Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH3:12])=[C:7]([CH2:9][NH2:10])[CH:8]=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:21].Cl>O1CCCC1>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:12])=[O:21])=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CSc1ccc(Cl)cc1CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)c1ccc(Cl)cc1CN
Reaction time: 2 h
Yield: 139.2 %

Procedure:
(Step 3) To a solution of 1-[5-chloro-2-(methylsulfanyl)phenyl]methanamine hydrochloride obtained in Step 2 (5.11 g) and triethylamine (4.61 g) in tetrahydrofuran (150 ml) was added di-t-butyl dicarbonate (6.47 g) at room temperature. The mixture was stirred at the same temperature for 2 hr, treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 ml), and m-chloroperbenzoic acid (5.62 g, containing water: Wako Pure Chemical Industries, Ltd.) was added at 0° C. The mixture was stirred at the same temperature for 2 hr, and treated with aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=2:1). The obtained residue was dissolved in methanol (100 ml), and 4N hydrogen chloride-ethyl acetate solution (10 ml) was added. The mixture was stirred at 60° C. for 30 min, and concentrated under reduced pressure to give 1-[5-chloro-2-(methylsulfinyl)phenyl]methanamine hydrochloride (3.81 g) as a solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:6]2[S:7][CH:8]=[C:9]([C:10]([O:12]CC)=[O:11])[C:5]=2[CH:4]=1.[OH-].[Na+]>>[F:20][C:2]([F:1])([F:19])[C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:6]2[S:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1csc2cc(OC)c(C(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2scc(C(=O)O)c2cc1C(F)(F)F
Yield: 76 %

Procedure:
Ethyl 5-trifluoromethyl-6-methoxybenzo[b]thiophene-3-carboxylate (D6) (0.5 g, 2 mmoles) was treated with sodium hydroxide as in the method of description 5 to give the title compound (D7) (0.42 g, 92%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[O:8]1[C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9]1.O1C(CC)C1>C[Si](C)(C)N[Si](C)(C)C.Cl.[O-2].[Zn+2]>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][C@@H:10]([OH:8])[CH:11]([CH3:13])[CH3:12])(=[O:7])[OH:6]
Reactant: CC(C)[C@H]1CO1
Reactant: NCCCP(O)O
Agent: CCC1CO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Product: CC(C)[C@H](O)CP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours after which a clear solution results. The excess hexamethyldisilazane is removed by distillation at atmospheric pressure under a slight positive pressure of inert gas to afford a colourless oil. The oil is cooled to circa 40° and treated with 0.64 g of anhydrous zinc oxide and 25 ml of (S)-(+)-1,2-epoxy-3-methyl-butane. An exothermic reaction occurs and the epoxybutane refluxes. Reflux is continued for 6 hours after which time thin layer chromatography indicates the reaction to be complete. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo at 40°. The residue is dissolved in water and stirred at room temperature for 1 hour and the water removed in vacuo to give an oily solid. This is dissolved in some 2.0M aqueous hydrochloric acid and washed with dichloromethane and ether. Removal of the water at 40° in vacuo affords a brown solid which is purified by ion-exchance chromatography on DOWEX® 50 W×8 (14-40 mesh) to give 3-aminopropyl[2-(S)-hydroxy-3-methyl-butyl]phosphinic acid, m.p. 187°-189°, [α]D20 =-14.5°.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OCl)(=O)=O.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:28](O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:26]([CH:25]=1)[O:9][CH:7]1[CH2:8][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6]1
Reactant: Oc1cc(Br)ccc1OCc1cccc(F)c1
Reactant: CC(C)(C)N1CC(O)C1
Agent: CS(=O)(=O)OCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CC(Oc2cc(Br)ccc2OCc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of the title compound of Step A (3 mmol), and triethylamine (6 mmol) in CH2Cl2 (50 mL), was added MeSO3Cl (4 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, ⅓ of the residue was dissolved in MeCN (20 mL). Next, 5-bromo-2-(3-fluoro-benzyloxy)-phenol (0.5 mmol) and K2CO3 (2 mmol) were added. The mixture was stirred at 100° C. for 16 h, concentrated and purified via PTLC providing the title compound (189 mg). MS (ESI): mass calcd. for C20H23BrFNO2, 407.1; m/z found, 408.0 [M+H]+. 1H NMR (CDCl3): 7.37-7.28 (m, 1H), 7.19-7.12 (m, 2H), 7.04-6.95 (m, 2H), 6.84-6.63 (m, 2H), 5.08 (s, 2H), 4.78-4.48 (m, 1H), 3.68-3.62 (m, 2H), 3.35-3.26 (m, 2H), 1.00 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:26]=[C:27]([C:31]2[O:36]C(C)(C)[O:34][C:33](=O)[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:33](=[O:34])[CH2:32][C:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([I:24])[CH:26]=1)=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(I)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(I)c1
Yield: 101 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (1.0 g, 3.24 mmol) and 6-(3-iodo-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J7) (1.78 g, 3.57 mmol) according to the general procedure K. Obtained as a light yellow solid (1.9 g).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[F:31][C:28]([F:30])([F:29])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:45]2[CH2:44][CH2:43][N:42]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][CH3:34])[CH2:47][CH2:46]2)=[O:22])[CH2:9]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2cccc(Cl)c2)CC1
Yield: 8 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 1-(2-methoxy-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (53.6 mg) in 8% yield as colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH:13]O>[OH-].[K+]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:12])=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: [K+]
Agent: [OH-]
Product: NC(=O)c1ccc2c(c1)CCC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-oxo-indan-5-carbonitrile (100 mg, 0.64 mmol) in KOH (25%, 0.21 mL) at 0° C., is added H2O2 (0.32 mL). The mixture is stirred at rt for 30 min, then at 50° C. for 1 h. After cooling to room temperature, the mixture is extracted with EtOAc (3×10 mL). The combined organic phases are washed with brine and dried over Na2SO4. Evaporation of the solvent affords 1-oxo-indan-5-carboxylic acid amide as a white solid. Aqueous HCl (4N, 3 mL) is added to the solid. The mixture is heated to 90° C. for 2 h. Then the reaction mixture is extracted with EtOAc (3×10 mL). The combined organic phasea are washed with brine. MeOH (5 mL) is added to the solution, followed by trimethylsilyldiazomethane (2M in ether) dropwise until all the carboxylic acid was consumed. Evaporation of solvent affords crude product, 1-oxo-indan-5-carboxylic acid methyl ester, which is pure enough for the next step. ESMS m/z 191.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccc(C)cc2n1
Solvent: CCO
Product: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reaction time: 16 h

Procedure:
To a solution of 3.00 g 4-Benzyloxycarbonylmethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 50 ml ethanol were added under argon 0.3 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethanol. The crude product was obtained after evaporation of the solvent. Yield: 1.90 g.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][O:9][C@@H:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][CH:12]=2)[O:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:30].[Na+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([C@@H:5]1[CH2:10][O:9][C@@H:8]([C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:30])=[CH:13][CH:12]=2)[O:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C#N)cc2)OC1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCC[C@H]1CO[C@H](c2ccc(C=O)cc2)OC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 4.91 g of p-(trans-5-butyl-1,3-dioxan-2-yl)benzonitrile in 50 ml of absolute toluene was placed at 0° C. in a sulphonation flask under argon gasification and treated within 3 minutes with 10 ml of a 3N solution of diisobutylaluminum hydride in toluene. After completion of the addition, the mixture was stirred at room temperature for a further 22 hours, then poured cautiously into 100 ml of 10% potassium sodium tartrate solution and extracted three times with 100 ml of diethyl ether each time. The organic phased were washed with 100 ml of 10% potassium sodium tartrate solution and once with 100 ml of saturated sodium chloride solution, dried over potassium carbonate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (5.5 g) on silica gel with petroleum ether/ethyl acetate/triethylamine (80:20:1) gave 5.08 g of p-(trans-5-butyl-1,3-dioxan-2-yl)benzaldehyde as a colourless viscous oil (purity 98.3%) which was used without additional purification.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=2)[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:34]1[S:35][C:36]([Cl:39])=[CH:37][CH:38]=1.O1CCOCC1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:39][C:36]1[S:35][C:34]([C:6]2[C:7]3[C:12](=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[CH:38][CH:37]=1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(NS(C)(=O)=O)cc21
Reactant: Clc1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2ccc(Cl)s2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 100 °C
Yield: 34.5 %

Procedure:
Method J Place N-[1-isopropyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-6-yl]-methanesulfonamide (266 mg, 0.70 mmol), potassium carbonate (242 mg, 1.75 mmol), 2-bromo-5-chloro-thiophene (207 mg, 1.05 mmol), dioxane (6 mL) and water (1 mL), followed by addition of tetrakis(triphenylphosphine) palladium (0) (20 mg, 0.018 mmol) in a sealed tube under nitrogen. Heat the reaction mixture at 100° C. overnight, then cool to room temperature. Dilute the reaction mixture with ethyl acetate, and sequentially wash the resulting mixture with water and brine. Dry the organic layer over MgSO4. Chromatograph the crude residue on silica gel column eluting with hexane and ethyl acetate (gradient) to give 89 mg (34%) of the title compound. 1H NMR (CDCl3) δ 7.79 (d, 1H, J=8.8 Hz), 7.42 (d, 1H, J=1.8 Hz), 7.35 (s, 1H), 6.97 (dd, 1H, J=2.0, 8.6 Hz), 6.93 (d, 1H, J=4.0 Hz), 6.88 (d, 1H, J=4.0 Hz), 4.50-4.67 (m, 1H), 2.97 (s, 3H), 1.52 (d, 6H, J=6.6 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]([N:14]1[CH2:17][CH:16]([F:18])[CH2:15]1)=[O:13])[CH2:9][CH2:10][CH3:11])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][C@H:8]([CH2:9][CH2:10][CH3:11])[C:12]([N:14]1[CH2:15][CH:16]([F:18])[CH2:17]1)=[O:13]
Reactant: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](N)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester (200 mg, 0.66 mmol) was dissolved in dichloromethane (4 ml) and trifluoroacetic acid (1.6 ml, 20.8 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h then concentrated to provide (R)-2-amino-1-(3-fluoro-azetidin-1-yl)-pentan-1-one trifluoroacetate as a pale brown oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].CN(C(O[N:34]1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC(C(O)=O)=NC=1>CC(N(C)C)=O.C(N(C(C)C)CC)(C)C>[CH3:9][N:8]1[C:36]([C:37]2[CH:38]=[CH:39][N:40]=[CH:35][N:34]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cn1c(-c2ccncn2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 150 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (50 mg, 0.14 mmol) in anhydrous DMA (5 mL) and diisopropylethylamine (0.5 mL) were added HATU (150 mg, 0.39 mmol), and pyrimidine-4-carboxylic acid (100 mg, 0.8 mmol). The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The resulting oil was dissolved in 10 mL of dichloromethane, and the solution was washed with 5 mL of water. The organic layer was dried over MgSO4, concentrated under reduced pressure, and the residue was dissolved in Acetic acid (2 mL). The reaction mixture was heated in a microwave reactor to 150° C. for 20 min, and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 3 mg of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.34 (s, 1H), 8.96 (d, 1H), 8.36 (s, 1H), 8.27 (d, 1H), 7.21-7.14 (m, 1H), 6.93 (d, 3H), 4.64-4.52 (m, 1H), 4.18 (s, 3H), 2.37 (dd, 2H), 1.85 (t, 2H); MS (EI) for C23H21N9O: 428.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][CH2:11][C@H:12]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13](=[O:26])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[NH:23][OH:24])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][CH2:11][C@H:12]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:13](=[O:26])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[N:23]([OH:24])[C:36](=[O:38])[CH3:37])=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)NCc1ccc(C(=N)NO)cc1
Solvent: CC(=O)O
Product: CC(=O)N(O)C(=N)c1ccc(CNC(=O)[C@H](CCC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Yield: 91 %

Procedure:
A solution of compound R (14.8 g, 20.0 mmol) and acetic anhydride (5.7 ml, 60.0 mmol) in acetic acid (100 ml) was stirred at room temperature for 45 min, and then solvent was evaporated in vacuo. The resultant residue was dissolved in EtOAc (300 ml) and extracted with water (2×75 ml) and brine (75 ml). The organic layer was then dried over MgSO4, evaporated and dried in vacuo to provide compound S (9.58 g, 18.2 mmol) as yellowish solid. LC-MS [M+H] 527.6 (C27H34N4O7+H, calc: 527.9). Compound S was used without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C:9]1([CH3:22])[CH3:21])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][C:9]([CH3:22])([CH3:21])[CH2:10]2)=[CH:19][CH:18]=1
Reactant: CC1(C)CN(c2ccc(F)cc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CN(c2ccc(F)cc2)CCN1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 1-benzyl-4-(4-fluorophenyl)-2,2-dimethylpiperazine (4.5 g, 15.08 mmol) in methanol and ethyl acetate (5:1, 60 ml) at 25° C. was added 10% palladium on charcoal (1.605 g). The reaction mixture was stirred at 50° C. for 5 h. The progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through a celite bed, washed with ethyl acetate (2×50 ml). The combined filtrate was concentrated under reduced pressure to obtain the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]O)[C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:40][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1)[C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(c1ccccc1)N(CCCCCO)CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCCCBr)CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Part C. A solution of the alcohol prepared in Part B above (4.71 g, 8.93 mmol) and carbon tetrabromide (4.15 g, 12.5 mmol) in methylene chloride (30 mL) was cooled to 0° C., and treated with a solution of triphenylphosphine (3.28 g, 12.5 mmol) in methylene chloride (30 mL) dropwise. After stirring overnight, the solution was evaporated, and the residue was separated by flash chromatography (1:1 ethyl acetatehexane) to afford the product, N-(5-bromopentyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-benzamide, as a low-melting solid (3.71 g, 6.28 mmol, 70%). 1H NMR (CDCl3): 11.08 (1H, br s); 7.61-7.20 (15H, m); 3.66-3.00 (8H, m); 1.98-1.40 (12H, m).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.C(O)C.C(OCC)(=O)C.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>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1

Procedure:
A suspension of EXAMPLE 4B (13.83 g, 34.3 mmol), 4-chlorophenylboronic acid (7.04 g, 45.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.481 g, 0.686 mmol, 2 mol %) and aqueous 2M Na2CO3 (22.5 mL, 45.0 mmol) in dimethoxyethane/H2O/ethanol (7:3:2, 200 mL) was heated at 90° C. for 4.5 hours and diluted with ethyl acetate (200 mL). The layers were separated and the organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient from 5%-40% ethyl acetate/hexanes to give the desired product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15](=O)[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][CH2:19][OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O1CCCC1>[CH2:7]([NH:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:22])[CH2:18][CH2:19][OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCNC(=O)CC(C)(C)CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCNCCC(C)(C)CCO
Temperature: 0 °C

Procedure:
Part B. A slurry of lithium aluminum hydride (5.50 g, 145 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C., and a solution of the amide prepared in Part A (11.48 g, 47.2 mmol) in tetrahydrofuran (50 mL) was added dropwise over 1 hour. The ice bath was removed, and the mixture was heated to reflux for 18 hours. After cooling to 0° C., the mixture was quenched by the slow dropwise addition of water (6 mL), aq. NaOH (18 mL, 15%), and water (18 mL). The solution was filtered through a plug of Celite®, dried over potassium carbonate, and concentrated under vacuum to afford N-heptyl-3,3-dimethyl-5-hydroxypentanamine as a clear, colorless oil (7.61 g, 33.2 mmol, 70%). 1H NMR (CDCl3) δ3.70(dt,2H,J=10.2,7.0Hz); 2.70-2.55(m,2H); 2.39-2.29(m,2H); 1.56(dt,2H,J=12.1,7.0Hz); 1.51-1.41(m,6H); 1.36-1.24(m,8H); 0.91(s,6H); 0.88(t,3H,J=6.9Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[CH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:34]2[CH2:35][CH2:36][N:31]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:15]4[C:14]5[C:19](=[CH:20][C:11]([Cl:10])=[CH:12][CH:13]=5)[N:18]=[CH:17][CH:16]=4)=[CH:23][CH:24]=3)(=[O:29])=[O:30])[CH2:32][CH2:33]2)[N:3]=1
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CCN(S(=O)(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)n1

Procedure:
In the manner given in Example 9, part E, 2-chloro-4,6-dimethylpyrimidine is heated with [[4-[(7-chloro-4-quinolinyl)amino]phenyl]sulfonyl]piperazine to give 1-[(4,6-dimethyl-2-pyrimidinyl)]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.