Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[Mg].[CH2:6]([N:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC.C1C=CC=CC=1>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([CH2:1][CH2:2][CH3:3])([O:20][CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCBr
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCC1(OCCO)CCN(Cc2ccccc2)CC1
Yield: 50.5 %

Procedure:
A solution of 108 g of propyl bromide in 250 ml of ether was added dropwise to a refluxing mixture of 19.2 g of magnesium in 100 ml of ether and then a solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 500 ml of benzene was added in increments. The ether was evaporated off and then cooled and hydrolyzed with a saturated aqueous ammonium chloride solution. The benzene phase was decanted and the aqueous phase was extracted with ether. The ether phase was washed with water until neutral, dried over sodium sulfate and the solvents removed under reduced pressure. The residue (B.p. = 129° C at 0.1mm/Hg) was rectified to obtain 28 g of 2-(1-benzyl-4-propyl-4-piperidyloxy)-ethanol as a yellowish oil. The product was dissolved in 250 ml of ether and 13 ml of a 5N hydrogen chloride solution in ether were added thereto. The product was vacuum filtered and crystallized from isopropanol and dried in vacuo to obtain 12.9 g of 2-(1-benzyl-4-propyl-4-piperidyloxy)-ethanol hydrochloride in the form of colorless crystals melting at 196° C.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][C:42]23[CH2:52][CH:51]2[CH2:50][C:45]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:44][CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][C:42]34[CH2:52][CH:51]3[CH2:50][C:45]3([O:46][CH2:47][CH2:48][O:49]3)[CH2:44][CH2:43]4)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCC4(CC2C3)OCCO4)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC4(CC2C3)OCCO4)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate of tert-butyl 5-chloro-2-fluoro-4-(spiro[bicyclo[4.1.0]heptane-3,2′-[1,3]dioxolan]-6-ylmethoxy)benzoate, the title compound was obtained as a colorless solid (1.30 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J=8.3 Hz, 1H), 6.42 (d, J=12.7 Hz, 1H), 3.95-3.86 (m, 4H), 3.84-3.70 (m, 2H), 2.22-1.98 (m, 4H), 1.82-1.72 (m, 2H), 1.64-1.57 (m, 2H), 1.56 (s, 9H), 1.49-1.35 (m, 2H), 1.11-1.04 (m, 1H), 0.80-0.75 (m, 11H), 0.65-0.60 (m, 1H), 0.56 (t, J=5.3 Hz, 1H); MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30](O)=[O:31])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:34][NH2:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30]([NH:35][CH3:34])=[O:31])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Reactant: CN
Product: CNC(=O)C(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 at 50° C. using 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}propanoic acid (Example 354) and methylamine. Purification was accomplished by preparative HPLC (method 1) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17](O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH3+:57])[CH3:56])=[CH:51][CH:50]=1)=[O:48].CCN(C(C)C)C(C)C>C(#N)C>[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH:57][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[O:18])[CH3:56])=[CH:51][CH:50]=1)=[O:48]
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(tert-butoxycarbonyl)indoline-7-carboxylic acid (0.5 g, 1.9 mmol), HATU (795 mg, 2.09 mmol) and (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride (511 mg, 2.85 mmol) were added to acetonitrile (12.7 ml). The solution was cooled in an ice bath and DIPEA (993 ul, 5.7 mmol) was added. The ice bath was removed and the mixture stirred for 2 hours at RT. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 8.40 (d, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.30 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 5.10 (m, 1H), 4.00 (m, 2H), 3.85 (s, 3H), 3.05 (m, 2H), 1.45 (d, 3H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:16][CH2:15][CH2:14][CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCCl)c2ccccc21
Temperature: 65 °C
Yield: 84.7 %

Procedure:
A mixture of 1-methyl-1H-benzo[d]imidazol-2(3H)-one (2 g, 13.5 mmol, 1 equiv), 1-bromo-3-chloropropane (3.98 ml, 40.5 mmol, 3 equiv), and potassium carbonate (2.79 g, 20.25 mmol, 1.5 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and diluted with ethyl acetate. After being washed with water and brine, the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified using the Biotage chromatography system (SNAP 100 g cartridge, Rf=0.6, gradient—10%-50% ethyl acetate/hexanes) to afford 1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one as a clear oil (2.57 g, 85%); 1H NMR (400 MHz, DMSO-d6): δ 2.05-2.12 (m, 1H); 2.14-2.21 (m, 1H); 3.32 (s, 3H); 3.53 (t, 1H, J=6.8 and 6.4 Hz); 3.66 (t, 1H, J=6.4 Hz); 3.92-3.97 (m, 2H); 7.05-7.09 (m, 2H); 7.12-7.16 (m, 1H); 7.17-7.21 (m, 1H); MS for C11H13ClN2O m/z 226.07 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15]O>Cl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Agent: Cl
Product: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
4-Hydroxy-3-(trifluoromethyl)benzoic acid (2 g, 9.7 mmol) was dissolved in methanol (40 mL) and 12N HCl (10 drops) was added thereto. The reaction mixture was stirred at 90° C. for 48 hours, cooled to room temperature and concentrated, and then ethyl acetate (100 mL) was added thereto. The reaction mixture was washed with sat. NaHCO3 Solution, and the organic layer was dried with Na2SO4, filtered and concentrated to obtain the title compound (2.07 g, 91%) without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:33](OS(F)(=O)=O)[CH3:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:40])[C@H:13]1[NH:41][C:42](=[O:50])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C.[Na+].[Cl-]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][S:11][C@H:12]1[N:15]([C:16](=[C:33]=[CH2:34])[C:17]([O:19][CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])[C:14](=[O:40])[C@H:13]1[NH:41][C:42](=[O:50])[CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(OS(=O)(=O)F)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Under a stream of dry nitrogen, the flask was charged with 500 mg (0.65 mmol) of diphenylmethyl 2-[(3R, 4R)-4-[(benzothiazol-2-yl)dithio]-3-phenylacetamido-2-oxo-azetidin-1-yl]-3-fluorosulfonyloxy-2-butenoate (XVf) and 5.0 mL of dry THF. After stirring the solution for 15 min at 0°-5° C., 92.0 μL (0.65 mmol) of triethylamine was added dropwise. Stirring at 0°-5° C. under a blanket of dry nitrogen was continued for 2 h. The solution was diluted with THF (10 mL) and poured into an aqueous saturated NaCl solution (30 mL). The phases were separated and the organic phase was dried 15 min over anhydrous MgSO4, filtered and concentrated to a small volume (ca. 6 mL). The solution was added dropwise into 36 mL of hexanes with vigorous stirring. After 30 min, the solid was collected by suction filtration and dried in vacuo for 3 h at 22° C. to yield 387 mg (92%) of the title product as a beige powder.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][O:47][CH3:48].[I-].[K+]>CN(C)C=O.O>[F:37][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH2:45][CH2:46][O:47][CH3:48])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: COCCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (81 mg) and potassium carbonate (105 mg) in N,N-dimethylformamide (5 ml) are added, at room temperature, 1-bromo-2-methoxyethane (84 mg) and potassium iodide (2.5 mg). The reaction mixture is stirred at 80° C. for 3 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(2-methoxyethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (41 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.CS(O)(=O)=O.[CH3:18][OH:19]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH3:18])=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=c1[nH]ccc2ccc(F)cc12
Agent: CS(=O)(=O)O
Product: COc1c[nH]c(=O)c2cc(F)ccc12
Yield: 84 %

Procedure:
To a solution of 7-fluoroisoquinolin-1(2H)-one (11 g, 67.4 mmol) in methanol was added iodozobenzenediacetate (21.7 g, 67.4 mmol) followed by methane sulphonic acid (7.78 g, 81 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered and washed with water to get crude compound (11 g, 84%) as light red color solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.06-8.04 (m, 1H), 7.96-7.93 (m, 1H), 7.62-7.54 (m, 2H), 6.74 (s, 1H), 3.89 (s, 3H); MS: MS m/z 194.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH:16]=[O:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH2:16][OH:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]3)=[CH:4][CH:3]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: OCc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a suspension of 2 g of 2-(p-chlorophenyl)-3-formylimidazo[2,1-b]benzothiazole in 100 ml of chloroform and 200 ml of ethanol was added 1 g of sodium borohydride and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and 900 ml of chloroform was added to the residue. After removing the insoluble materials which formed, the residue was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was recrystallized from isopropyl alcohol to provide 1.2 g of 2-(p-chlorophenyl)-3-hydroxymethylimidazo[2,1-b]benzothiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([F:18])[CH:3]=1.FC1C=C([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[F:18][C:4]1[CH:3]=[C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Fc1cc(Br)ccc1Nc1nc2ccccc2s1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)c(F)c2)OC1(C)C

Procedure:
N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine was prepared from N2-(4-bromo-2-fluorophenyl)-1,3-benzothiazol-2-amine (1.699 g, 5.258 mmol) in a manner similar to that used for N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.825 g, 42%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=14.48 min, 90%; m/z 371 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][CH3:18])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2=O.P(Cl)(Cl)([Cl:21])=O>C(OCC)C>[Cl:21][C:6]1[C:5]2=[N:4][N:3]([CH2:16][CH2:17][CH3:18])[C:2]([NH2:1])=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCn1nc2c(=O)[nH]c3ccccc3c2c1N
Solvent: CCOCC
Product: CCCn1nc2c(Cl)nc3ccccc3c2c1N
Temperature: 25 °C

Procedure:
A solution of 1-amino-2-propyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (86 mg, 0.36 mmol) in phosphorus oxychloride (3 mL) was heated at 100° C. for 45 minutes and then allowed to cool to ambient temperature. The reaction mixture was diluted with diethyl ether (10 mL). A solid was isolated by filtration, rinsed with diethyl ether, and dried to provide 4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-amine.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].C(O)C.O.[Br:25][C:26]1[C:27]2[C:28]3[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30](S)[C:29]=3[CH:36]=[CH:37][CH:38]=2>C(O)C>[Br:25][C:26]1[C:27]2[C:28]3[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:29]=3[CH:36]=[CH:37][CH:38]=2
Reactant: NCCCCCCCCCCn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1ccc2c3c(cccc13)C(NCCCCCCCCCCn1ccnc1)=N2
Yield: 70 %

Procedure:
A mixture of 2.8 g of 10-(1H-imidazol-l-yl)decanamine, dihydrochloride was treated with 2 ml of 10N sodium hydroxide in an ethanol-water mixture giving the base derivative. To this base was added 25 ml of ethanol, 2.33 g of 6-bromo-benz(cd)indole-2-thiol and 3.0 g of mercuric acetate. The procedure of Example 1 was then followed, giving 2.8 g of the desired product, mp 115° C.-116° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([OH:23])=[CH:15][C:14]=1[CH:13]=[C:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)(=O)C.[CH3:37][NH:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:39]([N:38]([CH3:37])[C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:12]1[C@@H:11]2[C@@H:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:23])=[CH:15][C:14]=3[CH:13]=1)[CH2:21][CH2:22][C@@:6]1([CH3:7])[C@H:8]2[CH2:9][CH2:10][C@@H:5]1[OH:4])[CH2:40][CH2:41][CH3:42]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C(CCCCCCCCCCC(=O)O)=Cc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: CCCCNC
Product: CCCCN(C)C(=O)CCCCCCCCCCC1=Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in the first two paragraphs of Example 1 was repeated except that 11-(17β-acetoxy-3-hydroxyoestra-1,3,5(10),6-tetraen-7-yl)undecanoic acid and N-methyl-N-butylamine were used as starting materials. There was thus obtained as an oil N-n-butyl-N-methyl-11-(3,17β-dihydroxyoestra-1,3,5(10),6-tetraen-7-yl)undecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [N:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5])[OH:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[N:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4](=[N:13][OH:14])[NH2:5])[OH:2]
Reactant: NO
Reactant: N#CC(=NO)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)C(=NO)c1cccnc1

Procedure:
A mixture of alpha-oximino-3-pyridylacetonitrile (41.0 g, 279 mmol), hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8 g, 620 mmol) in ethanol (99.9%, 500 ml) was refluxed for 4 h. After cooling, the precipitate was collected by filtration and dried. The precipitate contained the wanted product and sodium acetate (85 g, 168%); M+ : 180.
Reaction SMILES: CN([CH:4]=[C:5]1[C:9](=O)[CH2:8][CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6]1)C.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>CO>[NH2:18][C:17]1[N:19]=[CH:4][C:5]2[CH2:6][CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:9]=2[N:16]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CC(=O)C(=CN(C)C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1Cc2cnc(N)nc2C1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-[(dimethylamino)methylidene]-4-oxocyclopentanecarboxylate (71.7 mg, 0.36 mmol) in anhydrous methanol (2.5 mL) was added guanidine hydrochloride (124.7 mg, 1.3 mmol) followed by sodium methoxide in methanol (0.24 mL, 1.27 mmol). The mixture was heated to 90° C. in a sealed tube overnight. The crude reaction was quenched with 2 N HCl and concentrated in vacuo. The aqueous residue was purified by HPLC (30×100 mm Waters Sunfire column; 5 micron; 35 mL/min.; 210 nM; 0% to 40% CH3CN+0.05% TFA/water+0.05% TFA over 15 min.; the compound eluted at 10% CH3CN+0.05% TFA/water+0.05% TFA) to afford the title compound after lyophilization.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1ccccc1NN
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1nccc1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 2-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale pink solid (85 mg, 21%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>N1C=CC=CC=1>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CSC(=NC#N)SC
Solvent: c1ccncc1
Product: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 75 %

Procedure:
A solution of (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (15.00 g) and dimethyl N-cyanoimidodithiocarbonate [(CH3S)2C=N--CN] (10.05 g) in pyridine (75 ml) was stirred at 80° C. for 10 hours, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, and washed with 5% hydrochloric acid, brine, saturated aqueous sodium bicarbonate solution and brine, successively. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (300 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and concentrated in vacuo to give (3S,4R)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (16.3 g).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([Cl:29])=[O:25])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.1 %

Procedure:
A mixture of 20 g of m-tetradecyloxyphenylacetic acid, 10.93 g of oxalyl chloride and 41.95 mg of N,N-dimethylformamide in 250 ml of methylene chloride is stirred at ambient temperature for 5 hours. The solvent is removed and the concentrate dissolved in 1:1 ether:hexane and filtered through diatomaceous earth. The filtrate is evaporated to give 21.3 g of the desired product as a light yellow solid.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C>CCCCCC.CC(C)=O>[CH3:16][C@@:15]12[C:14](=[O:24])[CH2:13][CH2:12][C@H:11]1[C@@H:10]1[C:9]([CH:8]=[C:7]3[CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21][C@:20]3([CH3:23])[C@H:19]1[CH2:18][CH2:17]2)=[O:25]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
The last remains of the product (3) from the mother liquor were obtained by column chromatography of the mother liquor (adsorbed on silica gel) on a small column of silica gel (80-200 mesh) utilizing hexane-acetone (85:15) as eluent. An additional 0.15 gm of 7-oxo-DHEA-Ac (3) was obtained. Total yield 1.75 gm, 56.5% (based on 90% conversion), melting point 185-186° C.