Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)[CH:6]=[CH2:7])([O:3][CH3:4])=[O:2].O1CCCC1.ClC(OC)=O.[NH2:29][CH:30]1[C:56](=[O:57])[N:32]2[CH:33]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C:34]([C:37](=[O:39])[CH3:38])=[CH:35][S:36][C@H:31]12>CN(CC1C=CC=CC=1)C.C(OCC)(=O)C>[C:1]([CH:5]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:29][CH:30]1[C:56](=[O:57])[N:32]2[CH:33]([C:40]([O:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[C:34]([C:37](=[O:39])[CH3:38])=[CH:35][S:36][C@H:31]12)=[O:12])[CH:6]=[CH2:7])([O:3][CH3:4])=[O:2]
Reactant: C=CC(NC(C(=O)O)c1ccccc1)C(=O)OC
Reactant: CC(=O)C1=CS[C@@H]2C(N)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CN(C)Cc1ccccc1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(NC(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(C)=O)=CS[C@H]12)c1ccccc1)C(=O)OC
Temperature: -15 °C
Yield: 68 %

Procedure:
To a cooled (-15° C.), stirred slurry of 0.381 g. of 2-(1-carbomethoxy-2-propenylamino)-2-phenylacetic acid and 25 ml. of tetrahydrofuran was added three drops of N,N-dimethylbenzylamine and 0.109 ml. of methyl chloroformate. The reaction mixture was allowed to stir with cooling under an argon atmosphere for 10 minutes. The reaction mixture was then cooled to -20° C. and a solution of 0.521 g. of benzhydryl 7-amino-3-acetyl-2-cephem-4-carboxylate in 5 ml. of tetrahydrofuran was added dropwise. The resulting mixture was allowed to stir under argon with cooling for approximately one hour, after which time the mixture was transferred to a separatory funnel with the aid of cold ethyl acetate. The organic solution was washed with cold 1N.HCl, and brine, and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a product which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 0.556 g. (68 percent) of the title product as a tan froth:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[N:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)nc1
Reactant: Nc1cccc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Nc2cccc(Cl)c2)nc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A solution of tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate E, 250 mg, 0.798 mmol), 3-chloroaniline (122 mg, 0.958 mmol), Sodium tert-butoxide (115 mg, 1.198 mmol) in 1,4-dioxane (5 mL) was degassed for 30 min, tris(dibenzylidene acetone)dipalladium(0) (36 mg, 0.039 mmol) and 4,5-Bis(diphenyl phosphino)-9,0-dimethyl xanthene (138 mg, 0.39 mmol) was added and heated for 4 h at 80° C. After completion, the solvent was evaporated; the residue was poured into ice cold water (10 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography to give tert-butyl (trans)-2-(6-(3-chlorophenylamino)pyridin-3-yl)cyclopropylcarbamate (180 mg, 63%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].Cl>>[NH2:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([NH:18][S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)s1
Agent: Cl
Product: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous procedure to that described in Example 61, N-[5-(6-chloro-5-phenylsulfonylaminopyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide was hydrolysed with aqueous hydrochloric acid solution to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.11 (s, 3H), 7.24 (s, 2H), 7.50 (d, 1H), 7.60 (m, 2H), 7.68 (m, 1H), 7.77 (d, 2H), 8.14 (s, 1H), 10.42 (br s, 1H); Mass Spectrum: M+H+ 381.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Al].[CH2:10]=[CH:11][CH2:12][CH3:13].[OH-].[Na+]>[Hg](Cl)Cl>[CH3:8][C:2]1[C:1]([CH:1]([CH2:2][CH3:3])[CH3:6])=[C:6]([OH:7])[C:5]([CH:11]([CH2:12][CH3:13])[CH3:10])=[CH:4][CH:3]=1
Reactant: C=CCC
Reactant: Cc1cccc(O)c1
Agent: Cl[Hg]Cl
Agent: [Al]
Agent: [Na+]
Product: CCC(C)c1ccc(C)c(C(C)CC)c1O
Temperature: 200 °C
Reaction time: 10 h
Yield: 26.6 %

Procedure:
In an autoclave 162 g of m-cresol, 1.6 g of aluminium grit and 0.1 g of mercury(II) chloride are heated at 200° C for 1 h. After cooling at room temperature 168 g of n-butene are added. This mixture is stirred at 200° C for 10 h. Then 10 g of 10% aqueous sodium hyroxide solution are added and the mixture is fractionated. At 142° C (12 mm Hg) 43.9 g of 3-methyl-2,6-di-s-butylphenol are obtained.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].C(N(CC)CC)C.[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl.Cl>CN(C=O)C>[CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[N:4]([CH3:5])[S:19][C:18]([Cl:22])([Cl:21])[Cl:17]
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: ClSC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(=N[N+](=O)[O-])N(C)SC(Cl)(Cl)Cl
Yield: 57.1 %

Procedure:
To a cooled, stirred mixture of S,N-dimethyl-N'-nitroisothiourea (1.0 g), triethylamine (0.68 g) and DMF (10 ml) was added 1.2 g of trichloromethanesulfenyl chloride dropwise at 3°-7° C. After stirring at the same temperature for 1 hour, the mixture was poured into 50 ml of 2N hydrochloric acid and the resulting mixture was extracted with toluene (50 ml). The toluene layer was washed with water (50 ml), dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (8:1). The fractions containing the desired product were concentrated to afford 1.1 g of S,N-dimethyl-N'-nitro-N-trichloromethanesulfenylisothiourea as a pale yellow crystal, m.p. 75°-78° C.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23](F)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:18])[N:8]([CH:5]4[CH2:6][CH2:7][O:2][CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[N:24][CH:25]=1
Reactant: O=C1N(C2CCOCC2)CC[C@]12CCCNC2
Reactant: Fc1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(C2CCOCC2)CC[C@]12CCCN(c1ccc(Cl)cn1)C2
Temperature: 120 °C

Procedure:
A mixture of (5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (29.4 mg, 0.000107 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 92, steps 1-3), 5-chloro-2-fluoropyridine (17 mg, 0.00013 mol) and potassium carbonate (0.029 mL, 0.00032 mol) in N,N-dimethylformamide (0.6 mL, 0.008 mol) was heated at 120° C. for 5 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 350.2 (M+H)+.
Reaction SMILES: C(O)C.Cl.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O=[Pt]=O.O1CCCC1>[NH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Oc1ccc2cccnc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
PtO2 (528 mg, 2.33 mmol) was added to a dry flask. Ethanol (70 mL), tetrahydrofuran (70 mL), and hydrogen chloride (7.6 mL, 2N) were added after the flask was flushed with argon. Quinolin-7-ol (1000 mg, 6.89 mmol) was added into the flask under argon atmosphere. The solution was degassed and flashed with argon. Hydrogen gas was introduced to the flask by a balloon. The mixture was stirred at H2 atmosphere at room temperature overnight. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by MPLC (biotage) to afford 730 mg (71%) of the title compound. 1H-NMR (CDCl3) δ 6.77 (d, J=7.6 Hz, 1H), 6.10 (dd, J=8.0 Hz, 2.8 Hz, 1H), 5.95 (d, J=2.4Hz, 1H), 3.24 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.9Hz, 2H), 2.44 (m, 2H); Rf=0.74, 50% ethyl acetate-hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:28](O)=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:29])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-n-butylpiperazine (0.325 g, 1.34 mmol), 1-naphthalene carboxylic acid (0.230 g, 1.34 mmol), HOBT (0.203 g, 1.34 mmol), EDC.HCl (0.254 g, 1.34 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil (0.490 g).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Cl.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][N:35]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: Cl
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccn3)C2=O)nc1C
Yield: 55 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 2-(bromomethyl)pyridine hydrochloride to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 55% yield: MS (ES+) m/z 347.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[C:6]=1[CH2:12][NH2:13])[CH3:2].[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([C:27](OCC)=[O:28])[CH:21]=[N:20]2.C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:14]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[C:6]=1[CH2:12][NH:13][C:27]([C:22]1[CH:21]=[N:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([I:16])[CH:18]=2)[N:23]=1)=[O:28])[CH2:1][CH3:2])[CH3:15]
Reactant: CCOC(=O)c1cnc2cc(I)ccc2n1
Reactant: CCN(CC)Cc1ccnc(F)c1CN
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CC)Cc1ccnc(F)c1CNC(=O)c1cnc2cc(I)ccc2n1
Yield: 56.8 %

Procedure:
This compound was prepared, starting from compounds 90 (0.70 g, 3.31 mmol) and 9 (1.09 g, 3.31 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 91 (926 mg, 1.88 mmol) as a beige solid. Yield 57%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.38; mp 147-149° C.; IR (KBr) ν 1160, 1413, 1477, 1508, 1679, 2967 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.13 (t, 6H, J=7.1 Hz), 2.66 (m, 4H), 3.80 (se, 2H), 4.82 (d, 2H, J=6.0 Hz), 7.19 (m, 1H), 7.71 (d, 1H, J=8.8 Hz), 8.02 (dd, 1H, J=1.8, 8.8 Hz), 8.08 (d, 1H, J=4.8 Hz), 8.55 (d, 1H, J=1.8 Hz), 9.14 (m, 1H), 9.61 (s, 1H); ESI-MS m/z 493.9 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[S:15])([CH3:3])[CH3:2].[C:16]([NH2:21])([CH2:19][CH3:20])([CH3:18])[CH3:17]>C(N(CC)CC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:21][C:16]([CH2:19][CH3:20])([CH3:18])[CH3:17])=[S:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Reactant: CCC(C)(C)N
Solvent: CCN(CC)CC
Product: CCC(C)(C)NC(=S)Nc1c(C(C)C)cccc1C(C)C
Temperature: -10 °C
Reaction time: 12 h

Procedure:
11.0 g of 2,6-diisopropyl-phenyl isothiocyanate and 10 g of tert.-pentylamine are warmed with 5 ml of triethylamine for 10 minutes at 100°. After standing for 12 hours, the mixture which has partially crystallised out is stirred with petroleum ether and cooled to -10° C., and the product is filtered off and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH2:28][CH3:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[OH:16]O>C(O)(=O)C.C(OC(=O)C)(=O)C>[NH:1]1[C:6](=[O:16])[C:5](=[O:7])[NH:4][C:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:2]1=2
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: OO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 79.6 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (20 g, 100.9 mmol), recrystallized from acetic acid, was suspended in a mixture of 135 ml acetic acid and 135 ml acetic anhydride and hydrogen peroxide (9.8 ml, 35%) was added. After stirring overnight another portion (9.8 ml, 35%) of hydrogen peroxide was added. This was repeated five times over a week. The red precipitate was filtered off, washed with acetic acid and water and dried to give 18.5 g (79.6%) of the title compound, which could be further purified by dissolving in aqueous sodium hydroxide and precipitation by hydrochloric acid. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 7.15-7.45 (m, 4H), 12 (s, 1H), 12.8 (s, 1H).
Reaction SMILES: ClC1C=CC=CC=1CS([C:8]1[CH:29]=[CH:28][C:11]2[N:12](C(OC(C)(C)C)=O)[C:13](C3C=CC=CN=3)=[N:14][C:10]=2[CH:9]=1)(=O)=O.ClC1C=CC=CC=1CS(C1C=CC2N=C(C3C=CC=CN=3)N(C(OC(C)(C)C)=O)C=2C=1)(=O)=O.Cl.O1CCOCC1>CO.CCOCC>[NH:12]1[C:11]2[CH:28]=[CH:29][CH:8]=[CH:9][C:10]=2[N:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2cc(S(=O)(=O)Cc3ccccc3Cl)ccc21
Agent: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2ccc(S(=O)(=O)Cc3ccccc3Cl)cc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To stirred solution of tert-butyl 5-(2-chlorobenzylsulfonyl)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (or the isomer, tert-butyl 6-(2-chlorobenzylsulfonyl)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate) (0.015 g, 0.031 mmol) in methanol (1 mL) was added 4N HCl in dioxane (0.155 μL, 0.62 mmol). The reaction mixture was stirred for 15 h at room temperature, diluted with Et2O (15 mL) and the white precipitate was filtered and dried under vacuum at 45° C. for 15 h to afford 8.4 mg of 5-(2-chlorobenzylsulfonyl)-2-pyridin-2-yl)-1H-benzo[d]imidazole (59%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41]>CC(N(C)C)=O>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]5[OH:41])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (202 mg, 0.5 mmol) from Step 4 of this Example in DMA (4 mL) were added DIEA (129 mg, 1.0 mmol) and (1R,2R)-2-aminocyclohexanol (69 mg, 0.6 mmol) at rt. The mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a white solid (127 mg, 58%). 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.04-7.34 (m, 4H), 5.40 (s, 2H), 4.77 (br s, 1H), 3.76 (s, 6H), 3.51 (br s, 1H), 1.77-2.14 (m, 3H), 1.61 (br, 2H), 1.04-1.38 (m, 4H). LCMS (ESI) m/z 439 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[C:20]=1[C:21]([O:23]CC)=O.Cl.[C:30]([O:34][C:35](=[O:38])[CH2:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[C:20]=1[C:21]([NH:37][CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[O:23]
Reactant: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
DIPEA (0.05 mL, 276 μmol) was added to a stirred mixture of ethyl 5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroquinoline-6-carboxylate (24 mg, 92 μmol) and glycine tert-butyl ester hydrochloride (38 mg, 230 μmol) in 1,4-dioxane (3 mL). The reaction mixture was then stirred at 75° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the title compound as a crystalline white solid (15 mg, 47%). MS (m/z)=347 (M+H)+. Calculated for C18H22N2O5 346.4.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:15][CH:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1.O>C1(C)C=CC=CC=1>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=[N:15][CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[CH:3][CH:2]=1
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C(=NC1CN2CCC1CC2)c1ccc(-c2ccccc2)cc1
Yield: 59.3 %

Procedure:
4-Biphenylcarboxaldehyde (160 mg) and 3-aminoquinuclidine (110 mg) were heated under reflux in toluene (50 ml) for 2 hours using a Dean and Stark water separator. The toluene was evaporated and the residue was purified by medium pressure column chromatography on alumina (ICN Alumina N 32-63), eluting with ethyl acetate to give 3-[(biphenyl-4-ylmethylene)amino]quinuclidine (150 mg) as a colourless solid, m.p. 82-84° C.; microanalysis, found: C, 82.2; H, 7.7; N, 9.6%; C20H22N2 requires: C, 82.7; H, 7.6; N, 9.6%; NMR (CDCl3): 1.35-1.5(1H, m), 1.6-1.8(3H, m), 2.2-2.3(1H, m), 2.8-3.0(4H, m), 3.0-3.2(2H, m), 3.4-3.5(1H, m), 7.3-7.5(3H, m), 7.55-7.65(4H, m), 7.8(2H, dd) and 8.3(1H, s); m/z 291 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:42][C@H:41]([C:40]([O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)=[O:47])[CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1C(=O)OC(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
(S)-7-Nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tert-butyl ester (2.5 g, 7.76 mmol) was dissolved in DCM (100 ml). HOBt (1.16 g, 8.53 mmol) was added, L-leucine cyclopentyl ester (3.19 g, 8.53 mmol) was added followed by triethylamine (2.38 ml, 17.1 mmol). EDCl.HCl (1.46 g, 8.5 mmol) was added and the reaction stirred at room temperature for 16 h. To the reaction was added DCM (100 ml) and the organic layer washed with water (3×300 ml), dried with Na2SO4 and the solvent removed in vacuo. The crude product was purified by chromatography (EtOAc:heptane 1:2→EtOAc) to give the required product 3.14 g (82% yield), LCMS purity 100%, m/z 504 [M++H]+
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([OH:24])=O)[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(Cl)(=O)C(Cl)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>CN(C=O)C.O.N1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:42]3[CH2:41][CH2:40][N:39]([C:36]4[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=4)[CH2:44][CH2:43]3)=[O:24])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To a THF (20 ml) solution of 500 mg of 6-(3,4-dimethoxyphenyl)pyridine-2-carboxylic acid were added 0.18 ml of oxalyl chloride and one drop of DMF under ice cooling. After 30 minutes ofstirring, the reaction solution was added dropwise to a pyridine (10 ml) solution of 370 mg of 4-(4-methoxyphenyl)piperazine under ice cooling. The mixture was warmed to room temperature and further stirred for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and recrystallization was further carried out from ethyl acetate-acetonitrile to obtain 370 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-methoxyphenyl)piperazine as colorless crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:11][CH:12]=1>>[Br:1][CH2:2][CH2:3][CH2:4][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: BrCCCBr
Product: COC(=O)Cc1cccc(NCCCBr)c1

Procedure:
Using 1,3-dibromopropane (1.7 ml) and methyl (3-aminophenyl)acetate (280 mg), the same manner to Example 2-41 step (i) was conducted to give the titled compound as a solid. Yield: 200 mg (70%).