Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:30][CH2:29]1.N1C=CC=CC=1>>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:34]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:36])=[O:35])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH3:26]
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Product: CCOc1ccc(NS(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
120 mg (0.34 mmol) of the compound from example 42A are reacted with 319 mg (1.36 mmol) of 4-methyl-1-piperazinesulfonyl chloride in 8 ml (98.9 mmol) of pyridine overnight.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl.[N:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=1>>[N:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Agent: Cl
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccncc4)nc23)CC1
Yield: 61.4 %

Procedure:
Beginning with 0.200 gm (0.88 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.188 gm (1.06 mMol) 4-pyridinecarbonyl chloride hydrochloride, 0.180 gm (61%) of the title compound were prepared as an ivory solid essentially by the procedure described in Example 8. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].Cl[CH2:11][O:12][CH3:13]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:11][O:12][CH3:13])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: COCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCn1cnc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
Imidazole-4-carboxylic acid methylester (5.00 g) was dissolved in acetonitrile (100 mL), and under ice cooling and stirring, were added TEA (11.1 mL) and then chloromethylmethylether (4.47 mL), followed by heating to reflux for 3 days. After being allowed to cool to room temperature, the mixture was diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (methanol/chloroform=0%→7%) using silica gel column (product name: Hi-Flash Column 5 L, manufactured by Yamazen Corporation) to afford the title compound (3.64 g).
Reaction SMILES: CS(OC[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC(C(O)(C)C(F)(F)F)=CC=1)(=O)=O.C(N)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].[F:44][C:45]([F:76])([F:75])[C:46]([C:49]1[CH:54]=[CH:53][C:52]([N:55]2[CH2:60][CH2:59][N:58]([S:61]([C:64]3[S:65][CH:66]=[CH:67][CH:68]=3)(=[O:63])=[O:62])[CH2:57][C@@H:56]2[CH2:69][NH:70][CH2:71][CH:72]([CH3:74])[CH3:73])=[CH:51][CH:50]=1)([OH:48])[CH3:47]>>[CH3:73][CH:72]([CH3:74])[CH2:71][N:70]([CH2:69][C@H:56]1[CH2:57][N:58]([S:61]([C:64]2[S:65][CH:66]=[CH:67][CH:68]=2)(=[O:63])=[O:62])[CH2:59][CH2:60][N:55]1[C:52]1[CH:53]=[CH:54][C:49]([C:46]([OH:48])([CH3:47])[C:45]([F:44])([F:75])[F:76])=[CH:50][CH:51]=1)[S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Solvent: CC(C)CN
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(C)(=O)=O

Procedure:
This compound was synthesized following the scheme described for Example 195. The reaction of ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (Intermediate B) and isobutyl amine (Aldrich, St. Louis, Mo.), followed by sulfonamide formation (using MsCl) delivered 1,1,1-trifluoro-2-(4-((2S)-2-(((2-methylpropyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol as a mixture of two isomers.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.S([C:27]1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>COC(OC)(C)C.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9](=[CH:10][C@H:11]2[CH3:21])[CH:8]=[C:7]([O:22][CH3:27])[CH2:6][CH2:5]1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: COC1=CC2=C[C@@H](C)[C@@H]3[C@H]([C@@H](F)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Yield: 789.2 %

Procedure:
A solution of 2 g of 11β-fluoro-7α-methylestr-4-ene-3,17-dione in 20 ml 2,2-di-methoxypropane was stirred with 200 mg of pyridinium tosylate for 6.5 hours at 80° C. Then, it was diluted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 2 g of crude 11β-fluoro-3-methoxy-7α-methylestra-3,5-dien-17-one was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)[C@H:7]1[C@@H:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1.O.NN>CCO>[NH2:11][C@H:8]1[C@@H:7]([C@@H:22]2[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]2)[N:6]([CH2:5][C:4]2[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:3]=2[O:2][CH3:1])[C:9]1=[O:10]
Reactant: COc1ccc(CN2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2C(=O)[C@@H](N)[C@H]2[C@@H]2COC(C)(C)O2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of crude 2-((2S,3S)-1-(2,4-dimethoxybenzyl)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-oxoazetidin-3-yl)isoindoline-1,3-dione (631 g, 1.143 mol, assumed quantitative conversion from step 2) in EtOH (8.2 L) was added hydrazine hydrate (235 mL, 50-60%, ˜4 mol) over 20 min. The resulting mixture was heated to reflux for 3 h, cooled to rt, filtered, washed with EtOH and concentrated in vacuo. The residue was slurried in EtOAc (4 L), filtered and washed with water (2×1 L).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])C=2C=C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CC[O:32]CC1.S([O-])([O-])=O.[Na+].[Na+].C1COCC1.[CH3:47][C:48]([CH3:50])=[O:49]>O.[Os](=O)(=O)(=O)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:47]=2[CH:48]([OH:49])[CH2:50][OH:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: C=Cc1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC(=O)N(C)C
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(C(O)CO)n(CC(=O)N(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-vinyl-1H-indole-6-carboxylate (from Step 2) in THF/acetone (0.2 M, 1:1, v:v) was added N-methyl morpholine N-oxide (1.2 eq.). To the resulting suspension water was added (1 volume part), followed by a solution of osmium tetroxide in water (0.1 eq., 4% solution). The resulting solution was left stirring overnight at RT. After one night a saturated solution of sodium sulfite in water was added and the mixture was left stirring for 30 min. The solution was diluted with water and extracted with DCM (3×) and EtOAc (2×). The combined organic extracts were dried over Na2SO4 and evaporated in vacuo. The residual material was dissolved in DCM and precipitated with PE. The product was obtained as a greyish foam (91%).
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]C=2)[CH:13]=[CH:12]1.CN1CCOCC1.[CH3:27][N:28]([CH3:45])[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34][CH2:33][C:32](=[CH:35][C:36]([OH:38])=O)[CH2:31][CH2:30]1.C(NC1CCCCC1)(NC1CCCCC1)=O>CN(C)C=O>[CH3:45][N:28]([CH3:27])[C:29]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:30][CH2:31][C:32](=[CH:35][C:36]([N:11]2[CH2:12][CH2:13][CH:15]([C:16]3[C:5]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:2][CH:17]=3)[CH2:14][CH2:19]2)=[O:38])[CH2:33][CH2:34]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: On1nnc2ccccc21
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 41 %

Procedure:
1-hydroxybenzotriazole (540 mg, 4.0 mmole), 3-piperidine-4-yl)-1H-indole (400 mg, 2.0 mmole) and N-methylmorpholine (0.444 ml, 4.0 mmole) were added in succession under argon to a solution of (4-dimethylamino-4-phenylcyclohexylidene)-acetic acid (592 mg, 2.0 mmole) in dry dimethylformamide (10 ml). The solution was cooled in an ice bath and dicyclohexyldicarbodiimide (826 g, 4.0 mmole) was added. The reaction mixture was stirred for 4 days at RT, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Oily products thereupon precipitated out, which could not be separated by filtration. The reaction mixture was extracted with DCM (3×70 ml), the extracts were combined and the organic phase was washed with water (2×50 ml). After drying, the organic phase was concentrated by evaporation, 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[4-(1H-indol-3-yl)-piperidine-1-yl]-ethanone being obtained as a brown, oily crude product. After chromatographic separation on silica gel (70 g) with EE/methanol (2:1), 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[4-(1H-indol-3-yl)-piperidine-1-yl]-ethanone was isolated as a yellow foamy solid in a yield of 41% (359 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:38][CH2:39][CH2:40][CH3:41])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:2](=[O:3])[O:4][CH2:5][CH:6]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 70.8 %

Procedure:
Using the general method of Example 55, 9-fluorenylmethyl chloroformate (0.085 g, 0.33 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis: Calculated for C32H34N6O2+4H2O: %C, 71.29; %H, 6.45; %N, 15.59; Found: %C, 70.99; %H, 6.35; %N, 15.55.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([CH:23]1[CH2:25][CH2:24]1)#[CH:22]>C(NCC)C.CS(C)=O.C(OCC)(=O)C.[Cu]I>[CH:23]1([C:21]#[C:22][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:25][CH2:24]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C#CC3CC3)cn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
In a sealed tube, the mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 2.9 mmol), ethynylcyclopropane (482 mg, 7.3 mmol), tetrakis(triphenyl-phosphine)palladium (335 mg, 0.29 mmol) and copper(I) iodide (28 mg, 0.15 mmol) in diethylamine (10 mL) and dimethyl sulfoxide (10 mL) was stirred at 100° C. for 3 hours under nitrogen atmosphere. The mixture was then diluted with ethyl acetate (100 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate=15:1 to afford tert-butyl 4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazine-1-carboxylate (930 mg, 98%) as a yellow solid. MS (ES+) C18H24N4O2 requires: 328, found: 329 [M+H]+.
Reaction SMILES: [C:1](=O)([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2]CC1C=CC=C(Br)C=1.BrC1C=C(CO)C=CC=1.[OH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:1]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:2])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)CO
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Agent: OCc1cccc(Br)c1
Product: CCOC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared using a procedure analogous to 3-bromobenzyl 4-nitrophenyl carbonate except that (3-bromophenyl)methanol was replaced with ethyl 2-hydroxyacetate. LCMS, [M+Na]+=292.0. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=9.2 Hz, 2H), 7.37 (d, J=9.2 Hz, 2H), 4.72 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH:26]=O)([CH3:17])[CH3:16].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:28])[C:15]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1/[CH:26]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH3:17])[CH3:16]
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 72 %

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (43 g, 0.26 mol) and 2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid methyl ester (66 g, 0.26 mol) in methanol (700 mL) was added pyrrolidine (22 g, 0.31 mol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and resulting precipitate was collected, dried to give the title compound as a yellow solid (76 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Nc1nccs1
Reactant: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccc(F)cc2)nc1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 54.5 mg (0.54 mmol) 2-aminothiazole. Yield: 2.3 mg.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]1([C:18]2[CH:27]=[C:26]([C:28]([NH:30][C:31](=S)[NH:32][NH:33][C:34]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[O:35])=[O:29])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:42][C:43]([F:46])([F:45])[F:44])[CH:24]=3)[N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([C:18]2[CH:27]=[C:26]([C:28]([NH:30][C:31]3[O:35][C:34]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[N:33][N:32]=3)=[O:29])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:42][C:43]([F:46])([F:45])[F:44])[CH:24]=3)[N:19]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NNC(=S)NC(=O)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12)c1cccs1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1nnc(-c2cccs2)o1)c1cc(-c2ccccc2)nc2ccc(OC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
p-toluenesulfonyl chloride (32.7 mg, 0.17 mmol) was added to a pyridine (2 mL) solution of 4-(2-phenyl-6-trifluoromethoxy-4-quinolinecarbonyl)-1-(2-thiophenecarbonyl)thiosemicarbazide (70 mg, 0.14 mmol) described in Reference Example 28, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated. After that, to the residue, water was added, and the deposited crystal was collected by filtration, washed with water, dried, and then purified by silica gel column chromatography to obtain the title compound (16 mg, 0.03 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(C)[CH:8]=[O:9].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[N:1]1([C:8]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(=O)n2ccnc2)cc1
Temperature: 125 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
30 mmoles of [2-14C] imidazole were dissolved in 2.5 ml chloroform and mixed with 18 ml dimethylformamide containing 30.2 mmoles of p-fluorobenzonitrile and 3.2 g Na2CO3. The mixture was stirred at 125° C. for three days [Johnson, J. Med. Chem., Vol. 12, p. 1024 (1969)]. The product was isolated and recrystallized twice from benzene: hexanes (1:1). Yield 48%; mp 152°-154°; elemental analysis: found: 70.85% C, 4.13% H and 24.81% N; theoretical: 70.99% C, 4.17% H and 24.84% N.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[C:25]([CH3:33])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Si:1]([O:8][CH:9]([C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:32]=[CH:31][C:26]([CH2:27][OH:28])=[C:25]([CH3:33])[CH:24]=2)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=1[CH3:34])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CO)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a 0° C. solution of the methyl 4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methyl-benzoate (4.37 g, 8.09 mmol) in THF (50 mL) is added LiAlH4 (0.31 g, 8.09 mmol). The reaction is stirred for 10 m and allowed to warm to RT overnight. The mixture is cooled to 0° C. and quenched successively with H2O (0.3 mL), 15% NaOH (0.3 mL) and H2O (0.9 mL). The mixture is stirred for 10 m, warmed to RT, stirred for 20 m, filtered through celite with EtOAc (100 mL) wash, and concentrated to give the title compound (4.14 g, 8.08 mmol, 99%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][NH2:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[CH2:24](C(CC)(CC)C([O-])([O-])[O-])[CH3:25]>C1(C)C(C)=CC=CC=1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:24]([CH3:25])=[N:14][N:13]=[C:8]1[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(C(F)(F)F)ccc2n1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(C(F)(F)F)ccc3n12

Procedure:
In the manner given in Example 2, 6-(trifluoromethyl)-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethylorthoaceate are refluxed in xylene to give 7-(trifluoromethyl)-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a] quinoline.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5]2[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=[C:9]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])[C:10]=2[CH:11]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:2]1[C:3](=[O:28])[NH:4][C:5]2[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=[C:9]([S:12]([NH:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)(=[O:14])=[O:13])[C:10]=2[CH:11]=1)#[N:30]
Reactant: CN(C)C=O
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(Br)c(=O)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(C#N)c(=O)[nH]c2c1
Temperature: 135 °C

Procedure:
A mixture of 3-bromo-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide (16 mg, 0.034 mmol), zinc cyanide (20 mg, 5 equiv), Pd(PPh3)4 (4 mg, 10 mol %) and DMF was heated at 135° C. for 2 hours. The reaction mixture was purified by preparative HPLC to give 3-cyano-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3ccccn3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C2(C#Cc3ccccn3)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane (0.17 g, 0.39 mmol) and pyridinium p-toluenesulfonate (0.10 g, 0.39 mmol) in acetone (4 mL) and water (1 mL) was refluxed for three days, then was evaporated. Water was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 25:75 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(2-pyridylethynyl)cyclohexan-1-one as a wax. 1H-NMR (400 MHz, CDCl3) δ 8.61 (d, J=4.8 Hz, 1H), 7.68 (dt, J=7.8, 1.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.27 (m, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.15 (dd, J=8.5, 2.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.85 (s, 3H), 3.07 (dt, J=14.4, 5.8 Hz, 2H), 2.49 (d, J=14.8 Hz, 2H), 2.41 (m, 2H), 2.27 (dt, J=13.4, 3.9 Hz, 2H), 1.8-2.0 (m, 6H), 1.61 (m, 2H). Anal. (C25H27NO3.0.65 H2O) calcd: C, 74.84; H, 7.11; N, 3.49; found: C, 75.00; H, 6.83; N, 3.52.