Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[CH3:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]2[CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([CH:30]=[C:21]([CH3:20])[N:22]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: Cc1cn2cc(O)ccc2n1
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2nc(C)cn2c1
Yield: 13 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 2-methyl-6-hydroxyimidazo[1,2-α]pyridine obtained according to preparation 5, the desired product is obtained in the form of a white solid with a yield of 13%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:8][CH:14]=1
Reactant: Cc1ccc(C(N)=O)o1
Reactant: O=C(CCl)CCl
Product: Cc1ccc(-c2nc(CCl)co2)o1
Yield: 38 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-methyl-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-methyl-2-furyl)oxazole. The yield was 38%. Recrystallization from diethyl ether-hexane gave. Colorless needles, mp 93-94° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32]>O1CCOCC1.CCOCC>[ClH:32].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
1,1-Dimethylethyl 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboxylate (Example 1, 87 mg, 0.20 mmol) was dissolved in 1,4-dioxane (4 mL). Ether (3 mL) was added followed by addition of 4M HCl in 1,4-dioxane (3 mL) and 2M HCl in ether (3 mL). The reaction mixture was stirred at ambient temperature overnight. Ether (15 mL) was added, and the white solid was collected via filtration and washed with ether to yield 71 mg (95%) of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.98 (d, 2H, J=8.5 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.66 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 3.97 (d, 2H, J=5.8 Hz), 3.50-3.40 (m, 2H), 3.13 (s, 3H), 3.10-3.00 (m, 2H), 2.25-2.05 (m, 3H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 346 (M+H).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]([F:49])([CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([OH:48])[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH2:24]O>ClCCl>[F:22][C:23]([F:49])([CH2:26][C@H:27]([C@@H:29]1[C@:46]2([CH3:47])[C@H:32]([C@H:33]3[C@H:43]([CH2:44][CH2:45]2)[C@:41]2([CH3:42])[C:36]([CH2:37][C@@H:38]([OH:48])[CH2:39][CH2:40]2)=[CH:35][CH2:34]3)[CH2:31][CH2:30]1)[CH3:28])[CH2:24][O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15]
Reactant: C[C@H](CC(F)(F)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](CC(F)(F)COS(=O)(=O)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
The mixture of pyridine (124 μl) and trifluoromethanesulfonic anhydride (206 μl) in dichloromethane (5 ml) was stirred at -20° C. under argon atmosphere for 5 min. To this solution the alcohol (7) (400 mg, 1.02 mmol) in dichloromethane (10 ml) was added and the mixture was stirred at room temperature for 40 min. The usual work-up (dichloromethane for extraction) gave the triflate (8) (612 mg), which was used in the next step without further purification. 1H-NMR δ: 0.73 (3H, s, 18-H3), 1.00 (3H, s, 19-H3), 1.15 (3H, d, J=6 Hz, 21-H3), 3.56 (2H, m, THP), 3.85 (1H, m, 3-H), 4.50 (2H, t, J=12 Hz, 24-H2), 4.70 (1H, m, THP), 5.37 (1H, m, 6-H). 19F-NMR δ: +12.2 (3F), +41.3 (2F).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.Cl.[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1([CH2:65][CH2:66]O)[CH:64]=[CH:63][N:62]=[CH:61]1.C(O)(=O)C>C(Cl)Cl>[F:14][C:15]1[CH:34]=[C:33]([CH3:35])[C:32]([O:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:66][CH2:65][N:60]3[CH:64]=[CH:63][N:62]=[CH:61]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCCn4ccnc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Diethyl azodicarboxylate (160 mg, 1.4 mmol) was added to a solution of 4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (261 mg, 0.7 mmol), (prepared as described for the starting material in Example 22), triphenylphosphine (367 mg, 1.4 mmol) and 2-(imidazol-1-yl)ethanol (94 mg, 0.84 mmol), (J. Med. Chem. 1993, 25, 40524060), in methylene chloride (5 ml) and the mixture stirred for 1 hour at ambient temperature. Acetic acid (42 mg, 0.7 mmol) was added and the solvent was removed by evaporation. The residue was triturated with ether, the solid collected by filtration, dried under vacuum and purified by chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (250 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C@H:16]12[CH2:22][C@H:19]([NH:20][CH2:21]1)[CH2:18][N:17]2[CH2:23][C:24]1[N:25]([CH3:50])[C:26]2[C:31]([N:32]=1)=[C:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[N:29]=[C:28]([N:39]1[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]1[CH2:48][CH3:49])[N:27]=2>C(#N)C>[CH2:48]([C:40]1[N:39]([C:28]2[N:27]=[C:26]3[C:31]([N:32]=[C:24]([CH2:23][N:17]4[CH2:18][C@@H:19]5[CH2:22][C@H:16]4[CH2:21][N:20]5[C:5]([CH3:7])([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:9])[N:25]3[CH3:50])=[C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:29]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=1)[CH3:49]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)N1C[C@@H]2C[C@H]1CN2Cc1nc2c(N3CCOCC3)nc(-n3c(CC)nc4ccccc43)nc2n1C
Temperature: 80 °C
Yield: 56.7 %

Procedure:
2-Bromo-2-methylpropionic acid ethyl ester (90 μL, 0.61 mmol) was added to a solution of potassium carbonate (84 mg, 0.61 mmol) and 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (140 mg, 0.30 mmol) in anhydrous acetonitrile. The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 85:15) to afford 417 as a cream solid (100 mg, 58%). LCMS (Method I): RT=2.92 min, M+H+=588. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.29-7.23 (m, 2 H); 4.34 (m, 4 H); 4.15 (m, 2 H); 3.93-3.82 (m, 9 H); 3.64 (m, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.19 (m, 1 H); 2.81-2.63 (m, 3 H); 1.58 (m, 4 H); 1.45 (t, J=7.5 Hz, 3 H); 1.36 (m, 2 H) and 1.32-1.23 (m, 6 H)
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4](=NN)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[OH-].[K+]>C(O)COCCO>[Cl:19][C:16]1[CH:15]=[C:3]([CH2:4][C:5]2[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=2[F:11])[C:2](=[CH:18][CH:17]=1)[NH2:1]
Reactant: NN=C(c1cc(Cl)ccc1N)c1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(Cl)cc1Cc1c(F)cccc1F

Procedure:
In the manner given in Preparation 11, 2-amino-5-chloro-2',6'-difluorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 4-chloro-α-(2,6-difluorophenyl)-o-toluidine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[CH2:15])[C:6]=2[CH:16]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[CH2:15])[C:6]=2[CH:16]=1
Reactant: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCn1c(=O)nnc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 6-chloro-4-(2-propen-1-yl)-1,2,4-benzotriazin-3(4H)-one 1-oxide (see Example 60(c) for a preparation) (420 mg, 1.77 mmol) in MeOH (10 ml) was added sodium methoxide solution (25% w/v, 8.84 mmol, 1.9 ml) and then the reaction was stirred at rt for 2 h. The reaction was then treated with water (100 ml) and extracted with DCM (2×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-5% MeOH/DCM gradient, followed by trituration with diethyl ether (50 ml) to provide the desired compound as a yellow foam (205 mg, 53%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:24][CH2:23][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[CH2:22][CH2:21]1)([O-:10])=[O:9]
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
A solution of 2-fluoronitrobenzene (0.13 mL, 1.3 mmol) and 1-(4-pyridyl)piperidine-4-methylamine (242 mg, 1.27 mmol) in DMF (5 mL) was treated with potassium carbonate (175 mg, 1.3 mmol). After 16 h, the mixture was diluted with EtOAc, the organic layer was washed with water (3×), brine, dried with K2CO3, and concentrated. The residue was dissolved in 5% HOAc in MeOH and loaded onto an SCX ion exchange column. Elution with MeOH followed by 2 M NH3 in MeOH yielded 200 mg of the title compound; which was used without further purification.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(N)CN>O1CCOCC1.[Cu]I>[Br:20][C:18]1[CH:19]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[S:16][CH:17]=1
Reactant: Brc1csc(Br)c1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Yield: 63.2 %

Procedure:
(S)-Spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (471 mg, 2.58 mmol), 2,4-dibromothiophene (1.875 g, 7.75 mmole), copper (I) iodide (492 mg, 2.58 mmol), potassium carbonate (715 mg, 5.17 mmol) and ethylenediamine (170 μL, 2.58 mmol) in 1,4-dioxane (5 mL) were stirred at 110° C. overnight. The solution was allowed to cool, and then filtered, washed with aqueous ammonium hydroxide and evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a yellow solid (560 mg), m/z 343, 345 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1>>[CH:12]1([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Reactant: Nc1ccc(CCO)cc1
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(C3CCCC3)n2)cc1
Yield: 69 %

Procedure:
Following general procedure A1, 4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.100 g, 0.40 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.066 g, 0.48 mmol) to afford the title compound (0.097 g, 69%) as a white solid. MW=351.37. 1H NMR (DMSO-d6, 500 MHz) δ 9.93 (s, 1H), 7.68-7.54 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.92 (s, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.63-3.56 (m, 2H), 3.19 (quin, J=8.0 Hz, 1H), 2.70 (t, J=7.0 Hz, 2H), 2.05-1.96 (m, 2H), 1.89-1.60 (m, 6H); APCI MS m/z 352 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25])([O-:20])=[O:19]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.048 mMol 3-nitrobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2].[CH3:20][O:21][C:22]([N:24]=[C:25]=[S:26])=[O:23]>CC(C)=O>[CH3:20][O:21][C:22]([NH:24][C:25](=[S:26])[NH:19][C:6]1[CH:7]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])=[O:23]
Reactant: COC(=O)N=C=S
Reactant: CC(=O)Nc1ccc(SCc2ccccc2)cc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(SCc2ccccc2)ccc1NC(C)=O
Reaction time: 8 h

Procedure:
1.6 G. of 1-acetamido-2-amino-4-benzylthiobenzene is dissolved in 32 ml. acetone and treated with 2.4 g. methoxycarbonylisothiocyanate. The mixture is left overnight at room temperature, then concentrated and the residue triturated with ether. Pure 1-(3-methoxycarbonyl-2-thioureido)-2-acetamido-5-benzylthiobenzene is obtained by recrystallization from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[N:12]1([C:18]([S:20][CH3:21])=[S:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:15]1[CH2:16][CH2:17][N:12]([C:18]([S:20][CH3:21])=[S:19])[CH2:13][CH2:14]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
To 30 ml of ethanol were added 3.43 g (20 mmol.) of 2-nitrobenzyl chloride,3.52 g (20 mmol.) of methyl 1-piperazinecarbodithioate, and 2.12 g (20 mmol.) of sodium carbonate. The mixture was then stirred for 4 hours at room temperature and futher stirred overnight at 50°-60 ° C.Ethanol was distilled off under reduced pressure, and the residue was extracted using water and chloroform. The organic solvent portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was crystallized from 40 ml of ether,collected by filtration and washed with ether, to give 4.3 g of the desiredcompound, as a yellow crystalline product, yield 69.1%.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12]1)[CH:7]([CH3:9])[CH3:8].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:17]1([S:23]([N:15]2[CH:11]([O:10][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:12]=[CH:13][C:14]2=[O:16])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)COC1C=CC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)COC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
13.2 cm3 of a 1.6M solution of n-butyllithium in hexane is added to a solution cooled to -45° C. of 3.3 g of 1,5-dihydro-5-isobutyloxy-2H-pyrrol-2-one obtained at stage A, in 80 cm3 of tetrahydrofuran. The mixture is agitated for 30 minutes at -45° C./-40° C., then a solution of 3.74 g of benzenesulphonyl chloride in 12 cm3 of tetrahydrofuran is added. The temperature is allowed to return to the ambient over 2 hours. After evaporating to dryness, the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1), and 1.7 g of the expected product is obtained. m.p. 82°-83° C., crystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.CCCCCCC.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=4[O:15][N:14]=3)=[C:9]([CH2:24][CH2:25][CH3:26])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 5 (1.0 g, 2.5 mmol) in dichloromethane (15 mL) cooled at 0° C. was added a solution of boron tribromide in heptane (1.0 M, 5.0 mL, 5.0 mmol). The reaction was stirred at 25° C. for 30 min and then poured into aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[N:10]=[CH:9][C:8]([N:11]=CN(C)C)=[CH:7][N:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CCOCC>O1CCOCC1>[CH2:17]([O:16][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][N:10]=1)[CH3:18]
Reactant: CCOC(OCC)c1ncc(N=CN(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(OCC)c1ncc(N)cn1
Yield: 94.1 %

Procedure:
2-Diethoxymethyl-5-(dimethylaminomethyleneamino)pyrimidine (6.3 g, 25 mmol) and a 5% aqueous solution of potassium carbonate (69 ml) in dioxane (40 ml) were heated at reflux for 6 hours. The reaction mixture was concentrated to a yellow solid which was triturated with ether to 2-diethoxymethyl-5-aminopyrimidine as a cream solid (4.64 g, 92% yield):
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:25])[CH2:6][CH2:5]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCc2c(ccc(Br)c2C2CC2)N1
Solvent: Cc1ccccc1
Product: S=C1CCc2c(ccc(Br)c2C2CC2)N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-5-cyclopropyl-3,4-dihydroquinolin-2(1H)-one (147-6; 0.8 g, 0.0030 mol) in toluene (10 mL) was added Lawesson's reagent (1.2 g, 0.003 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 284.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:31])[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:31])[CH2:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: NNC(=O)CSc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(SCC(=O)NN=C2C(=O)Nc3ccc(I)cc32)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 61 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-[(2-hydrazino-2-oxoethyl)thio]-3-nitrobenzenesulfonamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 24 mg of the title compound (61%) as a yellow solid in 99.3% purity by HPLC (Rt: 3.51, 4.17, gradient of 8 rnin, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][C:26]1([CH3:35])[CH2:31][CH:30]([C:32](O)=[O:33])[CH2:29][CH2:28][O:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:32]([CH:30]3[CH2:29][CH2:28][O:27][C:26]([CH3:35])([CH3:25])[CH2:31]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: CC1(C)CC(C(=O)O)CCO1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCOC(C)(C)C2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(2,2-dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 2,2-dimethyl-tetrahydro-2H-pyrane-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 489.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1>CCO.[Pd]>[CH:14]1([C:9]2[NH:10][S:11](=[O:12])(=[O:13])[C:6]3[C:5]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:4][CH:3]=[CH:2][C:7]=3[N:8]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2c(Cl)ccc(-c3ccccn3)c21
Agent: [Pd]
Solvent: CCO
Product: O=S1(=O)NC(C2CCCCC2)=Nc2cccc(-c3ccccn3)c21
Yield: 82.2 %

Procedure:
5-chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.268 g, 0.713 mmol) was dissolved in 99% EtOH (50 ml) and hydrogenated using Pd/C (10%, 10 mg) at 4 bar pressure for 24 h. The mixture was filtered through a pad of Celite™ and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 ml) and washed with phosphate buffer (pH=7, 10 ml), dried (Na2SO4) and the solvent was removed under reduced pressure, yielding 200 mg (82%) of 3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals. The product was further transformed by Method F. M.p. 200–203° C.