Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC(CCC(OCC)=O)CC1)=O)C1C=CC=CC=1.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[CH2:41][CH2:40]3)=[O:38])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37]([N:39]3[CH2:40][CH2:41][CH:42]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:43][CH2:44]3)=[O:38])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Agent: CCOC(=O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1

Procedure:
In a similar manner to that described in Example 103, ethyl 3-(1-benzyloxycarbonylpiperidin-4-yl)propanoate was converted to ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate. The following intermediates were isolated: ethyl-1-bromoacetylpiperidin-4-ylpropanoate. NMR(CDCl3): δ, 1.1-1.4(2H,m); 1.25(3H,t); 1.5-1.7(3H,m); 1.7-1.9(2H,t); 2.3(2H,t); 2.5-2.7(1H,td); 3.0-3.2(1H,td); 3.8-4.0(2H,d+1H,m); 4.15(2H,q); 4.55(1H,m); m/e 306/308(M+H)+, ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate. m.p. 90°-92° C.; NMR(d6DMSO): δ, 0.85-1.0(1H,m); 1.05-1.2(1H,m); 1.2(3H,t); 1.5(3H,m); 1.7(2H,m); 2.3(2H,t); 2.5(4H,br.s); 2.8-3.0(1H,t); 3.1(1H,d); 4.05(2H,q+1H,m); 4.3(1H,d); 6.8(2H,d); 8.15(2H,d); m/e 389 (M+H)+ 411 (M+Na)+ ; calculated for C21H32N4O3 ; C, 64.9; H, 8.3; N, 14.4; found: C, 65.0; H, 8.5; N, 14.4%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:11][CH2:10][C:9]1=[O:30].C([O:34][CH2:35][CH3:36])(=O)C>CN(C)C=O>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:12]3[C:19](=[O:29])[C:20]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:36]4[C:35]3=[O:34])[C:9](=[O:30])[CH2:10][CH2:11]2)=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2N1CCCCCCCl
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCN1C(=O)CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-chlorohexyl)-5-(4-nitrobenzoyl) -1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (675 mg) and potassium phthalimido (291 mg) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 8 hours. The mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 5-(4-nitrobenzoyl)-1-(6-phthalimidohexyl) -1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (758 mg).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>CC(O)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:31]5[CH2:32][O:33]5)=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 45 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To a solution of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (2.32 g, 4.91 mmol) in 2-propanol (60 mL) and 3 N aq. NaOH (6 mL), (R)-epichlorohydrine (4.55 g, 49.1 mmol) is added. The mixture is stirred at 45° C. for 6 h before it is diluted with EA (100 mL) and washed twice with 1 N aq. NaOH (2×15 mL) followed by brine (25 mL). The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with heptane:EA 1:1 to give (S)-5-(2-cyclopentyl-6-methoxypyridin-4-yl)-3-(3-ethyl-5-methyl-4-(oxiran-2-ylmethoxy)phenyl)-1,2,4-oxadiazole (2.04 g) as a colourless wax; LC-MS: tR=1.52 min, [M+H]+=436.11; 1H NMR (CDCl3): δ 7.88-7.90 (m, 1H), 7.85-7.88 (m, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 4.14 (dd, J1=11.1 Hz, J2=3.1 Hz, 1H), 4.02 (s, 3H), 3.83 (dd, J1=11.1 Hz, J2=6.0 Hz, 1H), 3.40-3.44 (m, 1H), 3.19-3.29 (m, 1H), 2.94 (dd, J1=4.9 Hz, J2=4.3 Hz, 1H), 2.75-2.83 (m, 3H), 2.41 (s, 3H), 2.06-2.16 (m, 2H), 1.84-1.94 (m, 4H), 1.70-1.79 (m, 2H), 1.33 (t, J=7.5 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[C:26](OC)=[O:27])=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O.C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]2[CH2:26][OH:27])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COC(=O)C1CCCCN1C(=O)Cc1ccc(OC)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCCCC2CO)cc1OC
Yield: 80.9 %

Procedure:
2.33 g of lithium aluminum hydride was suspended into 50 ml of tetrahydrofuran and stirred. 3.94 g of methyl N-(3,4-dimethoxyphenylacetyl)piperidine-2-carboxylate was dissolved in 20 ml of tetrahydrofuran, which was dropped and, thereafter, refluxed for 30 min. After cooling with ice and decomposing the excess reagent with ethyl acetate, 2.3 ml of water, 2.3 ml of an aqueous 15% solution of sodium hydroxide and 7 ml of water were added successively and, further, anhydrous magnesium sulfate was added and stirred. Insoluble matters were filtered out and the filtrate was washed thoroughly with tetrahydrofuran. The filtrate was concentrated and purified on silica gel column chromatography (solvent: dichloromethane:methanol:concentrated aqueous ammonium=1000:100:2), to obtain 2.77 g of the above-captioned compound as white solid (yield: 81%).
Reaction SMILES: [NH3:1].Cl.CO[N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[NH:5])[NH2:1]
Reactant: N
Reactant: CON=Cc1ccc(O)c(OC)c1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=N)N)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 100 ml of anhydrous methanol and about 50 ml of liquid ammonia, was added slowly 8.7 g of 4-methoxyiminomethyl-2-methoxyphenol hydrochloride. The mixture was stirred overnight at room temperature. The colorless crystals precipitated from the reaction mixture were collected by filtration, washed thoroughly with methanol, and dried to obtain 7.4 g of 4-amidino-2-methoxyphenol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]([OH:12])[CH2:10][N:11]=2)=[CH:2]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]([O:12][C:26](=[O:27])[NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][N:11]=2)=[CH:2]1
Reactant: OC1CN=C(c2ccoc2)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccoc2)OC1c1ccccc1
Yield: 40 %

Procedure:
Working in a manner similar to that described in Example 12, but starting with (5RS, 6SR)-2-(3-furyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (2.6 g) and phenyl isocyanate (3.8 g), and after purification of the solid obtained by chromatography on a column (height: 30 cm; diameter: 4 cm) of silica (0.2-0.063 mm), eluting with a mixture of dichloroethane and ethyl acetate (90:10 by volume) and collecting 40-cc fractions, fractions 20 to 28 being combined and concentrated to dryness under reduced pressure (4 kPa) at 45° C., followed by recrystallizaiton in isopropyl ether (10 cc), (5RS, 6SR)-2-(3-furyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.55 g), m.p. 130° C., is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[N:3][CH:2]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:4]=[N:3][CH:2]=1
Reactant: Nc1cccc2cncnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cncnc12)c1ccccc1
Yield: 25.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, quinazolin-8-ylamine (Intermediate 480) (60 mg, 0.41 mmol), benzene sulfonyl chloride (94 mg, 0.53 mmol), DMAP (cat.) and pyridine (1 ml) at 150° C. for 2.5 h, gave title compound (30 mg, 54%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude compound of 4-[hydroxy(phenyl)methyl]benzoic acid (1.51 g, 6.6 mmol) in DMF (33 mL) was added tert-butyl piperazine-1-carboxylate (1.23 g, 6.6 mmol), triethylamine (3.7 mL, 26.5 mmol) and HATU (2.51 g, 6.6 mmol). The mixture was aged for 3 hours under a nitrogen atmosphere and was then poured into a saturated aqueous solution of NaHCO3. The resulting mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to a solid which was stirred in ethyl acetate at room temperature for 2 hours. The title compound was then recovered by filtration as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C(N(CC)CC)C.[CH3:33][N:34]=[C:35]=[O:36]>O1CCCC1>[CH3:33][NH:34][C:35](=[O:36])[NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5]
Reactant: CN=C=O
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,5-Dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (1.0 g) was suspended in tetrahydrofuran (10 ml). Triethylamine (0.38 ml) was added and the solution was stirred at room temperature for 15 minutes. Methyl isocyanate (0.19 ml) was added and the solution was stirred for 1 hour. The tetrahydrofuran was removed in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed with dilute hydrochloric acid, water and sodium bicarbonate solution. The organic extract was dried (Na2SO4) and evaporated. The residual solid was recrystallised from ethyl acetate/petroleum ether to yield the title compound, (1.17 g), m.p. 66°-68° C. 1H NMR (360 MHz, CDCl3) δ7.99 (1H, s), 7.52 (1H, d, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.16 (1H, t, J=8 Hz), 7.08 (1H, t, J=8 Hz), 6.96 (1H, s), 6.88 (2H, s), 6.76 (1H, s), 5.01 (2H, s), 4.83 (1H, m), 3.26 (2H, d, J=5 Hz), 2.65 (3H, s), 2.30 (6H, s). Found: C, 68.64; H, 6.36; N, 10.86. C22H25O3N3. 0.3(H2O) requires C, 68.57; H, 6.66; N, 10.90.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:10]([N:17]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccccc1C=NCc1ccccc1

Procedure:
A mixture of 5.0 mL of 2-hydroxy-benzaldehyde, 6.3 mL of benzylamine and 0.05 g of p-toluenesulphonic acid was refluxed in toluene for 2 hours using a Dean-Stark trap to remove liberated water. The volatiles were removed in vacuo yielding 10.1 g of crude 2-(benzylimino-methyl)-phenol
Reaction SMILES: COC.O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)Cl.CC(CC(C)C)=O.C(O)(=O)C>[CH:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[O:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccc(O)cc2)c(-c2ccccc2)o1
Agent: COC
Solvent: CC(=O)CC(C)C
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
Rf 0.50 silica gel 60 F254 chloroform:methylisobutylketone:acetic acid 50:50:1 A mixed melting point run with an authentic sample of the methyl ether of 4-(4-hydroxyphenyl)-5-phenyl-2-oxazolepropanoic acid (obtained from the metabolite of oxaprozin as disclosed by Janssen et al., Drug Metabolism and Disposition, 6, 495 (1978)), gave m.p. 92°-108° C., clearly demonstrating the lack of identity with the known metabolite. This, coupled with the identity of the 4'-methoxybenzoin starting material characterized the methyl ether as 5-(4-methoxy)-4-phenyl-2-oxazolepropanoic acid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH2:13]1[N:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1>C1(C)C=CC=CC=1>[N+:15]12([S:2]([N-:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])(=[O:4])=[O:3])[CH2:20][CH2:19][N:18]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2.[N:15]12[CH2:20][CH2:19][N:18]([CH2:17][CH2:16]1)[CH2:13][CH2:14]2
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[N-]S(=O)(=O)[N+]12CCN(CC1)CC2
Temperature: 3 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
Chlorosulfonyl isocyanate (45.2 Kg, 319.4 mol) was added to toluene (194.2 Kg) and the resulting solution cooled to between about 0-6° C. A solution of tert-butyl alcohol (23.6 Kg, 318.4 mol) in toluene (48.0 Kg) was then added over a period of 90 minutes, maintaining a temperature of between about 0-6° C. The mixture was then stirred until consumption of tert-butyl alcohol was complete (approximately 80 minutes). A solution of triethylenediamine (DABCO, 71.4 Kg, 636.5 mol) in toluene (293.0 Kg) was then added to the mixture over a period of 2.5 hours, maintaining a temperature of between about 0-6° C. The mixture was then warmed to 20-25° C. and stirred for 8 hours. The solid product was isolated by centrifugal filtration under a nitrogen atmosphere and washed with toluene (180.8 Kg) and then tert-butyl methyl ether (51.0 gallons) and spun until no further liquors were seen to be expelled (approximately 60 minutes). The solids were then further dried under vacuum to afford 132.9 Kg of (4-aza-1-azoniabicyclo[2.2.2]oct-1-ylsulfonyl)(tert-butoxycarbonyl)azanide-1,4-diazabicyclo[2.2.2]octane (1:1) hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]([NH:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1nnn[nH]1
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)Nc1nnn[nH]1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-phenyl-N-(1H-tetrazol-5-yl)-propionamide (prepared by reaction of N-Boc-L-phenylalanine with isobutyl chloroformate followed by 5-amino-1H-tetrazole) in DMSO to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])=[CH:5][C:4]=1[C:16]1[C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34]COC)[CH:29]=2)=[CH:24][C:23]2[C:22]([CH3:39])([CH3:38])[CH2:21][CH2:20][C:19]([CH3:41])([CH3:40])[C:18]=2[CH:17]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:16]1[C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:24][C:23]2[C:22]([CH3:39])([CH3:38])[CH2:21][CH2:20][C:19]([CH3:41])([CH3:40])[C:18]=2[CH:17]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2OCc2cccc(OCOC)c2)C(C)(C)CCC3(C)C)c1
Solvent: CCO
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCc1cccc(O)c1)C(C)(C)CCC2(C)C
Yield: 83.4 %

Procedure:
In a manner similar to that of Example 2(g) but in ethanol as solvent, starting from 1.9 g (3.4 mmol) of ethyl 3-{4-methoxy-3-[3-(3-methoxymethoxybenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]phenyl}acrylate obtained in Example 30(d), 1.38 g (79%) of the expected compound was obtained in the form of a white powder having a melting point of 131°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:11])=[CH:5][CH:4]=1.C(O)(=O)[C@@H](C1C=CC=CC=1)O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C@@H:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(C)NCc2ccccc2)cc1
Agent: O=C(O)[C@H](O)c1ccccc1
Product: COc1ccc(C[C@H](C)NCc2ccccc2)cc1
Yield: 22 %

Procedure:
A sample of 3.36 g (13.2 mmol) of the racemate 1-(4′-methoxyphenyl)-2-benzylaminopropane (42) was reacted with 2.0 g (13.2 mmol) of (R)-(−)-mandelic acid to give 740 mg (44% based on enantiomeric abundance) of the free amine after workup. 1H NMR, (CDCl3) δ□ 1.10 (d, 3H, J=6.2 Hz), 2.55-2.76 (m, 2H), 2.88-2.95 (m, 1H), 3.73-3.88 (m, 2H), 3.79 (s, 3H), 6.80 (d, 2H, J=8.7 Hz), 7.08 (d, 2H, J=8.4 Hz), 7.15-7.30 (m, 5H); MS (APCI+) m/z (rel): 256 (100); [α]D=+30.5° (c=1.1 MeOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12]([CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10](F)[C:9]=2[CH3:20])[CH2:4][CH2:3]1.[F-].[K+].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([CH3:20])=[C:10]([C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:15])[C:13]=2[F:14])[NH:26][CH:23]2[CH2:25][CH2:24]2)[CH2:4][CH2:3]1
Reactant: Cc1c(F)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(NC2CC2)c([N+](=O)[O-])c(C)c(F)c1N1CCN(C)CC1
Temperature: 100 °C
Reaction time: 23 h

Procedure:
To 2-(4-methyl-1-piperazinyl)-3,6-difluoro-4-methyl-5-nitrotoluene (1.73 g) are added anhydrous dimethyl sulfoxide (18 ml), potassium fluoride (0.53 g) and cyclopropylamine (2.2 ml) and the mixture is stirred at 100° C. for 23 hours. After cooling, the mixture is poured into ice-water, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane : methanol=40 : 1) to give 3-(4-methyl-1-piperazinyl)-4-fluoro-2,5-dimethyl-6-nitro-N-cyclopropylaniline (1.65 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:9][CH2:10][CH3:11])([CH2:6][C:7]#[N:8])=[O:5].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:25]>>[CH2:10]([O:9][P:4]([CH2:6][C:7]([NH2:8])=[S:25])(=[O:5])[O:3][CH2:2][CH3:1])[CH3:11]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC(N)=S)OCC
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A 250-mL round-bottom flask equipped with a dry-ice condenser and drying tube filled with potassium hydroxide pellets, was charged with 50.0 g (0.2822 mol) of diethyl cyanomethyl phosphonate (Aldrich Lot HY0151136Y), 79.0 mL (0.5668 mol) of triethylamine and 53.0 mL (0.6553 mol) of pyridine. To the resulting solution was added 3.3 g (0.390 mol) of hydrogen sulfide via submerged tube. The reaction flask was stoppered and stirred overnight (small samples were withdrawn, evaporated at 55° C. and 10 torr, redissolved in CDCl3 and checked by NMR spectroscopy for completion of reaction). After about 16 hours, the reaction mixture was evaporated at 55° C. and 10 torr, the crystalline residue was taken up in 200 mL of dichloromethane and the resulting solution was washed with 200 mL of a 1:1 water-saturated sodium chloride solution. The aqueous phase was reextracted with 100 mL of dichloromethane. 50 mL of 1:1 water-saturated sodium chloride solution was used to wash the first extract and then the second. The extracts were combined, dried over sodium sulfate, and evaporated to yield 50.46 g of (2-amino-2-thioxoethyl)phosphonic acid diethyl ester as an off-white, crystalline material after drying at 45° C. and 10 tort, 85% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].N>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:11]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:10]=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Br)c3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(-c4ccc(F)cc4)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 4, starting with 2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 166) in place of 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting cesium fluoride for sodium carbonate (yield: 0.62g, 62%). mp 222–225° C. 1H NMR (300 MHz, DMSO d6) δ 3.24 (s, 3H), 7.16 (m, 2H), 7.36 (m, 3H), 7.53 (m, 2H), 7.64 (m, 2H), 7.73–7.81 (m, 3H), 7.93 (m, 3H), 8.27 (s, 1H). MS (DCI/NH3) m/z 515 (M+H)+, 532 (M+NH4)+. Anal. calc. for C29H20F2N2O3S.0.25 H2O: C, 67.10; H, 3.98; N, 5.35. Found: C, 66.93; H, 3.99; N, 5.17.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)CCC>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:38]6[N:43]=[CH:42][CH:41]=[CH:40][N:39]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ncccn4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 110 °C
Yield: 17 %

Procedure:
According to the procedure described in example 8, (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 2-tributylstannylpyrimidine were heated for four hours at 110° C. to give the title compound (17% yield). 1H NMR (400 MHz, CDCl3): δ 0.32 (s, 3H), 0.83-2.87 (m, 24H), 4.47 (d, J=7.0 Hz, 1H), 5.80 (s, 1H), 7.18 (t, J=4.7 Hz, 1H), 7.28-7.31 (m, 2H), 8.32-8.35 (m, 2H), 8.79 (d, J=4.7 Hz, 2H).