Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].Cl.[CH2:4]([N:6]([CH2:34][CH3:35])[CH2:7][CH:8]([OH:33])[CH2:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:27][CH2:28][CH:29]([OH:32])[CH2:30]Cl)=[CH:13][CH:12]=1)[CH3:5]>CO>[CH2:4]([N:6]([CH2:34][CH3:35])[CH2:7][CH:8]([OH:33])[CH2:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:27][CH2:28][CH:29]2[O:32][CH2:30]2)=[CH:13][CH:12]=1)[CH3:5]
Reactant: CCN(CC)CC(O)CNc1ccc(NCC(O)CCl)c2c1C(=O)c1ccccc1C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CC(O)CNc1ccc(NCC2CO2)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium hydroxide (0.3 g, 5.36 mmole) was added to a solution of 1-(3-diethylamino-2-hydroxypropylamino)-4-(3-chloro-2-hydroxypropylamino)-9, 10-anthracenedione hydrochloride salt (1 g, 1.78 mmole), the compound of Example 3, in methanol. The mixture was stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, chloroform with a methanol gradient up to a ratio of 10:1) to give the title product 1-(3-diethylamino-2-hydroxypropylamino)-4-(2, 3-epoxypropylamino)-9, 10-anthracenedione which is compound 1b-1 of Table 1 (391 mg, 52%), mp 98° C.: NMR (CDCl3) δ 1.06 (t, J=7.1 Hz, 6H, CH3), 2.62 (m, 7H, CH2), 2.87 (m, 1H, CH2), 3.27 (m, 1H, CH2), 3.49 (m, 2H, CH2), 3.59 (m, 1H CH2), 3.77 (m, 1H, CH), 3.96 (m, 1H, CH), 7.35 (s, 2H, Ar (2, 3)), 7.71 (m, 2H, Ar (6, 7)), 8.35 (m, 2H, Ar (5, 8)), 10.80 (b, 1H, NH), 10.92 (b, 1H, NH); Anal. Calcd for C24H29N3O4 : C, 68.1; H, 6.90; N, 9.92. Found: C, 67.86; H, 6.96; N, 9.85.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[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.[NH2:48][CH2:49][CH:50]([OH:62])[CH2:51][N:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH2:61][N:52]1[CH2:51][CH:50]([OH:62])[CH2:49][NH:48][C:18]([C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][CH:21]=1)[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)O)c2)CC1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 28 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
The solution of 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (100 mg, 0.31 mmol) and HATU (119 mg, 0.31 mmol) in DCM (10 mL) was stirred at 28° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (64.4 mg, 0.31 mmol) and DIPEA (48.4 mg, 0.38 mmol) was added and the resulting solution was stirred at 28° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the crude title product (150 mg, Yield 94%). LCMS (m/z): 509.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:15][CH2:14]1
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1O
Yield: 42 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methoxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 42% of theory; LC (method 4): tR=1.93 min; Mass spectrum (ESI+): m/z=338 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15][C:14]2=1>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH:24][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)=[O:9])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: Cn1nccc1C(=O)O
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Cn1nccc1C(=O)NC1CCCc2c1[nH]c1ccc(Cl)cc21

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-5-carboxamide was prepared from 2-methyl-2H-pyrazole-3-carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid (30% yield). 1H-NMR (CDCl3): δ 8.69 (s, 1H), 7.45 (m, 2H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.48 (d, 1H), 6.26 (d, 1H), 5.28 (m, 1H), 4.22 (s, 3H), 2.71 (m, 2H), 2.28 (m, 1H), 1.95 (m, 3H); MS m/z 327 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)([OH:5])=[O:3]
Reactant: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)OCC)c2)cc1CCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)O)c2)cc1CCC(=O)O
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A solution of 510 mg of 5-(3-ethoxycarbonylphenoxy)-2-(decyloxy)benzenepropanoic acid in 20 ml of ethanol was treated with an excess of potassium hydroxide in a small amount of water. After stirring for 18 hours, the solution was concentrated in vacuo. Diethyl ether and water added, the layers were separated, and the aqueous layer was acidified with lN hydrochloric acid. The aqueous layer was extracted with diethyl ether, and this extract was dried over sodium sulfate and concentrated in vacuo. Two crystallizations from ethyl acetate/hexane provided 200 mg of the desired title product, m.p. 102°-104° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:28][C:6]1[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10](=[O:21])[N:11]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2nccs2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2nccs2)c1O
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-1-thiazol-2-ylmethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (16 mg, 0.041 mmol), β-alanine (472 mg, 5.3 mmol) and NaOMe solution (8 mL, 4.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 6.8 mg of the title compound as a light brown solid. MS: (+) m/z 451.18 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.C([N:8]1[CH2:16][CH2:15][CH2:14][CH:10]([C:11]([OH:13])=O)[CH2:9]1)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:3].[C:11]([CH:10]1[CH2:14][CH2:15][CH2:16][NH:8][CH2:9]1)(=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccccc1
Reactant: CC(=O)N1CCCC(C(=O)O)C1
Reactant: O=S(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cl
Product: O=C(c1ccccc1)C1CCCNC1
Temperature: 60 °C
Yield: 16 %

Procedure:
The method is that of U.S. Pat. No. 3,576,810. To 500 ml. of thionyl chloride was added 85.6 g. (0.5 mole) of 1-acetylnipecotic acid. The stirred mixture was heated at ca. 60° C. for two hours and then the solvent was evaporated at reduced pressure. The crude acid chloride was taken up in 200 ml. of dry benzene and the resulting solution added slowly to a mixture of 133 g. (1.0 mole) of aluminum chloride in 400 ml. of dry benzene. After the addition was complete the mixture was refluxed one hour and then poured onto cracked ice. The organic layer was separated and the aqueous layer was extracted with benzene. The combined extracts were dried over magnesium sulfate and the solvent was evaporated at reduced pressure. The residual oil which did not crystallize on cooling was distilled at reduced pressure and the fraction boiling at 160°-170° C./0.05 mm. collected. The crude product weighed 50 g. A mixture of 50 g. of the crude 1 -acetyl-3-benzoylpyrrolidine and 200 ml. of 6 N hydrochloric acid was refluxed 12 hours, cooled and extracted with benzene. The combined extracts were washed with water, dried over magnesium sulfate and the solvent evaporated at reduced pressure. The residual oil weighed 15.1 g. (16% yield). A portion (2.5 g.) of the free base was dissolved in 50 ml. of isopropanol and treated with ethereal hydrogen chloride. The white crystalline salt which formed weighed 2.4 g. and melted at 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)=O>>[CH:27]1([C:25]([NH:24][C:20]2[CH:19]=[C:18]([C:16]3[N:3]4[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]4[N:1]=[CH:14][CH:15]=3)[CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccc(NC(=O)C2CCC2)c1
Product: CCOC(=O)c1cnn2c(-c3cccc(NC(=O)C4CCC4)c3)ccnc12

Procedure:
A 0.78 g portion of 3-amino-4-carboethoxypyrazole ard 1.36 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclobutanecarboxamide were reacted as described in Example 13, giving 1.52 g of the desired product, mp 123°-125° C.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=O.C(OP([CH2:56][C:57]#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[CH:56][C:57]#[N:58])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4'-nitrophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3',4'-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4'nitrobenzophenone (4 g, 14 mmol), diethylcyanomethylphosphonate (2.5 mL, 15.4 mmol) and lithium hexamethyldisilazide (11.8 mL, 15.4 mmol, 1.3M) with a reaction time of 17 hours at room temperature. The crude product was purified by chromatography (silica gel, 3% hexane/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a yellow solid: mp 117.5-120° C.; 1H NMR (CDCl3) δ 8.40-8.20 (m, 4H), 7.70-7.46 (m, 4H), 7.06-6.75 (m,6H), 5.84 (s, 1H), 5.70 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H); 13C NMR (CDCl3) δ 160.3, 151.7, 151.1, 149.2, 148.9, 148.7, 148.5, 148.5, 143.5, 130.6, 129.9, 129.6, 128.2, 123.7, 123.1, 122.2, 117.4, 117.3, 112.3, 111.0, 110.5, 96.2, 94.9, 56.0, 56.0; Anal. Calcd for C17H14N2O4. Theoretical: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.45; H, 4.66; N, 8.82.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][NH:2][CH3:1])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1CCBr
Reactant: CN
Solvent: C1CCOC1
Product: CNCCc1ccc(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methylamine in THF (2 M, 200 mL) was added 1-(2-bromo-ethyl)-4-fluoro-2-nitro-benzene (13.2 g, 0.053 mole) in a pressure bottle, the reaction mixture was stirred at 60° C. overnight and the solvent was removed. The solid residue was treated with sodium hydroxide (1 N, 100 mL) and the aqueous extracted with methylene chloride (2×100 mL). The combined organic layers were washed with water (100 mL), saturated sodium chloride (100 mL), dried (sodium sulfate) and concentrated to provide 10.4 g of the title compound as a dark brown oil. 1H NMR (DMSO-d6): 7.60 δ (dd, 1H); 7.35 δ (dd, 1H); 7.20 δ (d of t, 1H); 3.05 δ (t, 2H); 2.85 δ (t, 2H); 2.40 δ (s, 3H); 1.60 δ (broad, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[N:24]=1>C(O)(=O)C.C1COCC1>[Cl:22][C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:3]=[C:4]([NH:20][CH3:21])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[C:13]([F:19])[C:14]([F:18])=[C:15]([F:17])[CH:16]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[N:24]=1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)n3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (80 mg, 0.255 mmol) was added to a solution of 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (86 mg, 0.383 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 120° C. for 4 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (15.5 mg, 0.025 mmol, 9.77% yield). LC-MS (M+H)+=502.0. 1H NMR (500 MHz, CDCl3) δ ppm 11.88-12.12 (1H, m), 8.63 (1H, s), 7.68-7.81 (1H, m), 7.60 (1H, s), 7.47 (1H, s), 6.92 (1H, t, J=7.2 Hz), 3.94-3.99 (1H, m), 3.52 (8H, s), 3.22-3.29 (1H, m), 2.87-3.01 (1H, m), 2.74-2.85 (1H, m), 2.22-2.38 (1H, m).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[Br:6][CH2:7][C:8](Br)=[O:9].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOCC>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:8](=[O:9])[CH2:7][Br:6]
Reactant: O=C(Br)CBr
Reactant: C#CCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN(C)C(=O)CBr
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 13.8 g (0.2 mol) of N-methylpropargylamine in 20 ml methylene chloride was added dropwise to a stirred and cooled (below 15°C.) solution of 40.2 g (0.2 mol) bromoacetyl bromide and 16 g (0.2 mol) sodium bicarbonate in 250 ml methylene chloride. The reaction mixture was allowed to warm to about 25°C. and stirred for 2 hours. The reaction mixture was then filtered and evaporated under reduced pressure to give an oily residue. The residue was diluted with 150 ml ether to form a two-phase mixture consisting of an ether phase and a dark oil. The ether phase was separated, dried over magnesium sulfate, and evaporated to give 32.3 g of N-methyl-N-propargyl-α-bromoacetamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:22])=[C:4]([Cl:23])[N:3]=1.CCO.[N:27]([O-])=O.[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[N:22]=[N:27][N:8]([CH2:9][C:10]3[N:15]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])[CH:13]=[CH:12][CH:11]=3)[C:6]=2[N:7]=1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)c(N)c(NCc2cccc(N3CCCC3=O)n2)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nc(Cl)c2nnn(Cc3cccc(N4CCCC4=O)n3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of 1-{6-[(2,5-diamino-6-chloro-pyrimidin-4-ylamino)methyl]pyridin-2-yl}pyrrolidin-2-one (2.10 g, 6.29 mmol) in glacial acetic acid mL) and EtOH (24 mL) at 0° C. was treated with a solution of sodium nitrite (0.564 g, 8.17 mmol) in water (1.5 mL), stirred for 2 h, warmed to room temperature and the resulting precipitate filtered and dried to give the title compound (1.67 g, 77%) as an off-white solid; LC-MS retention time 1.99 min, (M+H)+ 345.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])([CH:13]=[CH2:14])[C:8]2=O)=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO.O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH:13]=[CH2:14])([CH2:6]2)[CH2:15][CH2:16][C:17](=[O:19])[CH:18]=1
Reactant: C=CC1(CCC(C)=O)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reaction time: 48 h

Procedure:
Methyl {[6,7-dichloro-1-oxo-2-(3-oxobutyl)-2-vinyl-2,3-dihydro-1H-inden-5-yl]oxy}acetate (7.3 gm., 0.02 mole) is dissolved in a solution of methanol (100 ml) and water (50 ml.) containing sodium hydroxide (9.43 gm., 0.236 mole), taking care to keep the temperature below 25° C. The solution is kept at ambient temperature for 48 hours. The solution is concentrated in vacuo to 100 ml. in a rotary evaporator at room temperature and poured into water (250 ml.) containing concentrated hydrochloric acid (26 ml.) with cooling. The product is separated by filtration, washed with water, dried and recrystallized from a mixture of acetic acid and water to obtain [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3([O:26][CH2:25][CH2:24][O:23]3)[C@H:13](Br)[CH2:12]4)[C@H:9]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33]C(=O)C)[CH2:8][C:7]=2[CH:6]=1)(=O)C.[OH-].[K+]>CS(C)=O.CO>[CH2:25]1[CH2:24][O:23][C:14]2([CH:13]=[CH:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C:20]2[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=2[CH2:8][C@H:9]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[O:26]1
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@@]3(C)[C@@H](C[C@@H](Br)C34OCCO4)[C@H]12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Yield: 68.9 %

Procedure:
A solution of 74.1 g of 3-acetoxy-7α-(5-acetoxypentyl)-16α-bromo-17,17-ethylenedioxy-estra-1,3,5(10)-triene in 740 ml of dimethyl sulfoxide and 74 ml of methanol is stirred with 74 g of potassium hydroxide for 7.5 hours at a bath temperature of 85° C. Then, it is precipitated with ice/water/common salt, taken up with ethyl acetate, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 36.12 g of pure 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol is obtained as foam.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:33])[CH3:32])=[O:29]>ClCCl>[Cl:33][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH3:32]
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(C)Cl)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (428 mg, 1.51 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.33 mL, 3.02 mmol) and 1-chloroethyl chloroformate (0.164 mL, 1.51 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (40) as a mixture of two diastereomers (530 mg, 100%), which was used without further purification in the following example. 1H—NMR (CDCl3, 400 MHz): δ 0.87 (m, 6H), 1.13 (m, 2H), 1.63 (m, 1H), 1.76 (m, 3H), 2.15 (m, 1H), 2.34 (m, 2H), 3.10 (m, 1H), 3.27 (m, 1H), 5.11 (br.s, 3H), 6.53 (q, 1H), 7.33 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:27])[CH2:12]1)([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2].[CH3:28]S(C)=O.CN(C=O)C.CI>O>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]([CH3:28])[CH2:17]2)[C@H:13]([OH:27])[CH2:12]1)([O:4][P:5]([OH:7])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)C[C@H]2O)c(=O)[nH]1
Reactant: CS(C)=O
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)C[C@H]2O)c2nc(N)[nH]c(=O)c21
Yield: 28 %

Procedure:
Compound 5 (34 mg, 0.055 mmol) was mixed with 1 mL of dimethylsulfoxide, 1 mL of DMF, and 100 μL of methyl iodide at room temperature. After 3 h the reaction mixture was treated with 30 mL of cold water and extracted three times with 10-mL portions of diethyl ether. After neutralization with NaHCO3, chromatographic separation of the aqueous phase on DEAE-Sephadex, using a linear gradient of 0 to 0.8 M TEAB, gave Compound 7 (yield: 10 mg, 28%).