Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:12]([C:9]2[CH:10]=[CH:11][C:5]3[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=3[CH:8]=2)=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.7 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (556 mg, 2.45 mmol, 1.0 eq) is added at room temperature to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.45 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by 1-hydroxybenzotriazole (421 mg, 2.69 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (550 mg, 2.81 mmol, 1.15 eq) and N,N-diisopropylethylamine (962 μL, 5.50 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0/9/1, v/v/v) to afford 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow solid (621 mg, 62% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][Cl:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(NCl)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of a benzoylhydrazinecarboxylic acid tert-butyl ester (Example 7) in acetic acid (5 mL) is added N-chlorosuccinimide (1.2 eq.). After 1 hour, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under vacuum and purified via flash column chromatography (ethyl acetate/hexanes) to afford the corresponding chloro-benzoylhydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:28]C(C)([O-])C.[K+].IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH3:28])=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: COc1ccc(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Reactant: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(F)cc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To an ice-cold suspension of 0.07 g (0.17 mmol) 4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-nicotinamide in 1 mL tetrahydrofuran were added 0.019 g (0.17 mmol) potassium tert-butoxide followed by 10 μl (0.18 mmol) iodomethane. The suspension was stirred at room temperature for 16 hours, poured onto 10% aqueous citric acid solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting powder was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give 32 mg (44%) of the title compound as a white solid. MS (ESI): m/z=421.052 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH3:21][Si:22]([O:25][C:26](=[O:33])[CH2:27][O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[CH3:23]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:33][CH:26]([O:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:27][O:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of trimethylsilyl-2 -(trimethylsiloxy)acetate (24.4 mL, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath. The THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 min and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a mixture of geometrical isomers (4:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[CH:11][C:12]([Br:16])=[C:13]([NH2:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:18]([NH:26][C:27]([NH:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([CH3:17])=[CH:11][C:12]=1[Br:16])=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)c(N)cc1OCc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(Br)c(NC(=S)NC(=O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 5-benzyloxy-2-bromo-4-methyl-phenylamine (0.50 g, 1.71 mmol) in acetone (20 mL) was added benzoylisothiocyanate (0.28 mL, 2.08 mmol) dropwise at room temperature. The resulting reaction mixture was stirred for 30 min. at the same temperature. After completion of reaction (TLC monitoring), acetone was distilled off, the solid residue was stirred in hexane for 5-10 min and then filtered to obtain the desired product as white solid (0.70 g, 88%). 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 5.10 (s, 2H), 7.33 (m, 1H), 7.40 (t, J=7.20 Hz, 2H), 7.48 (d, J=7.60 Hz, 2H), 7.55 (m, 3H), 7.67 (m, 1H), 7.73 (s, 1H), 8.0 (d, J=7.20 Hz, 2H), 11.81 (br s, 1H) and 12.59 (br s, 1H).
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].C(N=C=S)(=O)C1C=CC=CC=1>O1CCCC1.CCOCC>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:2]=1)[CH2:8][CH3:9]
Reactant: CCCNC(=O)c1ccccc1N
Agent: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccccc1

Procedure:
To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.C(OC1C=C(C2O[N:32]=[C:31]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][NH:38]4)[N:30]=2)C=CC=1OCCC)CC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:32]=[C:31]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][NH:38]4)[N:30]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1ccc(C(=O)O)cc1Cl
Reactant: CCCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCCC
Product: CCCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1Cl
Yield: 35 %

Procedure:
When the product of Step C was substituted for 5-(3,4-dipropoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 43 Step C, the similar process afforded the title compound in 35% yield, as off white solid. 1H-NMR (CDCl3) 1.1 (tr, 3H, J=7.37 Hz); 1.78-1.95 (m, 2H); 4.09 (t, 2H, J=6.47 Hz); 7.03 (d, 1H, J=8.66 Hz); 7.34-7.39 (m, 3H); 7.56 (d, 1H, J=8.14 Hz); 8.04 (d, 1H, J=6.8 Hz); 8.1 (dd, 1H, J=8.6, 2.1 Hz); 8.28 (d, 1H, J=3.21 Hz); 8.38 (broad s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:12])=[C:5]([CH:7]=[C:8]([F:11])[C:9]=1[Cl:10])N)#[N:2].Cl.O.N([O-])=O.[Na+].O.[BrH:20]>>[C:1]([C:3]1[C:4]([Cl:12])=[C:5]([Br:20])[CH:7]=[C:8]([F:11])[C:9]=1[Cl:10])#[N:2]
Reactant: Br
Reactant: N#Cc1c(Cl)c(N)cc(F)c1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1c(Cl)c(F)cc(Br)c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
47.2 g of 3-cyano-2,4-dichloro-5-fluoroaniline (0.23 mol) were added to a solution of 150 ml of hydrochloric acid-water (1:1). The resulting mixture was stirred to be a slurry and then cooled to 0-5° C. A solution of sodium nitrite (16.7 g, 0.242 mol) and water (46 ml) was added thereto over 30 minutes. The resulting solution was added to a solution of cuprous bromide (0.275 mol) in 147 ml of hydrobromic acid. The reaction mixture was stirred for 2 hours and allowed overnight. The resulting mixture was wet-distilled. The distilled fraction was extracted with toluence. The oil layer was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, and dried over anhydrous sodium sulfate. After removing the solvent, the residue was crystallized from toluene to give 53.3 g of 3-cyano-2,4-dichloro-5-fluorobromobenzene (0.198 mol) in 86.2% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH3:21])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH2:31][CH2:30]1
Reactant: CCCc1cc(CCC=O)n(-c2cccc([N+](=O)[O-])c2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
67 mg (83.6%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-nitrophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (51 mg, 0.178 mmol), 1-(2-fluorophenyl)piperazine (42 mL, 0.266 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])[NH2:21])[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1>[C:24]1([S:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:21])[NH2:22])[CH:15]=4)[C:8]3=[O:23])[CH2:3][CH2:2]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with phenylsulfonyl chloride in tetrahydrofuran with triethylamine folowed by amidine formation as described above; HRMS (M+H)+ calc. 454.191287, found 454.191418.
Reaction SMILES: [C-:1]#[N:2].[Na+].C1(C)C=CC(S(O[CH2:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16]2)(=O)=O)=CC=1.C(OCC)C>CN(C)C=O>[C:1]([CH2:14][CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16]1)#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#CCC1CCc2ccccc2O1
Temperature: 0 °C
Reaction time: 10 h
Yield: 58.2 %

Procedure:
10.6 g (0.216 mol) of sodium cyanide are added to a solution of 57.31 g (0.18 mol) of 2-(p-toluenesulphonyloxymethyl)chroman in 800 ml of absolute dimethylformamide and the whole is heated, while stirring, to 60°. After 10 hours, ice-water is added to the reaction mixture and extraction is carried out with diethyl ether. The combined ethereal phases are washed thoroughly with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 30.0 g (96.2%) of crude product are obtained and are chromatographed on 1000 g of silica gel (0.040-0.063 mm) using toluene as the eluant. 18.16 g (58.2%) of 2-cyanomethylchroman are thus obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]([NH2:13])[N:7]=1)[CH2:2][CH2:3][CH3:4].N1C(N)=NC(N)=NC=1N.[C:23]1([CH3:29])[CH:28]=[CH:27]C=CC=1>>[CH2:27]([N:13]([CH2:29][CH2:23][CH2:28][CH3:27])[C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=[C:10]([NH:12][CH2:1][CH2:2][CH2:3][CH3:4])[N:9]=1)[CH2:28][CH2:23][CH3:29]
Reactant: CCCCNc1nc(N)nc(N)n1
Reactant: Cc1ccccc1
Agent: Nc1nc(N)nc(N)n1
Product: CCCCNc1nc(NCCCC)nc(N(CCCC)CCCC)n1
Yield: 4.8 %

Procedure:
After 1-butanol and water were distilled off from the crude reaction product, toluene was added to the residue. result, 2-n-butylamino-4,6-diamino-1,3,5-triazine in a yield of 4.8% (based on the starting melamine) and 55.5% of the starting melamine were obtained. The toluene solution was analyzed through HPLC. As a result, it was confirmed that a total amount of the other reaction product was extracted.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([C:20]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:22]([CH2:25][CH2:26]O)=[CH:23][N:24]=1)[CH2:17][CH2:18][CH3:19].C(N(C(C)C)CC)(C)C.[CH3:45][O:46][C:47](=[O:57])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH2:49]>C(Cl)Cl>[CH3:45][O:46][C:47](=[O:57])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH:49][CH2:26][CH2:25][C:22]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:24][CH:23]=1
Reactant: CCCCc1ncc(CCO)n1Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A solution of trifluoromethanesulfonic anhydride (0.954 g, 3.38 mmol) in methylene chloride (5 ml) was cooled to -78° C. under nitrogen, and a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(2-hydroxyethyl)-1H-imidazole (0.9 g, 3.07 mmol), diisopropylethylamine (0.44 g. 3.38 mmol) and methylene chloride (10 ml) was added dropwise. The mixture was stirred at -78° C. for an additional 15 minutes, then a solution of the free base of phenylalanine methyl ester (prepared from 1.33 q (6.15 mmol) of the hydrochloride salt) in methylene chloride (10 ml) was added. This mixture was stirred for 2 hours at -78° C. and an additional 18 hours at ambient temperature. The reaction mixture was washed with water, dried and concentrated and the crude product was flash chromatographed with 5% methanol in ethyl acetate to yield 0.9 g (65%) of N-[2-{1-[(2 chlorophenyl)methyl]-2-n-butyl-1H-imidazol-5-yl}ethyl ]phenylalanine methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:17])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 80 °C

Procedure:
Step H1. A mixture of 3,5-dibromo-toluene (4.25 g, 17 mmol), NBS (3 g, 17 mmol), and AIBN (150 mg) in carbon tetrachloride (50 mL) was heated at 80° C. for 3 hours. The resulting mixture was run through a silicon gel column with dichloromethane as the eluant. The fraction was collected and solvent was removed by rotovap, crude 1,3-dibromo-5-(bromomethyl)benzene was obtained as a white residue.
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:20]2[CH:28]=[CH:27][C:26]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:36]1
Reactant: OC1CCCNC1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(N2CCCC(O)C2)c(C(=O)O)c1
Yield: 15 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example S) from 2-Chloro-5-methylsulfamoyl-benzoic acid and rac-3-hydroxy-piperidine and obtained in 15% yield. MS (m/e): 312.9 (MH− 100%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH2:17][NH:18][CH3:19])[CH3:14]>>[CH2:13]([N:15]([CH2:20][CH3:21])[CH2:16][CH2:17][N:18]([CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH3:19])[CH3:14]
Reactant: O=Cc1ccc2c(n1)COC2=O
Reactant: CCN(CC)CCNC
Product: CCN(CC)CCN(C)Cc1ccc2c(n1)COC2=O
Yield: 63.6 %

Procedure:
In a process similar to that described in Preparation 8, 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (110 mg, 0.68 mmol) and N,N-diethyl-N′-methylethylenediamine (109 μL, 0.68 mmol) are reacted to provide the title compound as white solid (120 mg, 64%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:39]>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][C:28]([OH:39])([OH:33])[C:29]([F:30])([F:31])[F:32])[CH2:25][CH3:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)C(F)(F)F)C1=O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(O)(O)C(F)(F)F)C1=O
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one prepared above in Step A (100 mg, 0.189 mmol) in DCM (2.1 mL) was added water (17 μL, 0.95 mmol) and Dess-Martin periodinane (161 mg, 0.378 mmol) at rt and the resulting solution was stirred overnight. The reaction was quenched (1 M aq. Na2S2O3), extracted (2×DCM), and washed (2×sat. NaHCO3 and 1×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film. The product was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][CH:69]=1)[C:53]([NH:55][C:56]1[CH:65]=[C:64]2[C:59]([CH2:60][CH2:61][N:62]([CH3:66])[CH2:63]2)=[CH:58][CH:57]=1)=[O:54]>CN(C=O)C>[CH3:66][N:62]1[CH2:61][CH2:60][C:59]2[C:64](=[CH:65][C:56]([NH:55][C:53]([C:52]3[CH:51]=[C:50]([CH:69]=[CH:68][CH:67]=3)[CH2:49][NH:48][C:12]([C:10]3[S:11][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)=[O:14])=[O:54])=[CH:57][CH:58]=2)[CH2:63]1
Reactant: O=C(O)c1ccc(-c2cccnc2)s1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cccnc5)s4)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 5-pyridin-3-yl-thiophene-2-carboxylic acid (31 mg, 0.15 mmol) in DMF (1 mL) add Hunig's Base (0.10 mL, 0.54 mmol) and TBTU (52 mg, 0.16 mmol) and stir at rt for 20 min. To this add 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (50 mg, 0.1 mmol) and stir the solution for 18 h at rt. Concentrate the solution and purify the residue by prep-HPLC (10% to 90%, CH3CN/H2O) to provide the desired product 5-pyridin-3-yl-thiophene-2-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (62 mg, 0.087 mmol). MS, electrospray 483.8 (M+H), rt 0.88 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.Cl[C:56]1[S:57][CH:58]=[CH:59][N:60]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]2[S:57][CH:58]=[CH:59][N:60]=2)[CH2:49][CH2:48]1
Reactant: Clc1nccs1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(c2nccs2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 12 %

Procedure:
The desired compound was prepared according to the procedure of Example A157, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-chloro-1,3-thiazole as starting materials in 12% yield. LCMS for C27H28ClN8OS (M+H)+: m/z=547.2.