Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.[O:32]1[CH2:36][CH2:35][C:34](=O)[CH2:33]1>>[CH3:31][N:7]1[C:6]([CH2:5][CH:3]2[CH2:2][N:1]([C@H:34]3[CH2:35][CH2:36][O:32][CH2:33]3)[CH2:4]2)=[N:14][C:13]2[C:8]1=[N:9][C:10]([N:21]1[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]1[CH3:30])=[N:11][C:12]=2[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: O=C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN([C@H]4CCOC4)C3)n(C)c2n1

Procedure:
Following General Procedure L, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and dihydrofuran-3(2H)-one were reacted to give the racemic mixture. The enantiomers were separated by SFC to give 572. LCMS m/z: 245.2 (2M+H+)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[C:40]([C:37]1[CH:36]=[CH:35][C:34]([C:33]([NH:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([CH:26]=2)[NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[O:42])=[CH:39][CH:38]=1)#[N:41]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1N
Product: COc1cc2c(Nc3cc(NC(=O)c4ccc(C#N)cc4)ccc3C)ncnc2cc1OCCCN1CCOCC1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-4-cyanobenzamide to give the title compound in 52% yield; NMR: 2.15 (s, 3H), 2.3 (m, 2H), 3.0-4.1 (broad m, 10H), 3.95 (s, 3H), 4.3 (m, 2H), 7.35 (m, 2H), 7.65 (m, 1H), 7.88 (m, 1H), 8.02 (m, 2H), 8.14 (m, 3H), 8.53 (s, 1H), 10.65 (s, 1H), 12.1 (s, 1H); m/s: M+H+ 553.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[CH:22][C:21]=1[Cl:37].[CH:38]1[C:43]([N:44]=[C:45]=[S:46])=[CH:42][C:41]2[C:47]([O:49][C:50]3([C:60]4[CH:61]=[CH:62][C:63]([OH:65])=[CH:64][C:59]=4[O:58][C:52]4[CH:53]=[C:54]([OH:57])[CH:55]=[CH:56][C:51]3=4)[C:40]=2[CH:39]=1)=[O:48]>CN(C=O)C>[Cl:37][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])[CH:24]=[C:25]([Cl:26])[C:20]=1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:45]([NH:44][C:43]1[CH:42]=[C:41]2[C:40](=[CH:39][CH:38]=1)[C:50]1([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][C:52]=3[O:58][C:59]3[C:60]1=[CH:61][CH:62]=[C:63]([OH:65])[CH:64]=3)[O:49][C:47]2=[O:48])=[S:46]
Reactant: NCCOCCOCCOc1c(Cl)cc(Nc2ccccc2C(=O)O)cc1Cl
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Nc1cc(Cl)c(OCCOCCOCCNC(=S)Nc2ccc3c(c2)C(=O)OC32c3ccc(O)cc3Oc3cc(O)ccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N,N-Diisopropylethylamine (10 μL, 0.057 mmol) was added to a solution of the compound 4 (1.9 mg, 0.0035 mmol) and fluorescein isothiocyanate (FITC) (1.2 mg, 0.003 mmol) in DMF (1.0 ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography (silica gel, 1-20% methanol/methylene chloride) to give the desired compound 5 (1.5 mg, 52% yield); 1H NMR (CD3OD, 400 MHz) δ 8.14-8.10 (m, 1H), 7.88 (dd, 1H, J=2.0 Hz, 8.0 Hz), 7.80-7.62 (m, 2H), 7.34-7.30 (m, 1H), 7.24-7.18 (m, 1H), 7.18-7.12 (m, 3H), 6.86-6.78 (m, 1H), 6.72-6.64 (m, 3H), 6.54-6.50 (m, 2H), 4.21-4.04 (m, 4H), 3.92-3.66 (m, 8H); HRMS (ESI+) m/z: calcd for C40H33Cl2N3O10S+H+ 818.1342; found 818.1328 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]=[C:7]([Br:15])[C:6]=1[OH:16])[CH3:2].[CH:18](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[N:8]=[C:7]([Br:15])[C:6]=1[O:16][CH3:18])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1O
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cc(C(C)(C)C)nc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of the above bromopyridine (2.74 g, 9.07 mmol) in acetonitrile/methanol (9:1, 33 mL) was added N,N-diisopropylethylamine (2.50 mL, 14.2 mmol) followed by (trimethylsilyl)diazomethane (2.0M in hexane, 7.0 mL, 14.2 mmol). The red solution was stirred 0.5 h at room temperature then concentrated in vacuo. The residue was dissolved in methylene chloride, washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2-bromo-6-tert-butyl-3-methoxy-isonicotinic acid ethyl ester (2.65 g, 93%) as a red oil which was utilized without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27]Cl)=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:11][CH2:10]1.Cl>C1COCC1.C(Cl)Cl>[CH3:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:7]3[CH:6]=[CH:5][NH:4][N:3]=3)=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:11][CH2:10]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: c1cn[nH]c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCc1cc[nH]n1

Procedure:
0.5 g of sodium hydride was added to a solution of 0.68 g of pyrazole in 50 ml of THF. Next, 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) was added to the solution. The solution was reacted for 24 hours, while it was refluxed. After reaction, 2 N hydrochloric acid was added, acidifying the reaction solution. The solution was washed with 100 ml of methylene chloride. Ammonia water was added to the aqueous layer obtained, alkalizing the solution. Thereafter, the solution was extracted with 100 ml of methylene chloride. The organic layer obtained was dried over magnesium sulfate, and the solvent was removed in vacuo. The product obtained was refined by means of silica gel column chromatography using methylene chloride only. Thereafter, the solvent was removed in vacuo, yielding 0.44 g of N-(trans-4-methylcyclohexyl)-4-(2-pyrazolylethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]([C@H:16]1[NH:21][CH2:20][CH2:19][N:18]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=3[N:24]=[C:17]12)([CH3:15])[CH3:14]>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]3[C:22]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=4[N:24]=[C:17]3[C@H:16]2[CH:13]([CH3:15])[CH3:14])[N:7]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(Cl)n1)[C@@H]3C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (20.0 mg, 0.092 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added ZnCl2 (1M in diethyl ether, 0.2 mL, 0.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (31 mg, 0.09 mmol) in DCE (1 mL) and t-BuOH (1 mL) was added to the reaction mixture via syringe over 1 min at 0° C. After addition, the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (20 mg, 42.6% yield) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].CN(C)C(=N)N(C)C.[C:17]([O:21][C:22](N=[N+]=[N-])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:21][C:22]([CH:5]([CH2:4][CH2:3][CH2:2][NH2:1])[C:6]([OH:8])=[O:7])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCCN)C(=O)O
Yield: 70 %

Procedure:
5-Amino pentanoic acid (0.585 g, 5 m mol) was stirred for two days in dimethylformamide (5 ml) containing tetramethylguanidine (1.14 g, 10 m mol) and tert.butoxycarbonylazide (1.1 g, 7.5 m mol). The solution was evaporated and the residue partitioned between ethyl acetate (20 ml) and 10% citric acid solution (20 ml). The organic layer was washed with 10% citric acid (2×15 ml), water (3×15 ml) and brine 1×15 ml). Each aqueous wash was back extracted with ethyl acetate (20 ml). The combined organic layers were dried over anhydrous magnesium sulphate and evaporated to give an oil which slowly crystallised. Recrystallisation from diisopropyl ether/petrol gave 0.745 g (70% yield), mp. 47.5°-48.5° C., Rf silica gel 0.40 (benzene:dioxan:acetic acid 95:75:4).
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.[H][H]>C(OC)(=O)C.O1CCCC1.[Ni]>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1
Reactant: [H][H]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: COC(C)=O
Solvent: C1CCOC1
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1N

Procedure:
0.5 gm (0.00168 mol) of (E)-2-[(amino)-(2-nitrophenyl)methylene]-benzo[b]thiophen-3(2H)-one was dissolved in a mixture of 10 cc of methyl acetate and 10 cc of tetrahydrofuran, and after adding 0.5 gm of Raney nickel the mixture was hydrogenated at room temperature and a hydrogen pressure of 5 bar until hydrogen uptake was at an end. The catalyst was then filtered off, the solvent was evaporated at reduced pressure, and the residue was recrystallized twice in the presence of activated charcoal from tetrahydrofuran/petroleum ether (1:1). 330 mgm (73% of theory) of yellow crystals were obtained, m.p. 186°-187° C. (petroleum ether/tetrahydrofuran 1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[CH:5]2.ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][CH:6]=[C:5]2[C:17]#[N:16]
Reactant: Cc1cc2[nH]ccc2cc1F
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: Cc1cc2[nH]cc(C#N)c2cc1F
Temperature: 25 °C
Yield: 98.7 %

Procedure:
Into a solution of 5-fluoro-6-methyl-1H-indole (1.9 g, 12.8 mmol) in DMF (13 mL) at −78° C. was added chlorosulfonyl isocyanate (1.33 mL, 15.3 mmol). After addition the cooling bath was removed and the mixture was allowed to warm to room temperature. The mixture was then poured into ice water, filtered and washed with water and brine. The cake was then dissolved in acetonitrile and concentrated to give 5-fluoro-6-methyl-1H-indole-3-carbonitrile (2.2 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=[O:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:3]=1[F:23].[I:24](C1C=CC=C(CC([O-])=O)C=1CC([O-])=O)=O>C1C=CC=CC=1>[F:23][C:3]1[C:2]2[C:11](=[N:12][O:13][N:1]=2)[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:24])=[CH:18][C:17]=1[CH3:22]
Reactant: O=Ic1cccc(CC(=O)[O-])c1CC(=O)[O-]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Solvent: c1ccccc1
Product: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2nonc2c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture comprised of methyl 4-amino-3-fluoro-2-(2-methyl-phenylamino)-5-nitrobenzoate (from Step d, Example 1) and iodosobenzenediacetate (1.76 equiv.) in benzene is stirred at ambient temperature for 5 hours. The mixture is concentrated in vacuo and the residue purified by column chromatography to give the desired product.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]2[CH2:10][CH:6]([C:7]2([CH3:12])[CH3:11])[CH:5]1[CH3:13])(O)=[O:2].S(Cl)([Cl:16])=O>CO>[CH:6]12[CH2:10][CH:8]([C:7]1([CH3:12])[CH3:11])[CH2:9][CH:4]([C:1]([Cl:16])=[O:2])[CH:5]2[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC1C(C(=O)O)CC2CC1C2(C)C
Solvent: CO
Product: CC1C(C(=O)Cl)CC2CC1C2(C)C

Procedure:
15 g of (+)-3-carboxypinane of optical rotation [α]D25 = +20.2° (c = 1, CH3OH) are boiled with excess thionyl chloride under reflux in the absence of moisture, until the evolution of gas has ceased. The excess thionylchloride is then distilled, followed by the acid chloride boiling at from 62° to 64° C/0.08 mm Hg and having an optical rotation of [α]D24 = +28.1° (pure).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I:12][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[C:2]([I:1])[C:10]=1[OH:11]
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: NCCCCCCCCc1ccccc1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1

Procedure:
The title compound was prepared as a solid (0.718 g, 66%) from 3,5-diiodo-4-hydroxybenzoic acid using 8-phenyloctylamine and a procedure similar to step 2 of Example 93; 1H NMR (DMSO-d6) δ1.17-1.36 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.60 (m, 2H), 3.20 (dd, J=5.9, 8.8 Hz, 2H), 7.10-7.21 (m, 3H), 7.21-7.30 (m, 2H), 8.21 (s, 2H), 8.40 (t, J=4.4 Hz, 1H), 10.06 (s, 1H); mass spectrum [(+) ESI], m/z 578 (M +H)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:36][CH2:35][CH2:34][CH2:33][O:32][CH3:31])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: COCCCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: COCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 20.1 mg (0.23 mmol) of 3-methoxypropylamine are reacted together by general method E. 29.2 mg (49.8% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH2:8]1[C:12]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:11][CH2:10][NH:9]1.C(O)(=O)C>CC(O)C>[CH2:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:4]1[CH2:5][O:1][C:2](=[O:7])[CH:3]=1
Reactant: O=C1COC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: O=C1C=C(N2CCC3(CCNCC3)C2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available furan-2,4(3H,5H)-dione (0.433 g, 4.33 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (commercially available from multiple vendors, acetic acid salt, 0.65 g, 2.2 mmol) in 20 mL i-PrOH was heated in a sealed tube at 110° C. overnight. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in 30 mL DCM and 5 mL TFA and stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by preparative TLC (10% 2N NH3 in methanol-DCM). LCMS: [(M+1)]+=223
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (448 mg, 1.24 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357 mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (444 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13][C:14]1[C:15]([OH:54])=[C:16]([S:21]([N:24]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:25][C:26]2[CH:31]=[C:30]([CH2:32][NH:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:29]=[C:28]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:27]=2)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:13][C:14]1[C:15]([OH:54])=[C:16]([S:21]([N:24]([CH2:25][C:26]2[CH:27]=[C:28]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:29]=[C:30]([CH2:32][N:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:31]=2)[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)CNCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CN(Cc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 3,5-dichlorobenzenesulfonyl chloride (27.0 mg, 0.11 mmol) in CH2Cl2 (3 mL) was added 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-(4-fluorophenoxy)-5-((isobutylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (70 mg, 0.11 mmol, 80% purity), followed by the addition of Et3N (0.09 mL, 0.66 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with CH2Cl2 and saturated NaHCO3 solution. The organic layer was concentrated. To the residue was added 1 N NaOH/MeOH/THF. The resulting mixture was left for 2 h. The mixture was concentrated and the residue was diluted with CH2Cl2 and water. The organic layer was concentrated. The residue was dissolved in MODEL and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give a white solid (35 mg, 38%). 1H NMR (CD3OD): δ 7.67-7.63 (m, 4H), 7.57 (d, J=2.8 Hz, 1H), 7.14-7.04 (m, 4H), 6.91 (t, J=8.8 Hz, 2H), 6.87-6.83 (m, 2H), 6.70 (s, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 4.21 (s, 2H), 2.91 (d, J=7.6 Hz, 2H), 1.65 (m, 1H), 0.74 (d, J=6.4 Hz, 6H); MS (ESI): (M−H)−=843.0.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C([O:26][B:27]([O:32]C(C)C)[O:28]C(C)C)(C)C.Cl>C(OCC)C>[C:2]1([O:26][B:27]([OH:32])[OH:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)Oc1cccc2ccccc12
Temperature: -40 °C
Reaction time: 6 h

Procedure:
To one liter egg-plant type flask were added 55 g (0.27 mmol) of 1-bromonaphthalene and 300 ml of diethyl ether. The mixture was cooled to −70° C. on a dry ice/methanol bath, to which 170 ml (0.27 mmol) of a n-butyllithium/hexane solution (1.56 mol/l) was added dropwise. After addition was completed, the mixture was stirred for 6 hours while it was gradually brought to room temperature. The mixture was further cooled to −40° C. and to this were added dropwise 70 ml (0.30 mmol) of triisopropylborate and 100 ml of diethyl ether, and stirred overnight. To the reaction solution was added 200 ml of 2 N hydrochloric acid to cause hydrolysis. Diethyl ether (200 ml) was added to the reaction solution, which was washed with brine until it turned neutral. After drying over anhydrous sulfate, the solvent was distilled off under reduced pressure to give light yellow crystals of naphthyl boric acid.
Reaction SMILES: [N+:1](=[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]1=[O:17])=[N-:2].[K].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=1.Cl>O1CCOCC1.O>[N+:1](=[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=2)(=[O:15])=[O:14])[C:4]1=[O:17])=[N-:2]
Reactant: [N-]=[N+]=Nc1ccc(O)cc1
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Cl)C1=O
Agent: Cl
Agent: [K]
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=Nc1ccc(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)cc1

Procedure:
1,2-Dihydro-2-diazo-1-oxo-naphthalene-5-sulfonyl chloride (2.2 grams) is dissolved in dioxane (16 mls.) and the potassium salt of 4-hydroxyphenylazide (1.6 grams) in a mixture of water (4 ml.) and dioxane (4 ml.) is added gradually over a period of 10 minutes with stirring. The mixture is then stirred at room temperature (22°C) for 30 minutes to complete the reaction and then diluted with water (60 ml.) containing 3N hydrochloric acid (8 ml.). An oil separates out which solidifies on standing. The product is then collected and dried (2.5 grams). It is dissolved in benzene treated with carbon and filtered. Addition of 60°-80° pet. ether to the filtrate yields Compound 1. (1.7 grams) m.p. 136°-7° with decomposition.