Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:8]([O:10]C)=[O:9].N.Cl>O.C(OCC)(=O)C>[NH2:1][C:2]1[NH:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[N:4]=1
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of cyanogen bromide (5.0 mL, 5 M in acetonitrile, 25 mmol) was added to a mixture of methyl 3,4-diaminobenzoate (3.0 g, 18 mmol) in water (50 mL). The reaction was stirred at room temperature overnight. Aqueous ammonia (20 mL) and ethyl acetate (100 mL) were added to the reaction mixture and the layers were separated. The organics were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added 2 N aqueous hydrochloric acid (18 mL, 36.0 mmol) and the mixture was heated at reflux overnight. The reaction was concentrated to give the title compound (2.90 g, 97%). 1H NMR (400 MHz, DMSO-d6, δ): 8.75 (s, 2H), 7.84 (s, 1H), 7.77 (dd, J=1.2, 8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[CH2:16]P(=O)(OC)OC)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:25][C@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=2)[C@@H:29]([CH:43]=O)[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27]1>C1COCC1>[Si:3]([O:10][C@@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])/[CH:16]=[CH:43]/[C@H:29]1[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27][C@@H:26]([Cl:25])[C@@H:30]1[CH2:31][CH2:32][CH2:33][C:34]1[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: COP(=O)(CC(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)OC
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
To a suspension of 160.3 mg of sodium hydride (60% oil dispersion, 4.00 mmol) in 8 ml of THF at 0° C. was added a solution of dimethyl (S)-6-(tert-butyldimethylsilyl-oxy)-2-oxoheptylphosphonate 13 (1.41 g, 4.00 mmol) in 4 mL THF. The mixture was stirred at 0° C. for 30 min before a solution of aldehyde 7 (1.10 g, 2.65 mmol) in 4 ml of THF was added dropwise. The syringe containing the aldehyde was rinsed with 2 mL of THF to complete the addition and the mixture was stirred at 25° C. for 2.5 h. The reaction was worked up with addition of saturated aqueous ammonium chloride (50 mL) and the aqueous layer was extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were combined and washed with brine, dried over 30 g of anhydrous sodium sulfate, filtered and concentrated in vacuo. FCC (flash column chromatography) purification (silica gel, 6:1 hex/EtOAc) provided 1.60 g (95%) of enone 14.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)[C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:19])=[C:13]([CH2:16]I)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[OH:61][C:62]1[CH:63]=[C:64]([C:69]2[O:73][C:72]([SH:74])=[N:71][CH:70]=2)[CH:65]=[CH:66][C:67]=1[OH:68].C(=O)([O-])O.[Na+:79]>O>[NH2:41][C:38]1[S:39][CH:40]=[C:36]([C:5](=[N:4][O:3][CH2:1][CH3:2])[C:6]([NH:8][C@@H:9]2[C:34](=[O:35])[N:11]3[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][S:74][C:72]4[O:73][C:69]([C:64]5[CH:65]=[CH:66][C:67]([OH:68])=[C:62]([OH:61])[CH:63]=5)=[CH:70][N:71]=4)[CH2:14][S:15][C@H:10]23)=[O:7])[N:37]=1.[Na+:79]
Reactant: Oc1ccc(-c2cnc(S)o2)cc1O
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3ncc(-c4ccc(O)c(O)c4)o3)CS[C@H]12)c1csc(N)n1

Procedure:
A trifluoroacetate obtained by the same operation as in EXAMPLE 1 by using 1.0 g (1.06 mmol) of benzhydryl 7β-[2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (syn-isomer) and 0.260 g (1.2 mmol) of 5-(3,4-dihydroxyphenyl)-2mercaptooxazole, was suspended in water and adjusted to pH6.5 with a saturated sodium hydrogencarbonate aqueous solution. Insoluble substances were filtered off and the filtrate was subjected to reversed phase column chromatography (LC-Sorb RP-18, manufactured by Kemco Co.). The fraction (elution with a 20% methanol aqueous solution) containing the desired compound was collected, concentrated and freeze-dried to obtain 70 mg (yield: 10.2%) of the above identified compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][NH:10][C:11]2[N+:12]([O-:17])=[N:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1.ClCCl.[Br:23]Br>CC#N>[Br:23][C:14]1[N:13]=[N+:12]([O-:17])[C:11]([NH:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:19])[CH3:18])=[N:16][CH:15]=1
Reactant: CC(C)(CNc1nccn[n+]1[O-])c1ccc(F)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(CNc1ncc(Br)n[n+]1[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a solution of N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide (1.2 g, 7.4 mmol) in a 1:1 mixture of dichloromethane and CH3CN (40 mL) was added Br2 (1.0 mL, 19 mmol). The mixture was stirred at room temperature for 72 h. The solvents were evaporated and the residue was dissolved in ether. The solution was filtered through a plug of silica gel and the solvents evaporated to give the desired product (1.5 g, 58%) as an orange sticky solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1cccc(Cl)c1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)cccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichlorobenzene and isolated as white solid (5.8 mg, 32%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: Cc1cc(Cl)c(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(C)cc1Cl
Temperature: 60 °C
Yield: 88 %

Procedure:
To a solution of 2-chloro-5-iodo-4-methylbenzoic acid (Preparation 49, 2.50 g, 8.43 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.2 mL) and the reaction was heated at 60° C. for 18 hours. The reaction was cooled, concentrated in vacuo, diluted with water and basified with potassium carbonate until pH=9. The aqueous solution was extracted with EtOAc (3×100 mL), the organic layers combined, washed with water (100 mL), brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.3 g, 88%).
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:27])[CH:15]=[C:16]([C:25]#[N:26])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)=[O:12])[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[CH2:8]([O:10][C:11]([C:13]1[N:14]([CH3:27])[CH:15]=[C:16]([C:25]#[N:26])[C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:20][CH:19]=1)=[O:12])[CH3:9]
Reactant: [Zn+]C1CCCC1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)cn1C
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C3CCCC3)cc2)c(C#N)cn1C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Add cyclopentylzinc bromide (0.5M, 7.2 mL, 3.6 mmol) to 3-(4-bromo-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.50 g, 1.80 mmol, prepared in example E-3a or E-3b), tris(dibenzylideneacetone)palladium(0) (0.06 g, 0.07 mmol), and triphenylphosphine (0.07 g, 0.27 mmol) in dioxane and heat to 80° C. with stirring. After 18 hours, cool the reaction mixture, and pour into water. Extract the quenched reaction mixture with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexane to provide the title compound. Mass spectrum (m/e): 323.3 (M+1).
Reaction SMILES: [F:1][C@@H:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]([OH:7])[CH2:5][OH:6].O([Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Si:30]([O:7][CH:4]([CH2:5][O:6][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:2]([F:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](C(O)CO)[C@@H](F)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a 500 mL RBF containing tert-butyl (1S,2R)-1-fluoro-3,4-dihydroxy-1-phenylbutan-2-ylcarbamate (98.00 mg, 327 mmol) was added DCM (5 mL) and the mixture was allowed to stir at 0° C. for 5 min. At this time, TEA (274 μA, 1964 mmol) and tert-butyldimethylsilyl triflate (188 μl, 818 μmol) was added to the mixture via syringe. The reaction was allowed to stir for 30 min and then quenched with sodium bicarbonate (50 ml, sat). The aq. layer was extracted with DCM (3×25 ml). The combined organics were washed with brine, dried with sodium sulfate and passed through a plug of silica gel and concentrated to give 203 mg of a yellow oil that was taken directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.BrN1C(=O)CCC1=O.[CH2:31]([SH:34])[CH2:32][SH:33].[OH-].[Na+]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:34][CH2:31][CH2:32][S:33]1
Reactant: SCCS
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCS1
Temperature: 25 °C
Reaction time: 3.7 h
Yield: 120.1 %

Procedure:
To the solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-formyl-1H-pyrazole-3-carbonitrile (5.00 g, 13.7 mmol) in dichloromethane (100 mL) at room temperature was added N-bromosuccinimide (0.74 g, 4.1 mmol) followed by 1,2-ethanedithiol (1.98 g, 20.6 mmol). The resulting mixture was stirred at room temperature for 3.7 hr. It was then worked up by adding 2 N sodium hydroxide. The layers were separated and the organic layer was washed with brine and then dried (sodium sulfate). It was then concentrated to afford a light beige solid (7.0 g). 19F-NMR: −63.791.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[F:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:23]1[C:22]([C:12]2[CH:13]=[C:14]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[CH:32][N:31]=[C:30]([F:29])[CH:35]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 110 °C
Yield: 74.5 %

Procedure:
A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (104.72 mg, 0.264 mmol), 2-fluoropyridin-4-ylboronic acid (74.4 mg, 0.528 mmol), potassium phosphate (168 mg, 0.792 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (9.34 mg, 0.013 mmol). The vial was flushed with Argon, then dioxane (990 μL) and water (330 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (30-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (90 mg) as a light-yellow solid. MS m/z=458.2 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:18]1[C:22]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=2)=[CH:21][N:20]=[CH:19]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH3:17])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[N:24][CH:25]=2)[CH2:2][CH2:3]1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=0.93 min; Mass spectrum (ESI+): m/z=405 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:23])[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: CCOC(=O)c1c[nH]c2cnc3c(F)c(F)ccc3c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(F)ccc3c2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A suspension of 35 g of ethyl 7,8-difluoro-1-oxo-1,4-dihydrobenzo[f][1,7]-naphthyridine-2-carboxylate and 31.8 g of potassium carbonate in 350 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 3 hours. After cooling to 50° C., 65 g of methyl iodide were added; the mixture was heated at 90° C. for 3 hours. After cooling to 20° C., the insoluble material was dewatered, washed 4 times with 100 cm3 of water, 3 times with 100 cm3 of ethanol, and twice with 100 cm3 of diethyl ether. 25.5 g of ethyl 7,8-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of white crystals, which melted at 320° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]([CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:23]([CH3:22])[CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:29][CH:28]=2)=[N:3][CH:4]=1
Reactant: CN1CCC(N(C)c2ccc(N)cc2)CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 34 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide and N1-methyl-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in 34% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.60 (d, 1H, J=8.2 Hz), 8.06 (s, 1H), 8.18 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=7.7 Hz), 7.31 (d, 2H, J=8.9 Hz), 7.16 (t, 1H, J=7.5 Hz), 6.77 (d, 2H, J=8.9 Hz), 3.51 (tt, 1H, J=11.3, 3.8 Hz), 3.00 (d, 2H, J=10.6 Hz), 2.76 (s, 3H), 2.72 (s, 3H), 2.34 (s, 3H), 2.11 (t, 2H, J=10.2 Hz), 1.90 (q, 2H, J=11.3 Hz), 1.73 (d, 2H, J=12.0 Hz); MS (ESI): 530.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[C:20][Si](C)(C)C)[CH:14]=3)=[CH:12][C:3]1=2.C(=O)([O-])[O-].[K+].[K+]>CO>[C:19]([C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:25])([CH3:1])[C:3]=3[CH:12]=2)[CH:18]=[CH:17][CH:16]=1)#[CH:20]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4,4-dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.7 g, 2 mmol) and potassium carbonate (2 g, excess) in anhydrous methanol was stirred at rt under nitrogen for 4 hours. The mixture was treated with ice-water (100 mL) and extracted with ethyl acetate (2×80 mL). The organic layers were washed with brine and dried with MgSO4. The solvent was removed and the title compound was obtained as a off-white solid (0.4 g, 72%): mp 171-172° C.; 1H-NMR (DMSO-d6) δ10.3, (s, 1H), 7.78 (bs, 1H), 7.72-7.69 (m, 1H), 7.6-7.57 (m, 2H), 7.49-7.43 (m, 2H), 6.97 (d, 1H, J=7.98 Hz), 4.25 (s, 1H), 1.67 (s, 6H); MS (EI) m/z 277([M+], 100%); Anal. Calc. For C18H15NO2; 0.2 EtOAc: C, 76.56, H, 5.67, N, 4.75. Found: C, 76.34, H, 5.4, N, 4.7.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:26])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]([NH:13][NH:14]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][C:9](=[O:25])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](=O)[C:36]([F:39])([F:38])[F:37]>CO>[Cl:1][C:2]1[S:3][C:4]([Cl:26])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[N:13]=[N:14][CH:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[C:10]=2[C:9](=[O:25])[CH2:8]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)sc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CC(c2cc(Cl)sc2Cl)Cc2nncc(C(F)(F)F)c21
Yield: 50.9 %

Procedure:
To a mixture of 5-(2,5-dichlorothiophen-3-yl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), anhydrous potassium carbonate (0.9 g) and methanol (20 ml) was added, under ice-cooling, 1-bromo-3,3,3-trifluoropropan-2-one (1.24 g), and the mixture was stirred at the same temperature for 0.5 hours. To the mixture was added anhydrous potassium carbonate (1.2 g), and the mixture was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in acetic acid (15 ml). To the solution was added concentrated sulfuric acid (0.6 ml), and the mixture was refluxed for 30 minutes. To the reaction solution was added water (120 ml), and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with sodium hydrogen carbonate solution and concentrated. The residue was purified with silica gel column chromatography to give 7-(2,5-dichlorothiophen-3-yl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.867 g) as oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CN(C)C=O.C([O-])(=O)C.[K+]>ClCCl>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.26 g), 4-acetylphenylboronic acid (0.15° g), N,N-dimethylformamide (30 mL), potassium acetate (0.26 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(11), complex with dichloromethane (1:1) (40 mg) was heated at 90° C. over night. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 mL), brine (30 mL), dried and 3 concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueous lithium hydroxide solution (6.78 mL) and stirred for 16 hours. The reaction mixture was acidified to pH 2 using 0.1 M hydrochloric acid and extracted with ethyl acetate (3×25 mL). The extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50 mg). LC/MS System C: Rt=4.18 mins, m/z (ES−)=349 (M− for C21H18O5).
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@H:19]([O:34]C(OC)=O)[CH2:20][C@@H:21]3[O:29]C(OC)=O)=[CH:16][C@H:15]4[O:39]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C[O-].[Na+]>CO.O>[CH3:44][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:34])[CH2:20][C@@H:21]3[OH:29])=[CH:16][C@H:15]4[OH:39])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COC(=O)O[C@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
In 5 ml of methanol was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3α,7α- tris(methoxycarbonyloxy)pregn-5-ene, followed by addition of 30 mg of sodium methoxide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured in water and extracted with methylene chloride. The extracts were pooled, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The concentrate was recrystallized from ethyl acetate to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-5-ene-1α,3β,7α-triol showing the following physical properties.