Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[C:4]([CH3:19])[C:3]=1[CH3:20]>N.CO.O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH3:20]
Reactant: Cc1cc(N2C(=O)c3ccccc3C2=O)nc(Cl)c1C
Agent: N
Solvent: O
Solvent: CO
Product: Cc1cc(N)nc(Cl)c1C
Yield: 45 %

Procedure:
A solution of 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione (650 mg, 2.27 mmol) in ammonia in methanol (2 M, 50 mL) was stirred at the room temperature overnight. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give a crude residue that was purified by silica gel column chromatography (10-15% ethyl acetate in petroleum ether) to give 6-chloro-4,5-dimethylpyridin-2-amine (160 mg, 46%). 1H NMR (300 MHz, d-DMSO) δ 6.21 (s, 1H), 5.93 (brs, 2H), 2.11 (s, 3H), 2.05 (s, 3H). MS (ESI) m/z (M+H+): 157.2.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[C:29]([NH2:34])[N:28]=1>C(O)C>[Cl:26][C:27]1[CH:32]=[C:31]([N:11]2[CH2:12][CH2:13][O:14][CH:9]([C:7]3[NH:6][C:5]4[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=4[N:8]=3)[CH2:10]2)[N:30]=[C:29]([NH2:34])[N:28]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Clc1ccc2[nH]c(C3CNCCO3)nc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(Cl)ccc4[nH]3)C2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 5-chloro-2-(2-morpholinyl)-1H-benzimidazole (200 mg, 0.841 mmol) and Hunig's base (109 mg, 0.841 mmol) in ethanol (10 mL) stirred at room temperature was added 4,6-dichloro-2-pyrimidinamine (138 mg, 0.841 mmol), and the reaction mixture was stirred overnight at 85° C. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The solvent was evaporated in vacuo to give the crude product. The residue was triturated with EtOAc (1×5 mL). The resulting solid was filtered, and collected to afford the title compound (300 mg). LC-MS (ES) m/z=365, 367 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]>>[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:10][CH2:11]2)=[O:28])=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: COc1cc(C(=O)NCCC(O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)ccc1N

Procedure:
Prepared as described in Example 1 from 4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and 4-amino-3-methoxybenzoic acid (0.130 g). Title compound obtained as white solid (0.080 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:15])[CH:11]=[C:12]([NH2:14])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.[O:16]=[C:17](NC1N=C(C2C=CN=CC=2)SC=1)[C@@H:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:14][C:12]1[CH:11]=[C:10]([NH:15][C:17](=[O:16])[C@@H:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1csc(-c2ccncc2)n1
Reactant: Cc1cc(-c2cc(N)cc(N)c2)ccn1
Product: Cc1cc(-c2cc(N)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
This title compound was prepared from 51.1C (2.10 g, 10.0 mmol) according the procedure described above for conversion of 4.A to 4.B. The product 51.1D was purified by flash chromatography on silica gel using 0-7% MeOH/CH2Cl2 for elution.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12]CC)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[N:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:10]([OH:12])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[O:19][CH3:20])[CH:15]=[N:16]2)=[N:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCc3ccccc3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate and N-benzyl-6-hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3H) 4.53 (d, J=5.6 Hz, 2H) 7.27 (d, J=3.8 Hz, 1H) 7.36 (d, J=4.0 Hz, 5H) 7.42-7.59 (m, 2H) 8.47 (d, J=6.6 Hz, 1H) 8.98 (s, 1H) 9.28 (br. s., 1H). MS m/z [M+H]+ 426.4.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].O>C(=S)=S>[Cl:17][C:18]1[C:19]([C:20](=[O:21])[C:8]2[CH:9]=[CH:10][C:5]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)=[CH:23][CH:24]=[CH:25][N:26]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: O=C(c1ccc(-c2ccccc2)cc1)c1cccnc1Cl

Procedure:
26.7 g AlCl3 is added slowly while stirring to a solution of 9.2 g biphenyl and 10.6 g 2-chloronicotinoyl chloride in 170 ml carbon disulfide. The mixture is refluxed 5 hrs. After cooling, the S2C layer is poured off, and the residue is added to acidic ice: water, basified and extracted with methylene chloride. The combined extracts are washed, dried (MgSO4) and solvent removed in vacuo. The crude product is chromatographed on a silicagel column and eluted with benzene:ethyl acetate 15:1. Yield: 5 g of title product, m.p. 128°-32° C.; UV (ethanol): λmax. 295 nm, ε: 27,260; Cl 11.96 (12.07).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][N:5]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]4[C:15]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:22])=[N:29][CH:28]=3)=[O:31])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)CNc1ccsc1C2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3sccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 5,10-dihydro-4H-thieno[3,2-c][2]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:20][C:21]([F:24])([F:23])[F:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([OH:19])=[O:18])=[CH:8]2)#[N:2].[C:25]([OH:28])(=[O:27])[CH3:26]>[Pd]>[F:14][C:13]([F:16])([F:15])[C:10]([OH:27])=[O:11].[C:25]([C:26]1[CH:10]([C:13]([F:14])([F:16])[F:15])[O:11][C:12]2[C:3]([CH:1]=1)=[CH:4][C:5]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:6][C:7]=2[CH2:8][CH2:9][NH:2][CH2:1][C:3]1[CH:4]=[C:5]([O:20][C:21]([F:24])([F:22])[F:23])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]([OH:19])=[O:18])=[CH:8]2)([OH:28])=[O:27]
Reactant: N#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: CC(=O)O
Agent: [Pd]
Product: O=C(O)C(F)(F)F
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)cc(CCNCc3cc(OC(F)(F)F)cc4c3OC(C(F)(F)F)C(C(=O)O)=C4)c2OC1C(F)(F)F
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 8-cyano-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid prepared as in Example 21p, Step 2 (445 mg, 1.26 mmole) and 10% Pd/C (100 mg) in glacial acetic acid (20 mL) was hydrogenated at 20 psi for 1 h and the pressure released. After standing overnight, the catalyst filtered and the solvent was removed in vacuo. Purification by reverse phase chromatography (acetonitrile:0.5% TFA-H2O) gave 140 mg (32% yield) of the product: ESHRMS m/z 698.0694 (M+H, C26H16Fl2NO8, Calc'd 698.0679); 1H NMR (dmso-d6/300 MHz) 13.6 (brs, 1H), 13.1 (brs, 1H), 9.39 (brs, 2H), 9.39 (brs, 2H), 7.95-7.93 (m, 2H), 7.72-7.70 (m, 2H), 7.63-7.59 (m, 2H), 6.00-5.91 (m, 2H), 4.29-4.17 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH:28]([CH2:30][C@H:31]([OH:35])[C:32](O)=[O:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][N:19]([C:32](=[O:33])[C@@H:31]([OH:35])[CH2:30][CH:28]([CH3:29])[CH3:27])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](O)CC(C)C)CC1
Reaction time: 3 h
Yield: 49.1 %

Procedure:
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (Ic) (0.89 g, 2.54 mmol) was dissolved in DMF (17 mL) and treated with N,N-diisopropyletbylamine (1.77 mL, 10.17 mmol), L-2-hydroxyisocaproic acid (0.34 g, 2.54 mmol), and HBTU (0.96 g, 2.54 mmol). The reaction was stirred for 3 hours, then diluted with EtOAc (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 0.58 g (49%) of the desired product.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(I)cc1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
A stirred mixture of 4-iodophenol (0.50 g, 2.27 mmol), methyl 2-bromoacetate (0.382 g, 2.50 mmol), and powdered potassium carbonate (0.314 g, 2.27 mmol) in dry acetone under argon was sealed and heated at 70° C. for 4 hr. The cooled mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography (silica, 40 to 50% methylene chloride in cyclohexane) and the solvent was removed in vacuo to afford the titled intermediate as a white solid (0.41 g, 62%), mp 69°-70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.[Br:19]C1C=C2C(C(N)=NN2C)=CC=1>>[Br:19][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:6][N:7]2[CH3:11])=[CH:3][CH:2]=1
Reactant: Cn1nc(N)c2ccc(Br)cc21
Reactant: CN1CCN(c2nn(C)c3ccc(Br)cc23)CC1
Product: CN1CCN(c2nn(C)c3cc(Br)ccc23)CC1

Procedure:
Prepared in a manner similar to 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole but using 6-bromo-1-methyl-1H-indazol-3-amine instead of 5-bromo-1-methyl-1H-indazol-3-amine. LCMS-ESI+: calc'd for C13H17BrN4: 309.1, 311.1 (M+H+); Found: 309.2, 311.2 (M+H+).
Reaction SMILES: [C:1]([CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])([O:3][CH2:4][CH3:5])=[O:2].[C:20]([O:23][CH:24](OCC)[O:25][CH2:26][CH3:27])(=O)[CH3:21]>>[C:1]([C:6]([CH:24]([O:25][CH2:26][CH3:27])[O:23][CH2:20][CH3:21])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCOC(=O)C(C#N)Cc1ccc(OC)c(OC)c1
Product: CCOC(=O)C(C#N)(Cc1ccc(OC)c(OC)c1)C(OCC)OCC
Temperature: 95 °C

Procedure:
A mixture of α-Carbethoxy-β-[3,4-dimethoxyphenyl]propionitrile (10 g) and diethoxymethyl acetate (30 g) was heated at 95° C. for 20 hours. The volatiles were removed under vacuum pump pressure leaving 13.4 g (94%) of a nearly colorless oil which solidified on standing at -5° C. to a white solid, m.p. 62°-65° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@:19]2([CH2:20][OH:21])[C@@H:6]([CH2:7][C@@H:8]([CH3:23])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:22])[CH2:5][C:4](=O)[CH2:3]1.[CH3:25][C@@H:26]1[C:43](=O)[CH2:42][CH2:41][C@@:40]2([CH2:45][O:46][Si:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:27]1[CH2:28][CH2:29][C@@H:30]1[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]1[CH2:32][CH2:33][C@@H:34]2[O:66][Si:67]([C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.O[C@@]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)[C@H](CC(=O)CC1)CC3>>[CH3:1][C@@H:2]1[C@@:19]2([CH2:20][OH:21])[C@@H:6]([CH2:7][C@@H:8]([CH3:23])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:22])[CH2:5][CH2:4][CH2:3]1.[CH3:25][C@@H:26]1[CH2:43][CH2:42][CH2:41][C@@:40]2([CH2:45][O:46][Si:47]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:27]1[CH2:28][CH2:29][C@@H:30]1[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]1[CH2:32][CH2:33][C@@H:34]2[O:66][Si:67]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1)[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: C[C@@H]1C[C@H]2CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: C[C@@H]1C(=O)CC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]3CC[C@]4(C)[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: C[C@]1(O)CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C
Product: C[C@@H]1CCC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]3CC[C@]4(C)[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@H]4[C@@H]3CC[C@@H]12
Product: C[C@@H]1C[C@H]2CCC[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
Substituting 1α,7α-dimethyl-17β,19-dihydroxy-5α-androstan-3-one, 4α,6α,17α-trimethyl-17β,19-di(2'-tetrahydropyranyloxy)-5α-androstan-3-one, 4α,17α-dimethyl-17β,19-di(4'-tetrahydropyranyloxy)-5α-androstan-3-one, 17β,19-dihydroxy-6α,17α-dimethyl-5α-androstan-3-one diacetate and 4α-methyl-17β,19-di(triphenylsiloxy)-5α-androstan-3-one for the 17β,19-dihydroxy-17α-methyl-5α-androstan-3-one above results in the preparation of 1α,7α-dimethyl-5α-androstan-17β,19-diol, 4α,6α,17α-trimethyl-17β,19-di(2'-tetrahydropyranyloxy)-5α-androstane, 4α,17α-dimethyl-17β,19-di(4'-tetrahydropyranyloxy)-5α-androstane, 6α,17α-dimethyl-5α-androstane-17β,19-diol diacetate and 4α-methyl-17β,19-di(triphenylsiloxy)-5α-androstane, respectively.
Reaction SMILES: BrC1C=CN2C(C([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:29])[NH:21][CH2:22][CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:17]=[CH:16][C:15]=3[F:30])=O)=CN=C2C=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[CH:39][C:40]=2[C:41]([OH:43])=O)[CH:37]=1>>[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([N:38]=[CH:39][C:40]=2[C:41]([NH:13][C:14]2[CH:19]=[C:18]([C:20](=[O:29])[NH:21][CH2:22][CH2:23][O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:17]=[CH:16][C:15]=2[F:30])=[O:43])[CH:37]=1
Reactant: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: O=C(O)c1cnn2cc(Br)ccc12
Product: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnn3cc(Br)ccc23)c1

Procedure:
The title compound was prepared analogously to Intermediate 2A by replacing 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (step 2) with 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (commercially available);
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:15])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8][CH2:7]2.Cl.[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=O.[C:38](=O)([O-])O.[Na+]>O.C(O)C>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([CH2:38][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N:3]([CH3:15])[CH3:2])[CH:5]=3)[C:10]2=[O:14])[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)c1ccc2c(c1)CCCC2=O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc2c(c1)CCC(CN1CCN(C(c3ccccc3)c3ccccc3)CC1)C2=O

Procedure:
In 100 ml. of ethanol was dissolved 2 g. of 6-dimethylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride, 4 g. of 1-benzhydrylpiperazine hydrochloride and 4 g. of a 37% aqueous solution of formalin and the reaction was carried out at room temperature for 2 hours. The reaction mixture was diluted with 500 ml. of water, neutralized with sodium hydrogen carbonate and extracted with chloroform. The chloroform extract was dried and distilled under reduced pressure to remove the solvent, whereupon 2-[(4-benzhydryl-1-piperazinyl)methyl]-6-dimethylamino-3,4-dihydro-1(2H)-naphthalenone was obtained as an oil. This oily product was dissolved in 50 ml. of methanol and stirred with 2.5 g. of sodium borohydride at room temperature for 30 minutes. The reaction mixture was diluted with 500 ml. of water and extracted with chloroform. The extract was dried and the solvent was distilled off under reduced pressure. By the above procedure there was obtained 2-[(4-benzhydryl-1-piperazinyl)methyl]-6-dimethylamino-1,2,3,4-tetrahydro-1-naphthalenol as an oil. This oil was dissolved in 50 ml. of ethanolic HCl and the solution was heated under reflux for 2 hours. Upon cooling there was obtained 1.5 g. of 3-[(4-benzhydryl-1-piperazinyl)methyl]-7-dimethylamino-1,2-dihydronaphthalene hydrochloride as colorless needles melting at 190°-195° C.(decomposition).
Reaction SMILES: N1([CH:7]=[C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)CCCCC1.[CH3:24][C:25](=[O:28])[CH:26]=[CH2:27].C(O)(=O)C>C(O)C>[O:28]=[C:25]1[CH2:24][CH2:7][C:8]2([CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:13]2)[CH:27]=[CH:26]1
Reactant: O=C(OCc1ccccc1)N1CCC(=CN2CCCCC2)CC1
Reactant: C=CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
To a solution of EXAMPLE 265A (15.88 g) in ethanol (300 mL) was added but-3-enone (3.89 g). The mixture was stirred at reflux overnight. Then acetic acid (30 mL) was added to the mixture which was stirred at reflux again overnight. The mixture was then concentrated under vacuum and the residue was diluted with ethyl acetate (400 mL) and washed with water and brine and dried over Na2SO4. After filtration and evaporation of the solvent, column purification gave the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 43.5 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.15 g), 3-dimethylaminopropylamine (1.26 g) and triethylamine (0.62 g) in NMP (6 mL) was stirred and heated at 140° C. for 48 hours. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 5-10%. The resultant product was repurified by preparative TLC, eluting with a mixture of methanol and DCM (10%) to give (1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.08 g) as an off white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[F:8][C:9]([F:40])([F:39])[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([N:16]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)[CH:15]=1>O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:21]1[N:20]=[C:19]([C:18]2[C:17]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:16][N:14]3[CH:15]=[C:10]([C:9]([F:8])([F:39])[F:40])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][N:22]=1
Reactant: CN(C)CCCN
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(C(F)(F)F)cc3)nn3cc(C(F)(F)F)ccc23)n1
Solvent: O
Product: CN(C)CCCNc1nccc(-c2c(-c3ccc(C(F)(F)F)cc3)nn3cc(C(F)(F)F)ccc23)n1

Procedure:
3-(Dimethylamino)propylamine (0.04 mL) and methyl 4-{6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a white solid (0.012 g); 1H NMR (d6-DMSO) δ 9.52(1H, s), 8.50(1H, bs), 8.16(1H, d), 7.87(4H, dd), 7.69(1H, d), 7.26(1H, bs), 6.34(1H, bs), 3.25(2H, bs), 2.24(2H, bs), 2.11(6H, s), 1.63(2H, bs); m/z 509 (M+1)+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Mg+2].[O-:5][CH2:6][CH3:7].[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].S(=O)(=O)(O)O.[CH3:24]COCC>>[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([CH:3]([C:6](=[O:5])[CH3:7])[C:2](=[O:1])[CH3:24])=[O:12]
Reactant: CC[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(Cl)cc1Cl

Procedure:
A mixture of magnesium ethoxide (22.9 g, 0.2 moles) 2,4-pentanedione (20.0 g, 0.2 moles), and ether (150 ml) was heated at reflux for 1 hour. 2,4-Dichlorobenzoyl chloride (41.9 g, 0.2 mole) in ether (50 ml) was added to the mixture over a period of 15 minutes, and the resultant mixture was heated at reflux for an additional 0.5 hour. After cooling, the reaction mixture was poured into 200 ml of 10% sulfuric acid. The ether layer was separated and stirred with 250 ml of 5% copper (II) acetate. The resulting copper salt was filtered, washed with ether, and stirred with 6N hydrochloric acid to destroy the salt. The acidic aqueous solution was extracted with ether. The ether extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under vacuum yielding 21 g of the desired product as a yellow oil. It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy, and mass spectroscopy.