Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]1=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)CCC>[C:2]1([C:1]2[C:9]3[S:13][C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[C:10]=3[NH:20][N:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)C1Sc2ccccc2C1=O
Solvent: CCCCO
Solvent: O
Product: c1ccc(-c2n[nH]c3c2sc2ccccc23)cc1

Procedure:
A mixture of 2-benzoylbenzo[b]thiophen-3(2H)-one (1.50 g, supplied by the Maybridge Chemical Company, Tintagel, England) hydrazine hydrate (0.3 ml) and butan-1-ol (50 ml) was boiled under reflux under nitrogen for 7.5 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica using toluene/ethyl acetate (7.5:1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether, and filtered to give 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole, m.p. 236-238° C.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:28])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:28])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:19])[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2c(C)c(I)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Product: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Temperature: 25 °C
Yield: 73.9 %

Procedure:
8-Cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.51 g, 3.76 mmol) and 2-benzenesulfonyl-3-phenyloxaziridine (0.98 g, 3.76 mmol) were combined in dichloromethane (14 mL) and stirred at room temperature until no starting material remained. The solvent was removed in vacuo and the residue was purified by chromatography (gradient 50% ethyl acetate in heptane to 100% ethyl acetate) to provide 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.16 g, 74%) as a white solid. MS (ESI); M++1: Calc'd, 418, Found 418. 1H NMR δ (300 MHz, CDCl3) 9.13 (s, 1H), 6.14–6.02 (m, 1H), 2.98 (s, 3H), 2.80 (s, 3H), 2.27–2.06 (m, 4H), 2.00–1.87 (m, 2H), 1.72–1.63 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1.C1C(/C=N/O)=CC=[N+](C[N+]2C=CC(/C=N/O)=CC=2)C=1.[Br-].[Br-].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC=C1CCCCCO
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCC2=CCCC2=O)cc1

Procedure:
Treatment of 2-(hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm-1.
Reaction SMILES: [S:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:18]([C:26](O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:29]([NH:17][C@H:18]([C:26]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NCCCCN)cc1
Product: Cc1ccc(S(=O)(=O)NCCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Yield: 85.3 %

Procedure:
In substantially the same manner as in Example 5, N-tosyl-1,4-diaminobutane (1.27 g) was condensed with Boc-L-Phe-OH (1.47 g) to give N-(Boc-L-phenylalanyl)-N'-tosyl-1,4-diaminobutane (2.19 g) (yield 85%). After Boc group elimination with TFA, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (774 mg) as obtained in Reference Example 8 to yield the title compound (compound 32; 1.55 g) [yield 67%].
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[C:17]([NH:19][C:20](N)=[O:21])=[O:18].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:20]([NH:19][C:17](=[O:18])[C:16]1[CH:23]=[CH:24][CH:25]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1)=[O:21])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: NC(=O)NC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1cccc(C(F)(F)F)c1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared from 3-amino quinuclidine dihydrochloride (1.0 g, 5 mmol), 3-trifluoromethylbenzoylurea (1.16 g, 5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml), by refluxing under nitrogen overnight. The solvent was evaporated and the residue worked-up as in Example 1. The product (1.18 g) was converted to oxalate salt, mp 197°-200° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[C:3]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3.[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>CC(N(C)C)=O.O>[S:17]([NH:1][C:2]1[S:6][C:5]2[C:7]3[C:12]([CH2:13][CH2:14][C:4]=2[C:3]=1[C:15]#[N:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:20])(=[O:19])[NH2:18]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1c(N)sc2c1CCc1ccccc1-2
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1c(NS(N)(=O)=O)sc2c1CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-4,5-dihydronaphtho[1,2-b]thiophene-3-carbonitrile (Example 93b) (250 mg, 1.11 mmol) in dimethylacetamide (5 mL) was added sulfamoyl chloride (385 mg, 3.33 mmol). The reaction mixture was stirred at room temperature under nitrogen for about 1 hr, then it was diluted with water and extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product which was carried on for next step.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]3[C:26]4=[N:27][CH:28]=[C:29]([CH2:31][NH2:32])[CH:30]=[C:25]4[N:24]=[CH:23]3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=O)C.N1C=CC=CC=1.[C:39](Cl)([CH3:41])=[O:40]>C(Cl)Cl>[OH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]3[C:26]4=[N:27][CH:28]=[C:29]([CH2:31][NH:32][C:39](=[O:40])[CH3:41])[CH:30]=[C:25]4[N:24]=[CH:23]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(CN)cnc43)cc2s1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.12 mmol) from Example 91 in DCM (2 mL) were added pyridine (40 μL, 0.48 mmol) and AcCl (27 μL, 0.36 mmol). The resulting mixture was stirred at rt for 3 h before it was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford N-((3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide (45 mg, 82%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.40 (br s, 1H), 8.31 (s, 1H), 7.84-8.10 (m, 2H), 7.65 (s, 1H), 7.24-7.41 (m, 1H), 7.10-7.24 (m, 1H), 5.47 (s, 2H), 4.37 (d, J=5.5 Hz, 2H), 3.34 (d, J=8.7 Hz, 2H), 1.97-2.16 (m, 1H), 1.89 (br s, 1H), 1.86 (s, 3H), 1.61 (br s, 2H), 0.99-1.39 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Br)[CH2:11][CH:12]=[CH2:13].Cl>O1CCCC1>[CH2:13]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH2:12][CH:11]=[CH2:10]
Reactant: C=CCC[Mg]Br
Reactant: CCOC1=CC(=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: C=CCCC1=CC(=O)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethoxycyclopent-2-enone (2.37 g) in tetrahydrofuran (30 mL) was added dropwise a 0.5M tetrahydrofuran solution of 3-butenylmagnesium bromide (38.4 mL) under nitrogen atmosphere at −78° C. over 10 minutes, followed by stirring at −78° C. for 3 hours and then at room temperature overnight. Then, after addition of 2N aqueous hydrochloric acid solution, the reaction mixture was stirred for 30 minutes and then extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel to give 3-(3-butenyl)cyclopent-2-enone (1.1 g).
Reaction SMILES: [Li+].[I-].[CH3:3][CH:4]([CH:6]=[O:7])[CH3:5].Br[CH:9]([CH3:20])[C:10](=[O:19])[C:11]([CH3:18])([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14]>C1COCC1>[OH:7][CH:6]([CH:4]([CH3:5])[CH3:3])[CH:9]([CH3:20])[C:10](=[O:19])[C:11]([CH3:18])([CH3:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14]
Reactant: COC(OC)C(C)(C)C(=O)C(C)Br
Reactant: CC(C)C=O
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)C(C)(C)C(=O)C(C)C(O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 298 mg (2.42 mmol) CrCl2 and 29 mg (0.22 mmol) LiI in 6.0 mL abs. THF were added 100 μl (1.1 mmol) isobutyric aldehyde and 253 mg (1.0 mmol) 4-bromo-1,1-dimethoxy-2,2-dimethyl-pentan-3-one (225). After stirring at ambient temperature for one hour the brown solution was quenched with 5.0 mL brine. The aqueous phase was extracted three times with 5.0 mL of a diethylether-pentane mixture (5:1). The organic layers were combined, washed with conc. NH4Cl solution (3×5.0 mL), dried over MgSO4, filtrated and concentrated in vacuo. The remaining colourless oil (206 mg) was purified via flash chromatography (column dimensions: 3.5×20.0 cm, ethyl acetate/petroleum ether=1:8).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[C:10]([C:6]1[CH2:7][CH2:8][CH2:9][C:5]=1[S:2]([N:1]=[C:19]=[O:20])(=[O:3])=[O:4])([O:12][CH3:13])=[O:11]
Reactant: CCCCN=C=O
Reactant: COC(=O)C1=C(S(N)(=O)=O)CCC1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1

Procedure:
In 75 ml of dry xylenes was placed 4.0 g of methyl 2-(aminosulfonyl)-1-cyclopentene-1-carboxylate (VIII), 6.5 ml of n-butyl isocyanate, and 0.05 g of DABCO. The mixture was heated to reflux (ca 138°) then contacted with an excess of phosgene which was condensed into the mixture from a dry-ice condenser until the reflux temperature dropped to 126°. Over several hours the temperaure increased to 135° and additional phosgene was condensed into the mixture, again, lowering the temperature to 129°. This process was repeated until no temperature increase could be observed, indicating complete consumption of the sulfonamide. The mixture was then cooled and the xylenes removed under reduced pressure to yield ca 5 g of an amber oil. An infrared spectrum (neat) exhibited a strong absorption at 2230 cm-1 indicating the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)(=[O:3])[CH3:2].[CH3:11][Mg]Br.C(OCC)C>O1CCCC1>[Br:10][C:8]1[CH:9]=[C:4]([C:1]([OH:3])([CH3:11])[CH3:2])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (−78° C.) solution of 3-acetyl-5-bromo pyridine (1.98 g, 9.90 mmol) in tetrahydrofuran (33 mL) was added dropwise a solution of methyl magnesium bromide in diethyl ether (3.0 M, 6.60 mL, 19.8 mmol). The reaction was warmed to room temperature, and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 217.83 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.61 (s, 1 H), 8.53 (s, 1 H), 8.01 (d, J=1.9 Hz, 1 H), 2.38 (br s, 1 H), 1.61 (6 H).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 4-phenoxyaniline (1.85 g, 10 mmoles) and triethylamine (2.07 ml, 15 mmoles) in 25 ml dry dichloromethane, is added stepwise a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml dry dichloromethane. The resulting reaction mixture is stirred for 1 hour at room temperature. Afterwards said reaction mixture is washed with 2×30 ml HCl (2 N) 1×30 ml water, dried with sodium sulfate and the solvent evaporated. 2.48 g. (Yield 95%) of 2-chloro-N-(4-phenoxyphenyl)acetamide were obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5](=O)[CH2:6][CH2:7][CH:8]=O.[Cl-].[NH4+:14]>C(O)C.C(OCC)(=O)C>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]1[NH:14][CH:8]=[CH:7][CH:6]=1
Reactant: O=CCCC(=O)CCC(F)(F)F
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)CCc1ccc[nH]1
Yield: 14.5 %

Procedure:
Crude 7,7,7-trifluoro-4-oxo-heptanal (10 g, prepared above) in ethanol (100 ml) was treated with ammonium chloride (400 mmol, 21 g), then heated to reflux for 1 h. The resulting solution was diluted with ethyl acetate (300 ml) and washed with brine (2×50 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 1.3 g (21% overall from 4,4,4-trifluorobutyric acid) of 2-(3,3,3-trifluoro-propyl)-1H-pyrrole. 1H NMR (CDCl3) δ 7.98 (1H, br s), 6.71 (1H, dd, J=4.1, 2.6), 6.15 (1H, dd, J=5.9, 2.8), 5.99-5.94 (1H, m), 2.92-2.85 (2H, m), 2.52-2.35 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl.Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([C:25]#[N:26])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(c1O)CCC(=O)N2Cc1ccccc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (140 mg, 0.36 mmol) and CuCN (64 mg, 0.72 mmol) in DMF (5 mL) was refluxed for 30 min. After the mixture was cooled to r.t., CH2Cl2 (50 mL) was added. 4M HCl was added with stirring until no solid was present. The aqueous layer was extracted with additional CH2Cl2, and the organic layers were combined and dried over MgSO4. After evaporating the solvent in vacuo, the crude residue was chromatographed (20-100 EtOAc/hexanes+2% AcOH) to give 75 mg of the title compound. MS: (+) m/z 338.03 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:7])=[O:6].[Cl:27][C:28]1[CH:56]=[CH:55][C:31]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH2:42][NH:41][C:40]3=[O:54])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N:39]3[C@@H:43]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:52])([F:51])[F:53])[CH:45]=4)[CH2:42][N:41]([CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)(=[O:7])=[O:6])[C:40]3=[O:54])=[CH:37][CH:38]=2)=[CH:55][CH:56]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCCl)cc1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCCN2C[C@H](c3cccc(C(F)(F)F)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.1 %

Procedure:
To a solution of 3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30.0 mg, 0.075 mmol) and (S)-1-(4-(4-chloro-phenoxy)-phenyl)-5-(3-(trifluoromethyl)-phenyl)-imidazolidin-2-one (20.0 mg, 0.046 mmol) in DMF (0.8 mL) is added Cs2CO3 (22 mg, 0.069 mmol) and KI (1 mg). The resulted mixture is stirred at 80° C. for 14 h and is cooled down to room temperature. The mixture is poured into water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and purified by flash column chromatography to provide (S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30 mg, 82%). HPLC-MS calculated for C41H39ClF3N3O6S (M+H+) 794.2, found 794.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(Br)c1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: COc1cccc(N2CCCCC2)c1
Temperature: 105 °C

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 4.72 g of piperidine in 20 ml of o-xylene, a solution of 7.99 g of m-bromoanisole in 20 ml of o-xylene, and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 48 mg of palladium acetate in 5 ml of o-xylene (the ratio of palladium atom/m-bromoanisole=0.5% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.2 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 105° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, 80 ml of water was added to cool the reaction product. The mixture was introduced in a separatory funnel and the organic phase was separated. The lower aqueous phase was extracted with 40 ml of o-xylene. The organic phase was dried over sodium sulfate, concentrated, and then distilled to give N-(3-methoxyphenyl)piperidine. The yield of the isolated compound was 95% by mole.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[BrH:32].O.[OH-].[Na+]>CC(O)=O>[Br:32][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CO)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of {3′-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-biphenyl-4-yl}-methanol from Step 1 (1.0 eq.) in AcOH (0.3M) was added HBr (48%; 9.5 eq.). The mixture was stirred at 80° C. for 12 h, cooled to rt, poured in cold water containing 10 eq. of NaOH and extracted with EtOAc. The organic extract was washed with saturated aqueous NaHCO3 (3×), brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=3)[CH2:8][CH2:9][O:10][C:11]=2[N:12]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)=[N:12][C:11]=4[O:10][CH2:9][CH2:8][N:7]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: O=C1CNCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCNC(=O)C3)nc1OCC2

Procedure:
Following the procedures in Example 323, 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine and piperazin-2-one were reacted to give 324. MS: (ESI+)=395.1. 1H NMR (400 MHz, DMSO) δ 8.55 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 5.88 (dt, J=13.2, 6.6 Hz, 1H), 4.60-4.40 (m, 4H), 4.06 (s, J=8.0 Hz, 2H), 3.84-3.68 (m, 2H), 1.47 (d, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][NH:12][CH3:13])=[CH:5][NH:6]2.CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([OH:40])=O)=[CH:32][CH:31]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([N:12]([CH2:11][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[NH:6][CH:5]=2)[CH3:13])=[O:40])=[CH:32][CH:31]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c[nH]c2cccc(F)c12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1c[nH]c2cccc(F)c12)C(=O)/C=C/c1ccc(N)nc1
Yield: 35.4 %

Procedure:
According to the procedure of Example 24, except substituting 4-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.285 g, 1.74 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.2 g, 36%) was prepared as a white powder: MS (ES) m/e 325 (M+H)+.