Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)[CH:7]=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:3]1[C:2]([NH:1][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:7][C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)=[C:5]([F:19])[CH:4]=1
Reactant: Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.3 %

Procedure:
A mixture of 0.45 g (0.0014 mole) of 9-(5-amino-4-chloro-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, 0.18 g (0.0014 mole) of ethanesulfonyl chloride, and 0.22 g (0.027 mole) of pyridine in approximately 30 mL of methylene chloride was stirred at room temperature for two days. The reaction mixture was heated at 26° C. for approximately 24 hours, then at reflux for 36 hours. The solvent was evaporated from the mixture leaving an oily residue. The residue was washed with an aqueous, 10% hydrochloric acid solution. The washed residue crystallized upon standing and was recrystallized from ethyl acetate and n-heptane to give 0.12 g of 9-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 146°-148° C., Compound 11 of Table 1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:15])[O:11][C:12]([CH3:14])=[CH2:13])[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[O-:26][N+:6]1[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:4][C:5]=1[NH:9][C:10](=[O:15])[O:11][C:12]([CH3:14])=[CH2:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)OC(=O)Nc1cc(C(F)(F)F)ccn1
Solvent: ClC(Cl)Cl
Product: C=C(C)OC(=O)Nc1cc(C(F)(F)F)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropenyl [4-(trifluoromethyl)pyridin-2-yl]carbamate (1.2 g, 5.0 mmol) was suspended in CHCl3 (20 mL) and treated with m-CPBA (841 mg, 5.0 mmol). The reaction was stirred at rt overnight. The reaction was quenched with satd. NaHCO3 and extracted with CHCl3. The organic layer was dried (MgSO4) and concentrated. The crude residue was purified over silica using CH2Cl2 as the eluting solvent. An amber oil was collected (620 mg, 47%); 1H-NMR (DMSO-d6) δ 10.2 (s, 1 H), 8.56 (d, J=6.9 Hz, 1 H), 8.25 (d, J=2.6 Hz, 1 H), 7.52 (ddd, dd, J1=6.8 Hz, J2=2.5 Hz, J3=0.6 Hz, 1 H), 4.85 (q, J=1.2 Hz, 1 H), 4.80 (d, J=1.2 Hz, 1 H), 1.94 (d, J=0.4 Hz, 3 H).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH3:20])=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:17][C:16]=2[C:27](N(OC)C)=[O:28])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:33]1COC[CH2:34]1>>[CH3:20][C:19]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[C:16]([C:27](=[O:28])[CH2:33][CH3:34])[S:17][C:18]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C

Procedure:
To a stirred solution of 3-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-N-methoxy-N,4-dimethyl-5-morpholinothiophene-2-carboxamide (compound 24f, 0.120 g, 0.25 mmol) in anhydrous THF (10 ml) at 25° C., Grignard reagent (ethyl magnesium bromide, 0.17 g, 1.25 ml, 1.25 mmol) was added dropwise and the reaction mixture was heated to 70-75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., reaction mixture was quenched by adding a saturated ammonium chloride solution (10 ml) and the resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent in the dried organic layer was evaporated under a reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40-45% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 0.056 g of this compound in ethyl acetate (1.0 ml) and precipitating it by the slow addition of diisopropyl ether. The precipitate was filtered to obtain the title compound. (0.047 g, 48%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[N:10]1[CH2:14][CH2:13][CH2:12]C1.C(N)(=[O:18])C=C>C(O)(=O)C.O>[NH:10]1[C:14](=[O:18])[CH2:13][CH2:12][C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:1][C:2]1=2
Reactant: C1=C(N2CCCC2)Cc2ccccc21
Reactant: C=CC(N)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC2=C(Cc3ccccc32)N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1H-inden-2-yl)-pyrrolidine (5.34 g) and acrylamide (6.15 g) is stirred in argon atmosphere at 100° C. for 30 min. The temperature is then rised to 130° C. and stirring continued for another 15 min. After cooling to room temperature, water (50 mL) and acetic acid (5 drops) are added and the mixture is stirred for 30 min. The mixture is filtered and the organic phase of the filtrate is separated and washed with brine. After drying (MgSO4) and evaporating the solvent, the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give a brown solid that is triturated with ethyl acetate and dried to afford the title compound. Yield: 1.12 g (21% of theory); Mass spectrum (ESI+): m/z=186 [m+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][C:28]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>C(N(CC)CC)C>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:28]=4[CH3:27])=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1cccc(N)c1C
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
As described for Example 123, a mixture of 0.361 g of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)-carbonyl]benzoyl chloride, 0.101 g of triethylamine and 0.145 g of 2,3-dimethylaniline is stirred for 1.5 hr. and worked up to give 0.44 g of crystals, m.p. 248°-251° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([C@@H:58]3[CH2:62][CH2:61][CH2:60][C@H:59]3[C:63]([OH:65])=[O:64])=[O:57])=[CH:52][CH:51]=2)=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([NH:43][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([C@@H:58]5[CH2:62][CH2:61][CH2:60][C@H:59]5[C:63]([OH:65])=[O:64])=[O:57])=[CH:52][CH:51]=4)=[CH:48][CH:49]=3)=[O:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccc(C(=O)[C@@H]3CCC[C@H]3C(=O)O)cc2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (0.25 g, 1 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (0.47 g, 1 mmol) in methylene chloride was added racemic trans-2-(4′-amino-biphenyl-4-carbonyl)-cyclopentanecarboxylic acid (0.20 g, 0.78 mmol) and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated and the residue was re-dissolved in DMSO and acetonitrile. HPLC reverse phase purification with acetonitrile and water afforded 44 mg of racemic trans-2-{4′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-biphenyl-4-carbonyl}-cyclopentanecarboxylic acid as a white solid. LCMS calcd for C30H23F3N2O5 (m/e) 548, obsd 549 (M+H).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([CH3:15])[CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:18][CH2:19][CH2:20][CH3:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:23]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.C(Cl)Cl>[CH3:15][N:8]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6]([C:5]1[CH:16]=[CH:17][C:2]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:23]2)=[N:3][C:4]=1[S:18][CH2:19][CH2:20][CH3:21])=[O:7]
Reactant: COC(=O)C[C@@H]1CCCNC1
Reactant: CCCSc1nc(Cl)ccc1C(=O)N(C)C1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCC#N
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)N(C)C1CCOCC1
Yield: 57 %

Procedure:
6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.398 g, 1.21 mmol) was added to (S)-methyl 2-(piperidin-3-yl)acetate.HCl (0.353 g, 1.82 mmol) and potassium carbonate (0.753 g, 5.45 mmol) in butyronitrile (3 mL) was heated at 150° C. for 4 hours. The reaction mixture was diluted with DCM (60 mL), and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford methyl [(3S)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-yl}piperidin-3-yl]acetate (0.310 g, 57%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(Cl)ccc4nc3OC)CC2)c1
Yield: 70 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.30 (m, 4H), 3.76-3.80 (m, 6H), 4.08-4.14 (m, 4H), 6.46-6.57 (m, 3H), 7.20 (t, J=8.1 Hz, 1H), 7.34-7.44 (m, 1H), 7.50-7.67 (m, 1H), 7.80 (s, 1H).
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:21][C:22]=3[CH3:23])=[N:13][CH:14]=2)[S:3]1.Cl.C([OH:33])C>>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:33])[NH:6][C:5]2=[O:7])=[CH:14][N:13]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=N)NC2=O)cn1
Reactant: CCO
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)cn1
Yield: 59 %

Procedure:
A mixture of 2-imino-5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methyl]-4-thiazolidinone (0.76 g), 1N HCl (10 ml) and ethanol (10 ml) was heated for 20 hours while refluxing, followed by concentration under reduced pressure. The residual crystal was collected by filtration, washed with water and then recrystallized from ethanol-chloroform to yield 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methyl]-2,4-thiazolidinedione (0.45 g, 59%) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Yield: 51.6 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-aminonaphthalene (0.22 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.09 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (gradient from 2:1 to 1:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.29 g, 51%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (3H, s); 6.56 (1H, d, J=16.0 Hz); 7.16 (1H, dd, J=7.0 and 1.4 Hz); 7.27-8.14 (11H, m); 10.25 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:25]3[CH2:27][CH2:26]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH:31][CH2:30][CH2:28][OH:29])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:25]3[CH2:26][CH2:27]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1)NCCO
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetic acid (0.185 g, 0.48 mmol) in dimethylformaminde (7 mL) at 0° C. was added ethanolamine (0.044 mL, 0.72 mmol, 1.5 eq.) followed by diisopropylethylamine (0.34 mL, 1.94 mmol, 4.0 eq.) and HATU (0.221 g, 0.58 mmol). After stirring for 2 h, the reaction mixture was diluted with water (100 mL) and the resulting white solid isolated by filtration. The solid was purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)acetamide (67 mg, 33%) as a white solid. M.p. 131-133° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0, 1.5 Hz, 1H), 8.19 (d, J=1.5 Hz, 1H), 8.08 (t, J=5.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 4.68 (t, J=5.5 Hz, 1H), 3.44-3.39 (m, 4H), 3.13 (q, J=6.0 Hz, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.14-1.09 (m, 2H), 1.06-1.00 (m, 2H); APCI MS m/z 424 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][S-:11].[Na+]>CN(C=O)C.C(OCC)C>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([S:11][CH3:10])=[CH:7][N:6]=1)[CH3:9]
Reactant: C[S-]
Reactant: CCc1ccc(Br)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1ccc(SC)cn1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
A solution of 5-bromo-2-ethylpyridine (see part (i)) (3.0 g, 16.2 mmol) in dry DMF (4.5 ml) was treated with sodium methanethiolate (1.8 g, 24.3 mmol) and the suspension heated at 100° C. for 3 hours. The cooled mixture was diluted with diethyl ether (200 ml), washed with water (4×100 ml), then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by elution with dichloromethane. The appropriate fractions were combined and evaporated under reduced pressure. The resulting oil was distilled under reduced pressure (60 mm) at an oven temperature of 150° C. using a Kugelrohr (trade mark) apparatus to give the title compound, (1.4 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: NCC(=O)O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(Cc1ccccn1)Cc1ccccn1

Procedure:
2-Chloromethylpyridine hydrochloride (9.2 g, 8.53 mmol) and glycin (2 g, 26.6 mmol) were dissolved in water (30 mL) and stirred at room temperature for five days, with addition of 5 mol aqueous NaOH solution at intervals to maintain the pH at 8-10. The resulting dark red solution was extracted with ethyl acetate, neutralized with HCl and concentrated. The residue was dissolved in dichloromethane, and the insoluble sodium chloride was filtered. Pale yellow crystals formed from the filtrate, which were collected and dried under vacuum. Yield (2.87 g) (11.2 mmol, 42%). 1H NMR (CDCl3), 300 MHz): 3.39 (s, 2H), 3.98 (s, 4H), 7.06 (t, 2H), 7.30 (d, 2H), 7.56 (t, 2H), 8.36 (d, 2H). 13C NMR (CD3OD, 300 MHz): 57.36 (C, CH2), 59.77 (2C, PyCH2), 124.77 (2CH, Py), 125.15 (2CH, Py), 139.00 (C, CH2), 149.76 (2CH, Py), 156.10 (2C, Py), 173.05 (C, CO2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: N#CCOc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
(3-Aminophenoxy)-acetonitrile (3.0 g) was dissolved in 12 ml of pyridine, cooled in an ice bath, treated with 3.47 g of methanesulfonyl chloride, and stirred at room temperature for 3 hours. The mixture was poured into ethyl acetate, washed with hydrochloric acid, then with water, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (3:7) giving 3.0 g of N-(3-cyanomethoxyphenyl)-methanesulfonamide. An aliquot of this product was crystallized from ethyl acetate:hexane (3:7) to give a solid, mp 91-92° C. ##STR66##
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([N:14]1[CH2:18][CH2:17]OC1=O)([O:11][CH2:12][CH3:13])=[O:10].COCCOCCO>>[CH2:12]([O:11][C:9](=[O:10])[NH:14][CH2:18][CH2:17][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:13]
Reactant: CCOC(=O)N1CCOC1=O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: COCCOCCO
Product: CCOC(=O)NCCNc1ccccc1
Temperature: 160 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
A mixture of aniline hydrochloride (8.7 g, 66.9 mmole), N-carboethoxy-2-oxazolidinone (10.1 g, 63.5 mmole) and 25 ml of 2-(2-methoxyethoxy)ethanol was heated to 160° C. Gas evolution began occurring at 140° C. and continued for 3 hours. The dark homogenous reaction solution was allowed to cool to ambient temperature and worked up according to the procedure described in Example 1. Distillation at 170° C. (0.5 mm) gave a 26 percent yield of a clear oil which slowly solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:9]=[CH:8]2.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>ClCCl>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][S:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:6][C:5]=1[O:4][C:3]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:2]=1[F:1])(=[O:16])=[O:15]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(S(=O)(=O)Cl)cc21
Reactant: CN(C)CCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(S(=O)(=O)NCCCN(C)C)cc21
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To a cooled (0° C.) solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-sulfonyl chloride (0.20 g, 0.50 mmol) in dichloromethane under N2 atmosphere was added 3-(dimethylamino)propylamine (0.05 g, 0.50 mmol) and triethylamine (0.15 g, 1.5 mmol) drop-wise. The reaction mixture was stirred for 4 hours and then diluted with dichloromethane (20 mL), washed with water, saturated NaHCO3 and brine and then dried over MgSO4. The mixture was concentrated under reduced pressure and chromatographed on preparatory TLC plates eluting with dichloromethane/MeOH/Et3N (95:4:1) to afford the 93 mg of final product (40% yield). MS (APCI−) m/z 466 detected; 1H NMR (400 mHz, CDCl3) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.20 (m, 1H), 7.09 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.22 (d, 2H), 3.12 (t, 2H), 2.35 (m, 3H), 2.13 (s, 6H), 1.70 (m, 2H), 0.94 (d, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].[N+](=[CH:36][Si](C)(C)C)=[N-]>CO.C1(C)C=CC=CC=1>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH3:36])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: Cc1ccccc1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OC)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (1 g, 2.190 mmol) in MeOH (5 mL) and toluene (5.00 mL) was added (diazomethyl)trimethylsilane (1.642 mL, 3.28 mmol). The reaction mixture was stirred for 3 hours at room temperature. TLC indicated starting material was consumed and a new product was formed. The reaction mixture was concentrated under reduced pressure to give the desired product (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-methyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate as a white solid (1 g, 97%). 1H NMR (500 MHz, DMSO-D6) δ ppm 0.65 (s, 3H), 0.76 (s, 3H), 0.87 (d, J=12.67 Hz, 6H), 0.94 (s, 3H), 0.96-1.63 (m, 18H), 1.65 (s, 3H), 1.72-1.87 (m, 2H), 2.03-2.16 (m, 2H), 2.85-3.09 (m, 3H), 3.60 (s, 3H), 4.26 (d, J=4.58 Hz, 1H), 4.58 (s, 1H), 4.70 (d, J=1.83 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9](N)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[BrH:12]>[Cu](Br)Br>[Br:12][C:9]1[N:10]=[C:3]2[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: Br
Agent: Br[Cu]Br
Product: Brc1nc2c(Br)cccn2n1

Procedure:
2,8-Dibromo-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.50 g, 2.3 mmol) with copper(II) bromide (0.140 g, 0.627 mmol) and 48% aqueous hydrobromic acid (5 mL, 40 mmol) in a manner analogous to Step 68a. the reaction product was isolated as a pale yellow solid (0.55 g, 85%). MP=150-151° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.99 (d, J=6.7 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H). MS=276, 278, 280 (MH)+.