Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH3:18])[CH:12]=1.[H][H]>[Pt](=O)=O.C(O)(=O)C>[CH3:18][C:13]1[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH:16]=[C:15]([CH3:17])[N:14]=1
Reactant: Cc1cc(-c2cc([N+](=O)[O-])ccc2F)cc(C)n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(N)ccc2F)cc(C)n1

Procedure:
4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine, 180 g, was divided into four equal portions and each portion was reduced separately as follows. A mixture containing 45 g of 4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine, 200 ml of acetic acid and 800 mg of platinum dioxide was catalytically hydrogenated until hydrogen uptake ceased, about 4 hours with little hydrogen uptake the last thirty minutes. The catalyst was filtered off, washed with 300 ml of water, and the filtrate made basic by adding aqueous ammonium hydroxide. The solution was cooled to yield a oily material which solidified. The solid was collected, washed with water and dried to yield the desired amine. The remaining three 45 g portions of 4-(2-fluoro-5-nitrophenyl)-2,6-dimethylpyridine were reduced in the same way and the combined amine products were dissolved in 600 ml of concentrated hydrochloric acid and heated on a steam bath with stirring for 4 and 1/2 hours and then treated with decolorizing charcoal and filtered. The filtrate was made basic by adding aqueous ammonia and the resulting mixture was chilled to yield an oil which crystallized. The crystalline material was collected, washed with water and dried in an oven to yield 164.9 g of gummy solid. The solid was dissolved in ether containing 5% methanol and the solution was filtered through silica gel to remove the gummy impurities. The ether-methanol solvent of the filtrate was distilled off in vacuo and the residue was recrystallized from ether-isopropyl alcohol to yield 80.9 g of 3-(2,6-dimethyl-4-pyridinyl)-4-fluorobenzeneamine, m.p. 142°-145° C. Concentration of the mother liquor yielded another 43.4 g of the product, m.p. 141°-144° C., thereby giving a total yield of 82%.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>N1C=CC=CC=1>[N:28]1([C:33]([N:24]2[C:23](=[O:25])[O:22][N:21]=[C:20]2[C:16]2[CH:15]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:19]=[CH:18][N:17]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: O=C(Cl)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(N1CCCC1)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 15 h
Yield: 63.4 %

Procedure:
To 1 ml of pyridine were added 0.3 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.26 g of 1-pyrrolidinecarbonyl chloride was added at room temperature. After stirring for 15 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.27 g of 4-(1-pyrrolidinecarbonyl)-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (15)).
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.N([O-])=[O:15].[Na+].S([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>S(=O)(=O)(O)O>[OH:15][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)C(=O)CCCC2
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCCCc2ccc(O)cc21
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
To a solution of 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.53 g) in 10% sulfuric acid (130 ml) was added sodium nitrite (4.9 g) and sodium sulfite (694 mg) under ice-cooling. After being stirred for 20 minutes at this temperature, to the reaction mixture was added toluene (100 ml), stirred at the room temperature for 18 hours and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.08 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1(C)C=CC=CC=1.CN(C=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12]
Reactant: Oc1ncnc2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Oc1ncnc2ccc(-c3ccccn3)cc12
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Preparation D12, Step 2: A mixture of 6-bromoquinazolin-4-ol (173 mg, 0.77 mmol) and 2-tributylstannylpyridine (850 mg, 2.30 mmol) in toluene (10 mL), plus a few drops of DMF to improve solubility, was degassed under vacuum/argon, then a catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added, the mixture was degassed again, and then heated at reflux for 4 h. The reaction was cooled to room temperature, and some solids were removed by filtration. Analysis by LC/MS indicated that the desired product was present in both the solids and the filtrate. The solids were slurried in 8:2 methylene chloride/methanol, the mixture was filtered, the filtrate was combined with the original filtrate, and this mixture was concentrated in-vacuo. The residue was purified over silica gel, eluting with 50% EtOAc/hexanes, 75% EtOAc/hexanes, 100% EtOAc, 5% MeOH/EtOAc, to yield 106 mg of 6-(pyridin-2-yl)quinazolin-4-ol as a colorless solid. MS (ES+)=224 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([NH:20][CH:30]4[CH2:32][CH2:31]4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2cc(NC3CCOCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccnc(Cl)c1)c1cnc2c(NC3CC3)cc(NC3CCOCC3)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A solution of N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (7 mg, 0.013 mmol) in DCM (1 mL) was treated with TFA (0.5 mL, 6.49 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=35.169 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.5 mg, 35.9%). 1H NMR 400 MHz, DMSO-D6) δ ppm 11.40 (1H, s), 8.38 (1H, d, J=5.54 Hz), 7.97 (1H, s), 7.75 (1H, s), 7.70 (1H, d, J=5.79 Hz), 7.65 (1H, s), 7.10 (1H, d, J=6.55 Hz), 6.00 (1H, s), 3.85-4.06 (3H, m), 1.93-2.08 (2H, m), 1.43-1.61 (2H, m), 0.71-0.81 (2H, m, J=5.54 Hz), 0.57-0.68 (2H, m). HPLC Rt=4.160 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=428.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N)C.C(N(CC)CC)C>CN(C=O)C>[CH2:37]([NH:39][C:29]([CH2:28][C@@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:11]4)[C:27]=3[C:26]1=2)=[O:31])[CH3:36]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)C[C@@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
A 25-mL round-bottom flask was charged with intermediate 22.4 (200 mg, 0.43 mmol, 1.00 equiv), HOBt (90 mg, 0.67 mmol, 1.54 equiv), EDCI (191 mg, 1.00 mmol, 2.31 equiv), ethanamine hydrochloride (45 mg, 0.55 mmol, 1.27 equiv), triethylamine (135 mg, 1.34 mmol, 3.08 equiv) and 10 mL of distilled DMF. The resulting solution was stirred for 4 h at room temperature under nitrogen. The reaction was then quenched with water and extracted with 3×25 mL of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to provide the desired tert-butyl N-(4-[[(3S)-3-[(ethylcarbamoyl)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (24.1, 165 mg, 78%) as a white solid. MS: m/z 470 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 8 h
Yield: 82 %

Procedure:
1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine from a separate batch (0.257 g, 0.72 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.165 g, 0.043 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.194 g, 0.59 mmol, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 6.54 (s, 2H), 3.80 (s, 3H), 3.30-3.37 (m, 2H), 3.07 (s, 3H), 2.91-2.98 (m, 6H), 2.82-2.90 (m, 4H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[C:14](Cl)(Cl)=[O:15]>>[N:13]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([F:11])([F:10])[F:12])=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)ccc1C(F)(F)F
Product: COc1cc(N=C=O)ccc1C(F)(F)F

Procedure:
4-Isocyanato-2-methoxy-1-trifluoromethyl-benzene was prepared by reaction of 3-methoxy-4-trifluoromethyl-phenylamine with phosgene following the procedure of step 6 of Example 3.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[CH3:42][O:41][C:39](=[O:40])[NH:30][C:27]1[CH:28]=[N:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-ylamine (80 mg, 0.202 mmol), CH2Cl2 (0.5 mL), triethylamine (37 μL, 0.227 mmol), and methyl chloroformate (17 μL, 0.222 mmol) are combined and stirred at room temperature. Reaction complete in less than 15 minutes. Concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (39 mg, 42%).
Reaction SMILES: C([S:8][CH2:9][C:10]([CH2:16][S:17]CC1C=CC=CC=1)([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])C1C=CC=CC=1.N.[Na].[Cl-].[NH4+]>C(OCC)C.CO>[OH:12][CH2:11][C:10]([CH2:13][CH2:14][CH3:15])([CH2:16][SH:17])[CH2:9][SH:8]
Reactant: CCCC(CO)(CSCc1ccccc1)CSCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: CCCC(CO)(CS)CS

Procedure:
2,2-Di-(benzylthiomethyl)pentan-1-ol (8.0 g.) in dry diethyl ether (150 ml) was added to liquid ammonia (500 ml) which was stirred under nitrogen at -70°. Sodium (8.0 g.) was added in small pieces and the mixture was stirred at -70° for 3 hours. The mixture was allowed to warm to 20° and solid ammonium chloride (20 g.) was added. This was followed by careful addition of methanol (100 ml) to destroy excess sodium. Water (200 ml) was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. 2-Hydroxymethyl-2-n-propylpropan-1,3-dithiol was obtained as a colourless oil (4.6 g.).
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][NH2:28].Cl>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][NH:28][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1ccccc1F
Agent: Cl
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccccc4F)CC3)cc2o1

Procedure:
Coupling of ketone 5 and 3-(2-fluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-{trans-4-[3-(2-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (1.7 g, 45%) as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.86 (s, 2H), 7.34 (t, J=8 Hz, 1H), 7.35-7.26 (m, 1H), 7.19-7.15 (m, 3H), 7.02-6.97 (m, 2H), 3.10-3.03 (m, 1H), 2.98-2.92 (m, 2H), 2.72 (dd, J=8, 8 Hz, 2H), 2.57-2.50 (m, 1H), 2.18-2.13 (m, 2H), 1.98-1.92 (m, 2H), 1.89-1.85 (m, 2H), 1.57-1.46 (m, 4H).
Reaction SMILES: [Li]CCCC.[C:6]([O:10][C:11](=[O:21])[NH:12][C:13]1[CH:14]=[N:15][C:16]([Cl:20])=[C:17]([F:19])[CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.[I:30]I.Cl>C(OCC)C.C1COCC1>[C:6]([O:10][C:11](=[O:21])[NH:12][C:13]1[CH:14]=[N:15][C:16]([Cl:20])=[C:17]([F:19])[C:18]=1[I:30])([CH3:9])([CH3:7])[CH3:8]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)c(F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)c(F)c1I
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
nBuLi (107 mL, 2.5 M in hexanes, 268 mmol) was added dropwise to a cooled (−78° C.) solution of (6-chloro-5-fluoro-pyridin-3-yl)-carbamic acid tert-butyl ester (22 g, 89.2 mmol) and N,N,N′,N′-tetramethylethylenediamine (40.5 mL, 268 mmol) in anhydrous diethyl ether (400 mL) under an argon atmosphere, ensuring that the internal temperature of the reaction was maintained below −60° C. On complete addition, the reaction mixture was allowed to warm to −20° C. and stirred for 90 minutes. The reaction mixture was cooled to −78° C. and a solution of iodine (70 g, 280 mmol) in THF (125 mL) was added dropwise over 15 minutes. The reaction mixture was allowed to gradually warm to ambient temperature and stirred overnight. The reaction mixture was poured onto 1M HCl (200 mL) and crushed ice (50 g) and the aqueous phase was extracted with ethyl ether (2×200 mL). The combined organic layer was washed with water (200 mL), aqueous potassium carbonate solution (150 mL), aqueous sodium thiosulfate solution (150 mL), and brine (150 mL), dried (Na2SO4), filtered and concentrated in-vacuo to afford a residue. The resultant residue was triturated with ethanol and the resultant solid was collected by filtration, washed with pentane and dried in-vacuo to afford the title compound as a white solid (27.2 g, 82%). The trituration liquors were concentrated and purified by flash chromatography (silica: toluene to 5% ethyl acetate/toluene) to afford an additional batch of the title compound as a white solid (4.0 g, 12%). Total yield=31.2 g, 94%. 1H NMR (400 MHz, CDCl3): 8.82 (s, 1H), 6.71 (s, 1H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([N+:11]([O-])=O)=[C:6]([NH2:14])[CH:5]=1>CCO.[Pd]>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([NH2:14])[CH:5]=1
Reactant: COCc1cc(N)c([N+](=O)[O-])c(N)n1
Agent: [Pd]
Solvent: CCO
Product: COCc1cc(N)c(N)c(N)n1
Reaction time: 2 h

Procedure:
6-Methoxymethyl-3-nitro-pyridine-2,4-diamine (455 mg, 2.29 mmol) is dissolved in EtOH (50 mL) and 10% Pd/C (50 mg) is added. The mixture is hydrogenated at 50 psi for 2 hours. The reaction mixture is filtered through Celite and the Celite bed washed with EtOH (25 mL). The solvent is removed under reduced pressure to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:23](=[O:25])[CH3:24])OC(=O)C)(=O)C.[Na+]>>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:6][C:5]3[O:25][C:23]4[C:24](=[N:7][CH:1]=[CH:2][CH:3]=4)[CH:4]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1ccc(N2CCN(Cc3cc4ncccc4o3)CC2)cc1

Procedure:
The product from Example 35B, 1-phenylpiperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.78 (br, 4H), 3.28 (br, 4H), 3.85 (s, 2H), 6.89 (m, 4H), 7.20 (dd, J=4.75, 8.14 Hz, 1H), 7.26 (m, 2H), 7.73 (d, J=8.14 Hz, 1H), 8.54 (br, 1H); MS (DCI/NH3) m/z 294.2 (M+H)+; Anal Calcd for C18H19N3O: C, 73.69; H, 6.53; N, 14.32. Found: C, 72.19; H, 6.43; N, 14.09.
Reaction SMILES: [OH:1][C:2]([P:18](=[O:21])([OH:20])[OH:19])([P:14](=[O:17])([OH:16])[OH:15])[CH2:3][CH:4]1C[CH2:8][CH2:7][CH2:6][CH:5]1[S:10]C(=O)C.OC(P(=O)(O)O)(P(=O)(O)O)CC1CCCCC1S>>[OH:1][C:2]([P:18](=[O:21])([OH:19])[OH:20])([P:14](=[O:17])([OH:16])[OH:15])[CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[SH:10]
Reactant: CC(=O)SC1CCCCC1CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: O=P(O)(O)C(O)(CC1CCCCC1S)P(=O)(O)O
Product: O=P(O)(O)C(O)(CC1CCCC1S)P(=O)(O)O

Procedure:
Using essentially the same procedure as described in Example K, [1-hydroxy-2-(2-(acetylthio)cyclohexyl)-ethylidene]bis[phosphonic acid], prepared as described in Example L hereinbefore, is converted to [1-hydroxy-2-(2-mercaptocyclohexyl)-ethylidene]bis[phosphonic acid].
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(Oc1ccc(O)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 60.4 %

Procedure:
A mixture of 4-hydroxy-3-nitrophenyl benzoate (48.8 g, 0.19 mol), methyl bromoacetate (28.8 g, 0.19 mol), anhydrous potassium carbonate (33.8 g, 0.24 mol) and acetone (700 mL) was heated at reflux for 24 h. The mixture was evaporated in vacuo and the residue partitioned between aqueous NaOH (1 M, 1 L) and dichloromethane (3×200 mL). The combined organic extracts were washed with aqueous NaOH (1 M, 500 mL), water (500 mL) and brine (250 mL), then dried (Na2SO4) and evaporated in vacuo to give a solid. Crystallisation from methanol following decolourisation with charcoal gave the title compound (38 g, 61%) as pale yellow needles.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.C(N(S(F)(F)[F:16])CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:16][CH2:1][S:2][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CS(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: FCSc1ccccc1
Reaction time: 48 h
Yield: 85.8 %

Procedure:
To a stirred solution of (methylsulfinyl)benzene (23.0 g, 164 mmol) in chloroform (80 mL) under argon at room temperature was added diethylaminosulfur trifluoride (43.0 mL, 328 mmol) dropwise and the reaction mixture was stirred for 2 days at this temperature then at 60° C. overnight. The mixture was added dropwise to a stirred solution of saturated aqueous sodium hydrogen carbonate at 0° C. then extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to give (fluoromethyl)(phenyl)sulfane (20.0 g, 86%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Reaction time: 4 h

Procedure:
A solution of 1.98 g of 3,4-dichlorophenyl acetic acid and 1.56 of of carbonyldiimidazole in 17 ml of tetrahydrofuran was stirred at 20° to 22° C. for one hour and then, 1.679 g of [4aRS(4aα, 8α, 8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline (preparation given at the end of Example 4) were added in solution in 5 ml of tetrahydrofuran. The solution was stirred for 4 hours at 20° to 22° C. and the tetrahydrofuran was eliminated under reduced pressure at less than 45° C. The residue was triturated in 15 ml of ether and in 5 ml of a saturated solution of sodium bicarbonate, then separated and rinsed, first with water then with ether. After drying under reduced pressure, 2.320 g of [4aRS(4aα, 8α, 8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline melting at 138° C. were obtained.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[S:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)CCc1sc(Cl)nc1-c1ccccc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of methyl 3-(2-chloro-4-phenyl-5-thiazolyl)propionate (380 mg), 4-hydroxythiophenol (341 mg), potassium carbonate (373 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and-concentrated to give methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (464 mg, yield 93%) as colorless crystals. The crystals were recrystallized from toluene-hexane. melting point: 153–155° C.