methyl-1-benzenesulfonate (5.07 g, 10.8 mmol) in a tetrahydrofuran (50 ml) −10% perchloric acid water (50 ml) mixed solvent was stirred at 50° C. for 7 hours. The tetrahydrofuran was distilled off under reduced pressure, extraction was performed with ethyl acetate and the extract was washed with brine. After drying with anhydrous magnesium sulfate, the solvent was distilled off to yield a crude product which was then purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (5.14 g). This was used without further purification for the following reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].C1(C(=CC(=CC=1)C)C)C.C(O)(=O)C=[O:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]([OH:25])[C:11]([OH:13])=[O:12]
Reactant: Cc1cc(C)c(CC(=O)O)cc1C
Reactant: O=CC(=O)O
Agent: Cc1ccc(C)c(C)c1
Product: Cc1cc(C)c(C(O)C(=O)O)cc1C

Procedure:
Finally, a further possibility for preparing 2,4,5-trimethylphenylacetic acid is to initially react pseudocumene with glyoxylic acid to give 2,4,5-trimethylmandelic acid (Atti Accad., Lettere Arti Palermo, Pt. I24 (1965) 19–33) and then to reduce it to 2,4,5-trimethylphenylacetic acid (J. Amer. Chem. Soc. 58 (1936) 629–35). However, the preparation of 2,4,5-trimethylmandelic acid by the process specified has the disadvantage that the 2,4,5-trimethylmandelic acid which has already formed reacts with further pseudocumene under the customary reaction conditions and thus forms considerable proportions of 2,2′,4,4′,5,5′-hexamethyldiphenylacetic acid (Atti Accad., Lettere Arti Palermo, Pt. I24 (1965) 19–33), which of course reduce the yield and make necessary additional purification steps.
Reaction SMILES: [Cl-].[C:2]1([P:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])[O-])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[C:11]1([P:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=P([O-])(c1ccccc1)c1ccccc1
Reactant: C1CNCCN1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)N1CCNCC1
Reaction time: 4 h

Procedure:
20 g (84.5 mmol) diphenylphosphinate chloride dissolved in 30 ml DMF are added dropwise to a solution of 21.8 g (253 mmol) piperazine in DMF. After four hours, the solution is concentrated under vacuum, taken up in chloroform and extracted by shaking with 10% hydroxide solution. The organic phase is dried over sodium sulfate and solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/TEA (90/10/0 to 90/10/6): yield 12 g (49%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1>>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([NH:16][CH2:15][C:12]2[O:13][CH:14]=[C:9]([OH:8])[C:10](=[O:27])[CH:11]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)occ1OCc1ccccc1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)occ1O
Yield: 89.8 %

Procedure:
4-Chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-07) (14.0 g, 89.79%) was synthesized as a light brown solid from N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (7-07) (20.0 g, 49.38 mmol) following the procedure described for N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-01).
Reaction SMILES: C(O)(C)(C)C.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[C:18]([O:29]C)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CO>[C:18]([OH:29])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)(C)O
Solvent: CO
Product: CCCCCCCCCC(=O)O

Procedure:
25 ml of tertiary butanol was added to a mixture of 5.00 g (27.64 mM) of glucose and 1.03 g (5.55 mM) of methyl caprinate, and 100 mg of thermostable lipase derived from Candida antarctica (sp-382, manufactued by NOVO Co.) immobilized into an acrylic resin was further added. Then, they were refluxed under heating while stirring for 24 hours with an addition of 10 g of molecular sieves 5A as a methanol remover, to obtain glucose monocaprinate (C10 glucose ester).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(NCc2ccc(N3CCC(CN4CCCC4)CC3)cc2)cc1

Procedure:
Prepared from the product of Example 9 and 4-fluoroaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].S(Cl)([Cl:27])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])=[CH:9][C:5]=1[C:6]([Cl:27])=[O:7])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
0.3 Part of 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid and 0.83 part of thionyl chloride for 2 hours. After the reaction, the excess of thionyl chloride was removed under reduced pressure to give 0.31 part of 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride. The resulting benzoyl chloride was added dropwise to a mixture of 0.14 part of diethylaminomethyl phosphonate, 0.095 part of triethylamine and 6 parts by volume of benzene with ice cooling. After the addition, the mixture was stirred at room temperature for 4 hours, and water was added. The mixture was then extracted with benzene, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 0.3 part of the desired compound (100). The IR and NMR spectral data of the compound are shown in Table 1.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]([F:18])([F:17])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=O)C.CCCCCC.CC(=O)OCC>CCO>[F:18][C:9]([F:17])([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:8][CH2:7][OH:6]
Reactant: CC(=O)OCCC(F)(F)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: OCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A 35% aq. NaOH sol. (6 ml) was added to a solution of 1.9 g (8.2 mmol) of 3,3-difluoro-3-(4-fluorophenyl)propyl acetate in EtOH (25 ml), and the mixture was stirred for 2 h at RT. Concentration in vacuo was then carried out and the residue was taken up in water (80 ml). The solution was extracted with EA (3×80 ml) and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 9:1) of the residue yielded 1.1 g (5.8 mmol, 71%) of 3,3-difluoro-3-(4-fluorophenyl)propan-1-ol.
Reaction SMILES: [CH:1]1([CH2:7][N:8]([CH3:12])[C:9]([Cl:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.CO.[CH3:18][C:19]#N.O.CC#N>O>[CH2:7]([N:8]([CH:12]1[CH2:19][CH2:18]1)[C:9]([Cl:11])=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(CC1CCCCC1)C(=O)Cl
Reactant: CC#N
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(Cl)N(Cc1ccccc1)C1CC1

Procedure:
The title compound is prepared analogously as described for cyclohexylmethyl-methylcarbamoyl chloride. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9. MS (LC-MS): [M+H]+=210.2. tR (HPLC, Waters Symmetry C18 column, 20-100% CH3CN/H2O/5 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.67 min.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:39][C@@H:40]1[CH2:44][NH:43][C@H:42]([C:45]#[N:46])[CH2:41]1.CN(C=O)C.CCN(C(C)C)C(C)C>O.CC(OC)(C)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:10]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:25]([N:43]1[CH2:44][C@@H:40]([F:39])[CH2:41][C@H:42]1[C:45]#[N:46])=[O:27])([CH3:3])([CH3:1])[CH3:4]
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](F)C[C@H]1C#N)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A reactor was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (400 g, 1 wt, 1 eq.), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid (307.7 g, 0.77 wt, 1.01 eq.), O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexaflurophosphate [i.e. HATU] (408 g, 1.02 wt, 1.01 equiv.), and DMF (2.8L, 7 vol). The mixture was cooled to approximately 0° C. Hunig's base (376 mL, 0.94 vol, 2.04 equiv.) was added over at least 30 minutes. The mixture was heated to approximately 25° C. and was stirred at this temperature until the reaction was complete (ca. 3 hours). MTBE (2.8L mL, 7 vol) was added, followed by water (2L, 5 vol) over at least 30 minutes to quench the reaction. The aqueous phase was extracted with MTBE (1.2L, 3 vol). The combined organic phases were washed with water (2L, 5 vol). The organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes. Added ethanol (2L, 5 vol). The ethanol solution of tert-Butyl {(1 S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamatewas used directly in the next step.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]1([C:67]2[CH:75]=[CH:74][C:70]([C:71](O)=[O:72])=[CH:69][N:68]=2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.O>[O:20]=[C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)[CH2:18][NH:17][C:71](=[O:72])[C:70]1[CH:74]=[CH:75][C:67]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[N:68][CH:69]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.5 %

Procedure:
DIPEA (77 mg, 0.6 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (103 mg, 0.24 mmol) in DMF (1 mL). HOBT (33 mg, 0.24 mmol) and EDCI.HCl (46 mg, 0.24 mmol) were then added at room temperature. After 2 minutes, 6-phenyl nicotinic acid (40 mg, 0.2 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 70 mg (70.7% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-6-phenyl-nicotinamide. LCMS Purity: 92.6%, 1H NMR (DMSO-d6): δ 9.1 (s, 1H), 8.7 (t, 1H), 8.3 (d, 1H), 8.2-8.1 (m, 3H), 7.9-7.7 (m, 3H), 7.7-7.6 (m, 1H), 7.6-7.4 (m, 4H), 4.2 (m, 2H), 3.4-3.2 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].Cl.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH2:24]Cl)[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Br:17][C:18]1[CH:23]=[C:22]([CH2:24][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Reactant: ClCc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cncc(Br)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 10, step 3, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with 3-bromo-5-(chloromethyl)pyridine hydrochloride and cesium carbonate in N,N-dimethylacetamide to give N-(5-bromo-pyridin-3-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil. MS: 417.2 ([M+H]+)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]=[C:21]1[N:25]([CH2:26][CH2:27][NH2:28])[C:24](=[O:29])[CH2:23][S:22]1>>[O:20]=[C:21]1[N:25]([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[C:24](=[O:29])[CH2:23][S:22]1
Reactant: NCCN1C(=O)CSC1=O
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCN3C(=O)CSC3=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and [2-(2,4-dioxo-thiazolidin-3-yl)-ethyl]-amine to afford the title compound. MS: m/e=401 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CO[C:21](OC)([CH3:24])[C:22]#[N:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Reactant: COC(C)(C#N)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c2ncc(C#N)c(-c3ccccc3Cl)c2c1
Yield: 91.8 %

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (20.0 g), 2,2-dimethoxypropionitrile (11.5 g), p-toluenesulfonic acid hydrate (1.46 g) and toluene (200 ml) was refluxed for 3 hrs., with removal of water by a Dean-Stark apparatus. The mixture was washed with sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The resultant precipitate was collected by filtration and washed with hexane to give 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarbonitrile (20.7 g, 92.0%), which was recrystallized from ethanol to give pale yellow plates. m.p. 153°-154° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34]N)=[CH:33][C:28]=2[O:27][CH2:26]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCO2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccc4c(c3)OCO4)n2)c1
Yield: 10 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for Example 91 in 10% yield. MS: M=437.3 (M+H)+
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C@H:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH2:8][CH2:7]1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39](O)=[O:40])[S:36][C:35]=2[CH:42]=1>>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39]([NH:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[CH2:21][CH2:22]3)=[O:16])[CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]3)=[O:40])[S:36][C:35]=2[CH:42]=1
Reactant: CN1CCC(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: CN1CCC(C[C@@H](NC(=O)c2cc3ccc(Cl)cc3s2)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(1-methylpiperidin-4-yl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (52%).