Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH3:21].C1(C)C=CC=CC=1>[Pt].CC(O)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]=1[NH:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(=O)OCCNc1c(C)c(C)n2nnnc2c1N
Yield: 91.3 %

Procedure:
A Parr vessel was charged with acetic acid 2-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]ethyl ester (50.0 g, 170 mmol), 5% platinum on carbon (5.00 g), toluene (600 mL), and 2-propanol (50 mL) and purged with nitrogen. The vessel was then placed under hydrogen pressure (20 psi,) for 20 hours at room temperature. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with 90:10 dichloromethane:methanol. The filtrate was concentrated under reduced pressure to provide a dark gray solid, which was triturated with diethyl ether, isolated by filtration, and dried to provide 41.0 g of acetic acid 2-[(8-amino-5,6-dimethyltetrazolo[1,5-a]pyridin-7-yl)amino]ethyl ester as a light gray solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[NH:27][C:26]3[C:28]4[C:22]([C:23](=[O:29])[NH:24][N:25]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[N:11]1([CH2:15][C:16]2[NH:27][C:26]3[C:28]4[C:22]([C:23](=[O:29])[NH:24][N:25]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesized from compound 24. To a solution of 24 (1.5 g, 3.7 mmol) in 30 mL of CH2Cl2 was added 6 mL of TFA while stirring at room temperature. After 30 minutes, the solvents were evaporated and the residue was washed with acetonitrile to afford 1.0 g (90%) of analytically pure white solid. MP: 147-149° C.; MS (ES−): 297; 1H NMR (400 MHz, D2O): 1.96 (m, 2H), 2.82 (t, 2H), 3.01 (t, 2H), 3.28 (t, 4H), 3.53 (s, 2H), 7.22 (d, 1H), 7.47 (d, 1H), 7.61 (t, 1H). Anal. Calcd. for C15H18N6O. 1.1 CF3CO2H. 1.0 H2O.: C, 46.76; H, 4.81; N, 19.02; Found: C, 46.64; H, 4.98; N, 19.02.
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:32]>CO.ClCCl.O1CCOCC1>[ClH:32].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[S:15][CH:16]=3)=[CH:30][CH:31]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: c1cc(-n2cnnn2)ccc1OCc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of tert-butyl 4-(4-((4-(1H-tetrazol-1-yl)phenoxy)methyl)thiazol-2-yl)piperidine-1-carboxylate (0.60 g) in methanol/dichloromethane (1.0 mL/1.5 mL) was added 4N HCl in dioxane (1.7 mL) at 0° C., and then stirred at room temperature for 7 hours. After removal of solvents in vacuo, a crude desired compound HCl salt was obtained as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: NC1CC1
Reactant: O=Cc1cc(Cl)cc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1cc(Br)cc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a 4:1 (v/v) MeOH:THF solution (0.06 M) of 3-bromo-5-chlorobenzaldehyde (1 eq.) and cyclopropylamine (1.1 eq.) was added sodium cyanoborohydride (1.5 eq.) portionwise followed by neat acetic acid (3 eq.). The resulting mixture was stirred at RT for 20 h. The volatiles were then removed in vacuo. The resulting residue was taken up in ether and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[NH:9][N:8]=1)=[O:6].[H][H].F[C:19]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:20]=1[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>[Cl-].[Na+].O.CN(C=O)C>[CH3:15][O:14][C:12]([C:10]1[CH:11]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[N:8]([C:19]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:20]=2[C:21](=[O:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:9]=1)=[O:13]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)n(-c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a slurry of 5.3 g. (110 mmol) of 50% NaH in mineral oil in 425 ml. of dry DMF, stirred at 3° under argon, was added portionwise over a 20 minute time period, 20.26 g. (110 mmol) of 3,5-pyrazole dicarboxylic acid dimethyl ester*, maintaining a temperature of 5°-8°. When the vigorous hydrogen evolution had stopped, the ice bath was removed and the reaction allowed to warm to room temperature while stirring for 20 minutes. A solution of 24.5 g. (110 mmol) of 2-fluoro-5-nitrobenzophenone, in 100 ml. of dry DMF was added dropwise over 40 minutes and when addition was complete, the reaction was heated at 65° for 1.5 hr. After cooling, the mixture was poured over a mixture of ice and brine and extracted well with a 1:1 EtOAc:ether mixture. The combined extracts were washed with brine, dried over MgSO4 and concentrated. The crude mixture was chromatographed on silica gel using as an eluent benzene mixed with 0-100% EtOAc. The residue remaining after the solvents were evaporated was recrystallized from EtOAc/hexane to give the final product. The analytical sample was prepared by an additional recrystallization from EtOAc/hexane and was obtained as off-white needles: mp 150°-152°.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[C@@H:13]1[CH2:17][C:16](=[O:18])[C:15]([CH2:19][CH:20]=[CH2:21])=[C:14]1[CH3:22]>C(Cl)(Cl)Cl>[CH3:22][C:14]1[C@H:13]([O:2][N+:1]([O-:4])=[O:3])[CH2:17][C:16](=[O:18])[C:15]=1[CH2:19][CH:20]=[CH2:21]
Reactant: O=[N+]([O-])O
Reactant: C=CCC1=C(C)[C@H](O)CC1=O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: C=CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Yield: 96.5 %

Procedure:
Into a mixed solution of 8 g of fuming nitric acid and 24 g of acetic anhydride, kept at a temperature of -5° to 10° C. was added dropwise 6 g of (R)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one ([α]D24 : -7.81° (C=1.07, in chloroform), (R)-isomer/(S)-isomer=77.4/22.6). Thereafter, with the same operations as in Example 1, 7.50 g of crude (R)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25].Cl>>[CH2:23]([N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3o2)cc1
Reactant: CCCNCCC
Agent: Cl
Product: CCCN(CCC)CCCOc1ccc(/C=C/c2nc3ccccc3o2)cc1
Yield: 40 %

Procedure:
The title compound was prepared as described in Example 8 starting with (C) of Example 8 (2.0 g, 6.4 mmol) and using dipropylamine in place of dibutylamine to produce 1.2 g (40% yield) of the title compound as the HCl salt, mp 172°-173° C. IR(KBr): 3400, 1600 cm-1. MS: 379(MH+). 1H NMR (CDCl3): δ 8.48-6.95 (m, 10H), 4.19 (t, J=5.1 Hz, 2H), 3.21 (m, 6H), 2.49-0.91 (m, 12H).
Reaction SMILES: C([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1)=O.C1(P(=[CH:45][CH:46]=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(C)C=CC=CC=1>>[O:47]=[CH:46][CH:45]=[CH:48][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Reactant: Cc1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC=O)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
A stirred suspension of compound XI (4.00 g, 11.75 mmol), (triphenylphosphoranylidene)-acetaldehyde (3.60 g, 11.83 mmol) in anhydrous toluene (100 ml) was heated at 80° C. under nitrogen. After 2 days, the reaction mixture was concentrated and directly purified by flash chromatography on silica gel (AcOEt/hexane:30/70) to afford the title compound XVI (3.70 g, 10.10 mmol, 86% yield) as a yellow sticky solid (slightly contaminated with the diene). 1H NMR (300 MHz, CDCl3) δ(ppm): 9.75 (d, J=7.8 Hz, 1H), 9.49 (bs, 1H), AB system (δA=8.03, δB=7.65, J=8.4 Hz, 4H), 7.85–7.72 (m, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.33–7.05 (m, 3H), 7.05–6.90 (m, 1H), 6.78 (dd, J=15.6, 7.8 Hz, 1H), 1.53 (s, 9H).
Reaction SMILES: [CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5](/[CH:6]=[CH:7]/[CH2:8][C:9]3[S:10][CH:11]=[CH:12][C:13]=3[S:14](N3C=CC=C3)(=[O:16])=[O:15])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].S(Cl)([Cl:31])(=O)=O>C(O)(C)C>[Cl:31][S:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[CH2:8]/[CH:7]=[CH:6]/[C:5]1[CH:22]=[CH:23][C:24]2[O:25][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1ccsc1C/C=C/c1ccc2c(c1)OCO2)n1cccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(Cl)c1ccsc1C/C=C/c1ccc2c(c1)OCO2

Procedure:
3-Chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene was prepared in the same manner as described in Example 15E from N-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole by basic hydrolysis (using isopropanol and potassium hydroxide) to the corresponding potassium sulfonate (100%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 31% overall yield.
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9](OC(=O)C)[CH2:10][CH2:11][C:12]([CH3:14])=[CH2:13])[CH2:3][O:4]C(=O)C.Cl.CC(CC(O)=O)=O>O>[CH3:1][C:2](=[CH:8][CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH:3]=[O:4]
Reactant: C=C(C)CCC(C=C(C)COC(C)=O)OC(C)=O
Agent: CC(=O)CC(=O)O
Agent: Cl
Solvent: O
Product: CC(C)=CCCC=C(C)C=O
Yield: 65 %

Procedure:
A mixture of 11 parts of 2,7-dimethyl-1,4-diacetoxyocta-2,7-diene, 35 parts of water and 4.3 parts by volume of 1N hydrochloric acid (0.1 equivalent of HCl, based on 1 mole of the diacetate) is refluxed for 4 hours. An aldehyde/water mixture is then taken off, as described in Example 1. The resulting organic phase is fractionally distilled, and 4.3 parts (65% of theory) of 2,7-dimethylocta-2,6-dienal of boiling point 80°-82° C./16 mbar, nD20 =1.4776, are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:24])([F:23])[F:25])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(3,4-Dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.38) (0.4 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as light brown foam (0.41 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2](=[O:27])[C@H:3]([NH:8][C:9]1[CH:18]=[C:17]([C:19]#[N:20])[C:12]([C:13](OC)=[O:14])=[C:11]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[N:10]=1)[CH2:4][CH:5]([CH3:7])[CH3:6]>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH3:6][CH:5]([CH3:7])[CH2:4][C@@H:3]([NH:8][C:9]1[N:10]=[C:11]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[C:12]2[C:13](=[O:14])[NH:20][CH2:19][C:17]=2[CH:18]=1)[C:2]([NH2:1])=[O:27]
Reactant: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1-c1cnn(C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](Nc1cc2c(c(-c3cnn(C)c3)n1)C(=O)NC2)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A mixture of (R)-methyl 6-(1-amino-4-methyl-1-oxopentan-2-ylamino)-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (20.3 mg, 0.055 mmol) and palladium hydroxide (10 mg, 0.094 mmol) in MeOH (2 mL) and HOAc (2 mL) was stirred at RT for 3 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 (20 mL) and EtOAc (20 mL) for 12 h. The mixture was extracted with EtOAc (2×20 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (DM1020, EtOAc/MeOH=15/1-10/1) to give the title compound as a white solid (10.2 mg, 54%). 1H-NMR (DMSO-d6) δ ppm 0.88-0.95 (m, 6H), 1.52-1.60 (m, 2H), 1.73-1.76 (m, 1H), 3.88 (s, 3H), 4.21 (s, 2H), 4.48 (br s, 1H), 6.43 (s, 1H), 6.90 (s, 1H), 7.03 (br s, 1H), 7.42 (s, 1H), 8.01 (s, 1H), 8.41 (s, 1H), 8.92 (s, 1H). [M+H] calc'd for C17H23N6O2, 343. found, 343.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(O[CH2:21][C@@H:22]([OH:32])[CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1.C([Li])CCC>C1COCC1.CCOC(C)=O>[OH:32][C@@H:22]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)COCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC(C[C@@H](O)COCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
Phenylacetonitrile (4.59 g, 39.2 mmol) and (2S)-2-hydroxy-3-[(phenylmethyl)oxy]propyl 4-methylbenzenesulfonate (13.20 g, 39.2 mmol, 1 eq) were dissolved in 50 mL THF, cooled to −78° C., and treated with 2.5M butyllithium in hexanes (35 mL, 86.3 mmol, 2.2 eq) added dropwise over 30 min. The reaction mixture was stirred 4 h at −78° C., allowed to warm to ambient temperature and stirred an additional 16 h. The reaction mixture was diluted with EtOAc, washed successively with water and brine, dried over MgSO4, filtered and concentrated to give the diastereomeric product as an orange oil in quantitative yield which was carried on without purification. ES-LCMS m/z 304.33 (M+Na).
Reaction SMILES: C(O[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15])[CH2:10][N:9]([C:18](=O)[C:19](F)(F)F)[CH2:8][CH2:7]2)C.[F-:24].[K+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:24][C:4]1[CH:5]=[CH:6][C:11]([S:14]([C:13]2[C:4]([N:9]([CH3:10])[CH3:8])=[CH:5][C:6]3[CH2:7][CH2:8][N:9]([CH3:10])[CH2:18][CH2:19][C:11]=3[CH:12]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: [F-]
Reactant: CCOc1cc2c(cc1S(=O)(=O)Cl)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCc2cc(N(C)C)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Yield: 173.9 %

Procedure:
To a solution of 6-ethoxy-2-(2,2,2-trifluoro-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (0.34 g, 0.92 mmol) in acetonitrile (3.8 mL) was added potassium fluoride (0.28 g, 4.8 mmol) and 18-crown-16 (1 crystal). The mixture was stirred at room temperature overnight before addition of aqueous sodium bicarbonate to pH 8. The resulting mixture was extracted with ethyl acetate, dried over MgSO4 and evaporated to dryness yielding the subtitled compound as a white solid (0.29 g). MH−354. 1H NMR δ (CDCl3) 1.43-1.53 (3H, t), 2.95-3.07 (2H, m), 3.80-3.93 (2H, m), 4.14-4.26 (2H, m), 4.70-4.80 (2H, d), 6.82-6.90 (1H, d), 7.68-7.75 (1H, d).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].[CH3:16][C:17]1([CH3:32])[CH2:22][CH2:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH2:18]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:20]2[CH2:21][CH2:22][C:17]([CH3:32])([CH3:16])[CH2:18][CH:19]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
A solution of 177 mg (0.604) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid methylamide (as prepared in Example 30, step (c)) in toluene (5 mL) and EtOH (2.5 mL) was treated with 157 mg (0.664 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 2.40 mL (4.83 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 70.0 mg (0.0604 mmol) of Pd(PPh3)4, and heated to 80° C. for 17 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×10 mL). The aqueous layer was extracted with EtOAc (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 65.0 mg (33%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 6.90 (dd, 1H, J=8.0, 2.0 Hz), 6.85 (d, 1H, J=2.0 Hz), 6.63 (d, 1H, J=8.0 Hz), 5.65-5.59 (m, 1H), 5.00-4.91 (m, 1H), 4.06-3.97 (br s, 2H), 3.26-3.18 (m, 2H), 2.93-2.85 (m, 2H), 2.67 (d, 3H, J=5.2 Hz), 2.29-2.21 (m, 2H), 2.18 (s, 2H), 2.02-1.96 (m, 2H), 1.58-1.50 (m, 2H), 1.02 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33].CCOC(C)=O.CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:32]([F:35])([F:33])[F:34])[CH:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 eq) in anhydrous DMF is added NaH (1.1 eq) at room temperature. After 5 minutes, 1-chloro-4-chloromethyl-2-trifluoromethyl-benzene (1.1 eq) in DMF is added. The resulting mixture is stirred for 30 minutes. After aqueous work up, flash column chromatography (10% EtOAc/hexane) gave 4-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester. [MS: (ES+) 490.3 (M+1)+].
Reaction SMILES: [Si]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])(C(C)(C)C)(C)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH2:38]([O:45][CH:46]([CH3:49])[CH2:47][NH2:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1>[OH:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:20]([NH:48][CH2:47][CH:46]([O:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:49])=[O:22]
Reactant: CC(CN)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(CNC(=O)Nc1ccc([N+](=O)[O-])cc1O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
To a solution of 2-tert-butyldimethylsilyloxy-4-nitroaniline (300 mg, 1.125 mmol) in toluene (10 mL), triphosgene (126 mg, 0.45 mmol) and triethylamine (0.195 mL, 1.35 mmol) were added. The reaction mixture was stirred at 80° C. for 3 hours. Then it was cooled to room temperature and all solvent was evaporated. The residue was dissolved in DMF (1 mL) and 2-benzyloxypropylamine (185.6 mg, 1.125 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. Chromatography of the resulting liquid on silica gel (50% Ethyl acetate/Hexane) gave desired product (160 mg, 41%). EI-MS m/z 346.4 (M+). mp: 64.6-65.2° C.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.C(N)[C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1.NC1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>[OH-].[Na+]>[CH2:9]([NH:8][C:6](=[O:7])[NH:3][CH2:2][C:1]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=1)[C:10]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCc1ccccc1)NCc1ccc(C(=O)O)cc1
Yield: 93.2 %

Procedure:
N,N-carbonyldiimidazole (1.62 g, 10 mmol), benzyl amine (1.07 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide solution are used according to the method for the production of compound III in Method two to obtain 2.65 g of 4-[(3-benzylureido)methyl]benzoic acid (intermediate M-32) as a white solid, with a yield of 93.0%.
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1.B.C1COCC1>FC(F)(F)C(O)=O.O1CCCC1>[CH2:1]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c(c1)cc1n2CCCNC1
Agent: B
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc2c(c1)CC1CNCCCN21
Reaction time: 0.17 h

Procedure:
70 milligrams of 2,3,4,5-tetrahydro-1H-[1,4]-diazepino [1,2-a]indole (prepared as described in U.S. Pat. No. 3,867,374) was dissolved in 3 milliliters of trifluoroacetic acid and the mixture was stirred for 10 minutes under nitrogen. Thereafter, 1.5 milliliters of a 1 M solution of BH3.THF in tetrahydrofuran was added dropwise with stirring and the resulting mixture stirred for 40 minutes to obtain a 2,3,4,5,11,11a-hexahydro-1H-[1,4]-diazepino[1,2-a]indole product in the reaction mixture. Water (0.5 milliliter) then was added dropwise to the mixture cooled in an ice bath, followed by 10 percent NaOH until pH tested about 9 (pH test paper). The alkaline solution was extracted with methylene chloride and the methylene chloride solution washed with saturated sodium chloride solution and dried over potassium carbonate. The dried solution was filtered to remove the drying agent and evaporated in vacuo to obtain 60 milligrams (85 percent yield) of 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[ 1,2-a]indole product as an oil having NMR and mass spectra appropriate for the compound. The hydrochloride salt of the product melted 238°-240° C.