Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[N:10]=[C:11]([NH2:13])[S:12][CH:2]=1)=[O:5])[CH3:8]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of 90% ethyl bromopyruvate (54.2 g, 0.25 mol) and thiourea (20 g, 0.263 mol) in 500 mL absolute ethanol was heated at reflux for 1 h and then stirred at ambient temperature for 2 h. Ethanol was removed in vacuo and the residue was suspended in ice-water and neutralized with solid potassium carbonate until basic. The solid was filtered, washed thoroughly with water and air-dried to give 42 g of ethyl-2-amino-4-thiazolecarboxylate.
Reaction SMILES: C(OC([NH:8][C:9]([NH:23]C(OC(C)(C)C)=O)=[N:10][C:11]1[N:12]=[CH:13][N:14]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH:15]=1)=O)(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[ClH:31].[CH3:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:14]2[CH:15]=[C:11]([NH:10][C:9]([NH2:23])=[NH:8])[N:12]=[CH:13]2)[CH:21]=1
Reactant: Cc1ccnc(-n2cnc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(-n2cnc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(1-(4-methylpyridin-2-yl)imidazol-4-yl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at ambient temperature for 23 hours. The solvent was evaporated under reduced pressure. To the residue was added 2-propanol, and the resultant precipitate was collected by filtration and dried under reduced pressure to give (1-(4-methylpyridin-2-yl)imidazol-4-yl)guanidine dihydrochloride (94 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)CC(C)OB([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])O1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.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.COCCOC>[CH3:22][C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:31](=[CH2:36])[C:32]([F:35])([F:34])[F:33])=[N:3][N:4]=[CH:5]2
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Reactant: C=C(B1OC(C)CC(C)(C)O1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: ClCCl
Product: C=C(c1nncc2cc(-c3cc(C(=O)OC)ccc3C)ccc12)C(F)(F)F
Temperature: 80 °C
Yield: 31.3 %

Procedure:
Methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (563 mg, 1800 μmol), 4,4,6-trimethyl-2-(1,1,1-trifluoroprop-2-en-2-yl)-1,3,2-dioxaborinane (799 mg, 3600 μmol), tetrakis(triphenylphosphine)palladium (208 mg, 180 μmol), ethyl alcohol (200 proof; 2000 μl), 1,2-dimethoxyethane (8000 μl), and potassium carbonate (2M aqueous solution; 2700 μl, 5400 μmol) were combined in a sealed tube and heated at 80° C. for 2 h, during which LC-MS indicated 100% conversion. The cooled reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. CombiFlash purification (20% to 80% EtOAc/Hexanes) afforded methyl 4-methyl-3-(1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-yl)benzoate (210 mg, 31% yield) as a golden yellow foam. MS (ES+): 373.2 (M+H)+.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.Cl.[CH3:10][O:11][NH:12][CH3:13].[NH2:14][C:15]1[C:37]([Cl:38])=[CH:36][C:18]([C:19]([NH:21][CH2:22][C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH2:24]2)=[O:20])=[C:17]([O:39][CH2:40][CH3:41])[CH:16]=1>C(Cl)Cl>[NH2:14][C:15]1[C:37]([Cl:38])=[CH:36][C:18]([C:19]([NH:21][CH2:22][C@@H:23]2[O:28][CH2:27][CH2:26][N:25]([CH2:29][CH:30]3[CH2:31][CH2:32][N:33]([C:5](=[O:4])[N:12]([O:11][CH3:10])[CH3:13])[CH2:34][CH2:35]3)[CH2:24]2)=[O:20])=[C:17]([O:39][CH2:40][CH3:41])[CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNOC
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CN(CC2CCNCC2)CCO1
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CN(CC2CCN(C(=O)N(C)OC)CC2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of trichloromethyl chloroformate (0.15 ml) and O,N-dimethylhydroxyamine hydrochloride (0.24 g) in methylene chloride (10 ml) was added TEA (1.02 ml) at room temperature, and the mixture was stirred for 1 hour. The suspension was added dropwise to a solution of (S)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-piperidinylmethyl)-2-morpholinyl]methyl]benzamide (Example 26) (1.0 g) in methylene chloride (10 ml) under ice cooling. After completion of addition, the internal temperature of the reaction solution was warmed to room temperature, and the solution was stirred for 2 hours. The reaction solution was washed with water, then brine, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (0.8 g) as a white solid. Melting point 127-129° C. (recrystallized from EA/H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O1C=CN=C1C1C=C(N2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CC(=O)N(c2cccc(-c3ncco3)c2)c2ccc3ccccc3c2N1
Reactant: Nc1cccc(Br)c1
Product: O=C1CC(=O)N(c2cccc(Br)c2)c2ccc3ccccc3c2N1

Procedure:
The titled compound was prepared from 1-nitro-2-naphthyltriflate and 3-bromoaniline in a procedure similar to that of example 6 (1), example 1 (2) and (3).
Reaction SMILES: [CH2:1]1[O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][N:7]([S:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=3[CH3:28])(=[O:17])=[O:16])[C@H:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][C:3]=2[O:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.C[Si](C)(C)[NH:46][O:47][Si](C)(C)C>C(Cl)Cl.CO>[OH:47][NH:46][C:9](=[O:10])[C@H:8]([N:7]([CH2:6][C:5]1[CH:29]=[CH:30][C:31]2[O:32][CH2:1][O:2][C:3]=2[CH:4]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)O)C(C)C)c(C)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)NO)C(C)C)c(C)c1C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)amino]-3-methylbutyric acid (3.82 g, 8.24 mmol) in dry methylene chloride (20 mL) was added oxalyl chloride (2.2 mL, 24.72 mmol) and a drop of dimethylformamide. The reaction mixture was stirred for 4 h and then concentrated. The residue was dissolved in methylene chloride (20 mL) and N,O-bis-trimethylsilylhydroxylamine (8.8 mL, 41.2 mmol) was added. After 4 h, methanol (1 mL) was added and the stirring was continued for 30 min. Silica gel (10 g) was added and the material was concentrated to dryness. The resultant powder was flash chromatographed on a silica gel column and eluted with 50% ethyl acetate/hexanes to give N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyramide (2.46 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH:37]=O>ClCCCl.CC(O)=O>[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:20][N:1]([CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10](=[O:11])(=[O:12])[NH2:13])=[CH:8][CH:9]=1)[CH2:37][C:36]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: Cn1ccnc1C=O
Reactant: CC(C)(C)OC(=O)C=O
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-aminoethyl)benzenesulfonamide (1.40 g, 7.0 mmol), AcOH (0.30 mL) and 1-methyl-1H-imidazole-2-carboxaldehyde (0.77 g, 7.0 mmol) in DCE (40 mL) was heated at 80° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated sequentially with NaBH(OAc)3 (4.45 g, 21 mmol) and tert-butyl glyoxalate (1.80 g). The reaction mixture was stirred at room temperature overnight and quenched with water. The reaction mixture was then extracted with DCM and the organic layer was dried and concentrated under reduced pressure. The residue obtained was purified by flash chromatography over silica gel to tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (0.63 g, 22%). 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J=8.4 Hz, 2 H), 7.26 (s, 2 H), 7.21 (d, J=8.0 Hz, 2 H), 6.99 (d, J=0.8 Hz, 1 H), 6.73 (d, J=0.8 Hz, 1 H), 3.76 (s, 2 H), 3.38 (s, 3 H), 3.28 (s, 2 H), 2.79 (t, J=7.2 Hz, 2 H), 2.69 (t, J=6.8 Hz, 2 H), 1.40 (s, 9 H); ESMS m/z: 409 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[S:21][C:20]([SH:22])=[N:19][C:18]=1[CH3:23])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[S:21][C:20]([S:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[N:19][C:18]=1[CH3:23])[CH3:13]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)Cc1sc(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1sc(Sc2ccc(C(F)(F)F)cn2)nc1C
Temperature: 65 °C
Yield: 57 %

Procedure:
2-Chloro-5-trifluoromethylpyridine (Ishihara Corporation, 600 Montgomery St., San Francisco, Calif. 94111) (0.5 g, 2.8 mmol) and 5-(2-ethoxy-2-oxoethyl)-2-mercapto-4-methyl-1,3-thiazole (K. Fleishmann, K. H. Scheunemann, H. U. Schortemmer, G. Dickneite, J. Blumbad, G. F. Fischer, W. Durckheimer, and H. H. Sedlacek, Arzneim-Forsch./Drug Res., 1989, 39(II), 743) (0.6 g, 2.8 mmol) were dissolved in acetone (15 ml) under a reaction inert atmosphere. Freshly ground K2CO3 (0.42 g, 3.0 mmol) was added to this solution and the reaction was heated to 65° C. for 16 hours. The K2CO3 was filtered off and the acetone was removed via rotary evaporation. The remaining slurry was diluted with a saturated aqueous solution of sodium bicarbonate, extracted three times (200 ml) with methylene chloride, dried over MgSO4 and filtered. The solvent was then stripped off and the resulting solid was purified via flash chromatography (50% ether in hexane) to afford the title compound of this Example (0.57 g, 57% yield). 1H NMR (CDCl3): δ 8.69 (1H, d, J=2), 7.75 (1H, dd, J=8,2), 7.29 (1H, d, J=8), 4.20 (2H, q, J=7), 3.79 (2H, s), 2.43 (3H, s), 1.28 (3H, t, J=7).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46])[CH2:37][CH2:36]3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1>Cl.CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:46])[F:47])[CH2:37][CH2:36]3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCN(CCCC(F)(F)C(F)(F)F)CC2)cc1
Agent: Cl
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCN1CCN(CCCC(F)(F)C(F)(F)F)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
7-(Methoxymethoxy)-3-(4-methoxymethoxyphenyl)-4-{9-[4-(4,4,5,5,5-pentafluoropentyl)piperazinyl]nonyl}-3-methylchroman (210 mg, 0.294 mmol) was dissolved in 2N-HCl solution in methanol, and the mixture was stirred at 50° C. for 1 hour. The mixture was cooled down to room temperature, adjusted to pH=9 using aqueous NaHCO solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic solvent was removed under reduced pressure. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=1:1) to give 162 mg (yield: 88%. (3RS,4RS):(3RS,4SR)=8:5) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].N1C=CC=NC1=O.[C:25]([Mg]Br)([CH3:28])([CH3:27])[CH3:26]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH2:16][CH3:17])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCOc1cc2c(cc1Br)C(=O)CCC2(C)C
Agent: O=c1nccc[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 7-bromo-6-ethoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound A-4, 2.0 g, 6.73 mmol) in THF (20 mL), ether (20 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1])-pyrimidinone (8 mL) at −30° C. was added a solution of tert-butylmagnesium bromide (2M in ether, 13.5 mL, 27 mmol). The reaction was allowed to warm to room temperature over 5 h. The reaction was quenched with ice water and extracted with ether. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was then dissolved in methanol (20 mL). After catalytic amount of p-toluenesulfonic acid was added, the reaction was stirred at 50° C. for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 1% ethyl acetate in hexane) to afford the title compound as a pale yellow oil
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=S>O1CCOCC1>[OH2:11].[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:14]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[NH:1][C:2]=2[CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)c(Cl)cc1S(N)(=O)=O
Solvent: C1COCCO1
Product: O
Product: O=S1(=O)N=C(n2ccnc2)Nc2cc(Cl)c(Cl)cc21

Procedure:
A mixture of 2-amino-4,5-dichlorobenzenesulfonamide (10 g) and thiocarbonyldiimidazole (22 g) in dioxane (160 mL) was refluxed for 2-3 h. The solvent was removed by distillation under reduced pressure and the residue was dispersed in water (100 mL). The addition of an aqueous solution of NaOH (16 g/160 mL) gave a solution which, after cooling, abundantly precipitated the crystalline sodium salt of the title compound. The salt was collected by filtration and dissolved in a 1:2 mixture of methanol and water (300 mL), treated with charcoal, filtered, and the filtrate was adjusted to pH 2 with 12N HCl. The precipitate was collected by filtration, washed with water and dried (yield: 11.3 g); m.p.: 312-315° C.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH:11]=[CH:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH:11]=[CH:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Yield: 69.7 %

Procedure:
A suspension of 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraene in 25 ml of methanol and 2.5 ml of water is refluxed at a bath temperature of 100° C. with 1.1 mg of oxalic acid for 1.5 hours. Then, it is added to water, extracted with dichloromethane, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.6 g of 17-difluoromethylene-estra-1,3,5(10),6-tetraen-3-ol is obtained as colorless crystals with a melting point of 132-134° C., [α]D22 =-167.9° (c=0.505% in pyridine).
Reaction SMILES: O(C1C=C(C=CC=1)N)C1C=CC([NH2:6])=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.[C:38]1(=[O:48])[O:43][C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>CN1CCCC1=O>[CH:46]1[CH:47]=[C:39]([C:38]([NH2:6])=[O:48])[C:40]([C:41]([OH:43])=[O:42])=[CH:44][CH:45]=1
Reactant: Nc1ccc(Oc2cccc(N)c2)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminatedimide polymer with theoretical number average molecular weight of 11,600 g/mole. 3,4'-Oxydianiline (ODA) (47.5 mmole, 9.5117 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (2.50 mmole, 0.7308 g) were dissolvedin N-methylpyrrolidinone (NMP) ( ~ 35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. 3,3',4,4'-Biphenyl tetracarboxylic dianhydride (BPDA) (48.043 mmole, 14.1354 g) and phthalic anhydride (PA) (3.914 mmole, 0.5797 g) were slurried in NMP (~ 35 mL) and were added to the solution. Afterwashing with ~ 30 mL of NMP to provide a 20% solids content reaction, an exotherm of 10°-15° C. was observed. The exotherm quickly subsided and the reaction was stirred at 25° C. for 16 hours to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ninh) of the phthalamide acid-terminated polyamide acid was 0.54 dL/g in NMP at 25° C. To imidize, toluene (30 mL) was added and the reaction was heated at 160° C. for 24 hours. After cooling, a powder precipitated which was washed twice in water and dried to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was insoluble in NMP and had a glass transition temperature 253° C. and melting endotherms at ~ 340 and ~ 373° C. A film cast from the polyamide acid solution and dried one hour each at 100°, 225°, and 371° C. had a Tg of 253° C. and a Tm at 340° C. and 373° C., and was tough and creasible.
Reaction SMILES: [Br:1][C:2]1[CH:3]=C([CH:7]=[C:8]([O:10][C@@H:11]([CH3:18])[CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)C#N.[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>O>[Br:1][C:2]1[CH:3]=[C:22]([CH:7]=[C:8]([O:10][C@@H:11]([CH3:18])[CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)[C:21]([OH:19])=[O:23]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Br)cc(C#N)c1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](COC(C)(C)C)Oc1cc(Br)cc(C(=O)O)c1

Procedure:
To a stirred solution of 3-bromo-5-[(1S)-2-tert-butoxy-1-methylethoxy]benzonitrile (1.00 equiv, 42.60 mmoles, 13.30 g) in ethanol (135 mL) and water (13.30 mL) was added sodium hydroxide liquor (46/48% w/w, 5213.0 mmol, 12.10 mL, 18.27 g). The resultant yellow solution was heated to reflux for 1 hour and the solvent removed in vacuo to give a wet orange solid. The mixture was partitioned between water (150 mL) and MTBE (100 mL). The coloured upper organic phase contained two layers and was separated from the lower aqueous phase. Note: high solubility of the product sodium salt in the organic phase; only minor loss to the aqueous layer. The organic layers were concentrated to give a gummy orange solid (approx 18 g). The residue was partitioned between aqueous HCl (1M, 200 mL) and MTBE (150 mL). The Layers were separated and the aqueous phase further extracted with MTBE (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange gum (12.85 g), which solidified on standing.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH2:22])[CH3:14])=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)Cc1ccc(OCCCCl)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)Cc1ccc(OCCCCl)cc1
Reaction time: 5 h

Procedure:
A 1.36 g sample of 4-(3-chloropropoxy)phenylacetone, prepared above, was dissolved in 200 mL of methanol. To this was added 7.71 g of ammonium acetate followed by 0.76 g sodium cyanoborohydride with stirring. After 5 hours, the solvent was evaporated in vacuo, the residue was dissolved in 150 mL diethylether and 200 ml of 1N hydrochloric acid solution. The aqueous phase was separated and washed with a second portion of diethylether, basified to a pH of 10-12 with 6N sodium hydroxide, and extracted with three, 100 mL portions of diethylether. The basic ether extracts were combined, dried, and evaporated to dryness in vacuo to yield1.11 g of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:39][C:35]2[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
The compound (403 mg) obtained in Example 62-2 was dissolved in anhydrous methanol (16 ml) and added with 1-methyl-2-imidazole carboxaldehyde (151 mg) and sodium cyanoborohydride (172 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The resultant was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (333 mg) as a colorless oily substance.