Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:34]2[CH:33]=[CH:32][C:31]([N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[CH:36][CH:35]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)c(C)n1
Temperature: 50 °C
Yield: 30 %

Procedure:
Next, there were put 0.36 g of 2-chloro-3,5-dimethylpyrazine, 0.92 g of 4,4,5,5-tetramethyl-2-(4-diphenylaminophenyl)-1,3,2-dioxaborolane obtained in Step 1, 0.26 g of sodium carbonate, 0.011 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile in a recovery flask equipped with a reflux pipe. The air in the flask was replaced by argon. This reaction container was heated by microwave irradiation (2.45 GHz, 100 W) for 20 minutes. After that, the reaction container was cooled to 50° C. or lower, water was added to the reaction solution, and the organic layer was subjected to extraction with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled, and the obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane and ethyl acetate as a developing solvent, thereby obtaining the objective pyrazine derivative Hdmdpappr (white powder, 30% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, produced by CEM Corporation). The synthesis scheme of Step 2 is shown by (b-2).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C.O>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=Cc1ccc(OCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Aqueous 1N Sodium hydroxide solution (6.0 mL, 12.0 mmol) was added to a solution of 4-hydroxycinnamic acid (536.0 mg, 3.2 mmol) in ethanol (10.0 mL). 2-Bromoethylbenzene (575.0 mg, 3.1 mmol) was then added to the reaction mixture and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to afford a white residue, which was taken up in water. The aqueous phase was then acidified with concentrated hydrochloric acid to produce a white precipitate which was isolated by filtration and washed with water, then dried to afford (544.0 mg, 66.8%) of the desired 4-phenethyloxycinnamic acid as a white powder. 1H NMR (300 MHz, DMSO) δ 3.82 (3H, s, OCH3), 4.78 (2H, s, CH2), 6.92 (2H, d, 2×ArH, J=7.5 Hz), 7.16 (2H, d, 2×ArH, J=7.5 Hz), 7.52-7.60 (1H, m, ArH), 7.62-7.72 (1H, m, ArH), 7.98 (1H, m, ArH).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc(Cl)c2ccccc2n1
Reactant: Cc1ccccc1N
Solvent: CCO
Product: Cc1ccccc1Nc1nc(N)nc2ccccc12
Yield: 61 %

Procedure:
2-Amino-4-chloroquinazoline (0.64 g, 0.0036 mol) was heated to 170° in o-toluidine (1 ml, 0.008 mol) for 1 hour. The reaction mixture was dissolved in ethanol, stripped and partitioned between chloroform and NaOH solution (pH 9). The organic solution was dried, filtered and excess solvent removed to give an oil which afforded crystals of 2-amino-4-(2-methylphenylamino)-quinazoline (0.55 g, 62%) m.p. 273°-275° (from ethanol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH:23]=[O:24])[CH3:21])[CH3:16]>>[CH2:1]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH:23]([OH:24])[CH2:22][CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]=[C:15]([CH3:14])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CBr)COCc1ccccc1
Reactant: CC(C)=CCCC(C)CC=O
Product: CC(C)=CCCC(C)CC(O)CC(C)COCc1ccccc1

Procedure:
This compound was prepared starting from the rac. 3-benzyloxy-2-methyl-1-propyl bromide and racemic citronellal using the procedure described in Example 4. Rac.-1-benzyloxy-2,6,10-trimethyl-9-undecen-4-ol was obtained as a colorless oil, b.p. 145°-150° C. (bath temperature) (0.01 mm Hg.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[CH3:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([O:19][C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1)=[O:9]
Reactant: Nc1ccc(O)cc1
Agent: CNC(=O)c1cc(Cl)ccn1
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].IC.[CH2:15](N(C(C)C)C(C)C)C>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:15])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=S(O)c1cc(F)c(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CI
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 2,4,5-trifluorobenzenesulfinic acid (34 g, 173 mmol), in DMF (200 mL), was added iodomethane (21.6 mL, 347 mmol), and N-ethyl-N-isopropylpropan-2-amine (60.5 mL, 347 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction was concentrated and partitioned between water and ethyl acetate and extracted with CH2Cl2. The combined organic layers were concentrated and purified over silica gel (15-100% EtOAc in hexanes) to afford 1,2,4-trifluoro-5-(methylsulfonyl)benzene (25.8 g, 123 mmol, 71% yield) as yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1)[CH3:3].[OH-:24].[Na+].OO.O>CO>[O:24]1[C@H:14]2[C:13](=[O:23])[CH:12]=[C:11]3[C@:16]([CH3:17])([C@@H:15]12)[C@@H:18]1[C@H:8]([C@H:7]2[C@:21]([CH3:22])([CH2:20][CH2:19]1)[C@@H:4]([C@H:2]([OH:1])[CH3:3])[CH2:5][CH2:6]2)[CH:9]=[CH:10]3
Reactant: [OH-]
Reactant: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of 2.79 g (8.92 mmol) of (20R)-20-hydroxy-pregna-1,4,6-trien-3-one in 27 ml of methanol is treated with 0.83 ml of 10% methanolic sodium hydroxide, cooled to 0° C., and 5.4 ml of 30% hydrogen peroxide solution are added dropwise during 10 minutes with stirring. The solution is stirred at 0° C. for 45 minutes and then at room temperature for 3 hours. The suspension formed is treated with a total of 60 ml of water in portions, cooled to 0° C. and excess peroxide is destroyed by the addition of sodium hydrogen sulphite solution. The mixture is freed from methanol in a water-jet vacuum and the residue is extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. Chromatography of the residue on 80 g of silica gel with hexane/ether (1:1) gives 1.77 g (60.4%) of uniform (20R)-1α,2α -epoxy-20-hydroxy-pregna-4,6-dien-3-one in the form of colourless crystals. The analytical sample is obtained by recrystallisation from methylene chloride/ether; melting point 206°-207° C., [α]D25 =+231.6° (c=0.5 in chloroform); UV (ethanol): λmax 292 nm (ε=21050).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67](O)=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: NCC(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCC(F)F)c3)ccc2n1CC1CCOCC1
Yield: 1.6 %

Procedure:
Following the same procedure in Example 31, method B, using 2,2-difluoroethylamine (138 mg, 1.7 mmol), N,N-diisopropylethylamine (0.8 ml, 4.4 mmol), HATU (646 mg, 1.7 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (1.1 mmol) in DMF (15 mL). The crude product was purified on LCMS using high pH column 40-70% acetonitrile gradient to afford 9 mg (2% yield) of the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.51 (m, 3 H), 1.51-1.58 (m, 2 H), 1.60 (s, 9 H), 3.22 (q, J=7.36 Hz, 1 H), 3.33 (d, J=2.93 Hz, 1 H), 3.62 (m, 1 H), 3.68-3.76 (m, 1 H), 3.90 (dd, J=10.64, 3.42 Hz, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 5.90 (m, 1 H), 6.68 (dd, J=3.03, 1.46 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.87 (s, 1 H), 7.90-7.99 (m, 2 H), 8.28 (s, 1 H); MS (APPI) (M+H)+=509.3.
Reaction SMILES: [C:1]1(C(C(C)C)CN)[CH:6]=CC=C[CH:2]=1.Cl.[C:14]1([CH:20](CC(C)C)[CH2:21][N:22]([CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH2:40][C:41](=[CH:45][C:46]([OH:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=2[Cl:34])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:34].[C:14]1([CH:20]([CH:1]([CH3:6])[CH3:2])[CH2:21][N:22]([CH2:35][CH2:36][CH2:37][O:38][C:39]2[CH2:40][C:41](=[CH:45][C:46]([OH:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[C:25]=2[Cl:34])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: CC(C)C(CN)c1ccccc1
Agent: Cl
Product: CC(C)C(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1

Procedure:
The titled compound was prepared from 2-phenyl-3-methylbutylamine (Acta. Pharmaceutica Nordica (1992), 4(2), 105-9) in the same manner as the preparation of N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine, hydrochloride, Example 189e-h. MS (ESI) 548 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=O)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: O=CNCc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccn2cncc2c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a 100-mL round-bottom flask, was placed a solution of N-((4-bromopyridin-2-yl)methyl)formamide (compound 39.2, 3.0 g, 90%, 12.6 mmol) in dichloromethane (20 mL). The solution was cooled to 0-5° C. then trifluoroacetic anhydride (1.93 mL, 13.9 mmol) was added drop-wise. The resulting solution was stirred for 1 h at room temperature, then the pH was adjusted to 7 by careful and slow addition of aqueous sodium carbonate (sat.). The aqueous phase was extracted with dichloromethane (3×20 mL) and the combined organic layers were washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/1) as the eluent to yield the title compound as a brown solid (1.0 g, 40%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([N:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:20])=[CH:9][N:8]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:5]2=[N:6][CH:7]=1.[CH3:40][N:41]([CH3:53])[C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:40][N:41]([CH3:53])[C:42](=[O:43])[C:44]1[CH:45]=[CH:46][C:47]([C:2]2[N:3]=[C:4]3[C:10]([N:11]4[CH2:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12]4=[O:20])=[CH:9][N:8]([C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:5]3=[N:6][CH:7]=2)=[CH:48][CH:49]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: O=C1c2ccccc2CN1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4ccccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 65 °C

Procedure:
2-(2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl)isoindolin-1-one (20 mg, 0.3500 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (81.06 mg, 0.4200 mmol) and Na2CO3 (525.0 μL of a 2M aqueous solution, 1.050 mmol) combined in 1,4-dioxane (3 mL) and the mixture de-gassed (×2 vacuum-N2 cycles). Pd(tBu3P)2 (17.89 mg, 0.03500 mmol) added and the mixture de-gassed (×2 cycles) then heated at 65° C. overnight. Reaction mixture cooled to ambient and partitioned between DCM and water. Aqueous phase extracted with DCM and combined organics dried and concentrated to a yellow solid, which is taken up in DCM (4 mL) under N2 and used in the next step without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[Cl:27])=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: Nc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1Cl
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.2 g, 0.025 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.024 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of 2-chloroaniline (3.2 g, 0.25 mole) and triethylamine (2.5 g, 0.025 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into water (350 ml). The mixture was allowed to precipitate and filtered. The filter cake was twice suspended in water (250 ml) and filtered. The filter cake was air dried and twice recrystallized from tetrahydrofuran to give 4.22 g (40%) of a white solid, mp. 230.5°-232° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:32]4[CH:31]=[C:30]([Br:29])[CH:34]=[N:33]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(Br)cn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-Bromo-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].I[CH3:13]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:13]
Reactant: Oc1cc(F)ccc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride (0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) was heated to 60° C., stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]3[N:23]=[CH:24][CH:25]=[CH:26][C:14]=3[N:13]2[C:27]=1[C:28]1[CH:29]=[CH:30][C:31]([C:34]2([NH2:38])[CH2:37][CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 92.7 %

Procedure:
tert-Butyl (1-{4-[2-(1,3-benzoxazol-2-yl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (11.3 mg, 0.0189 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 17.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (10.6 mg, 92.7%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.73 (s, 1H), 8.67 (br s, 3H), 8.16 (dd, J=4.8, 1.6 Hz, 1H), 8.00 (dd, J=7.9, 1.6 Hz, 1H), 7.75-7.71 (m, 1H), 7.68-7.64 (m, 1H), 7.63-7.49 (m, 4H), 7.46-7.31 (m, 4H), 7.21-7.13 (m, 1H), 6.95 (dd, J=7.9, 1.6 Hz, 1H), 6.77 (dd, J=7.9, 4.8 Hz, 1H), 2.70-2.43 (m, 4H), 2.27-2.13 (m, 1H), 1.93-1.78 (m, 1H); LCMS: 497 [M+H].
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.C(Cl)(Cl)(Cl)[Cl:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:29][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O

Procedure:
A solution of 78.7 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 12e) in 1.41 of carbon tetrachloride and 475 ml of acetonitrile is stirred with 71 g of triphenylphosphine for 8.5 hours at room temperature. Then, it is extracted with water, aqueous sodium bicarbonate and common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 48.0 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione is obtained as crystals with a melting point of 51°-53° C. [α]D22 =+78.5°(c=0.5% in chloroform).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].O>CO.Cl>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Add to 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol (1.0 g.) in methanol (50 cc.), 3N hydrochloric acid (20 cc.); shake the mixture for 2 hours, pour into water, and extract the product with ether. Work up in the usual way and take up the resulting gum in benzene and chromatograph on neutral alumina. Elute with ether to give a crystalline material and recrystallize from a mixture of ether and pentane to yield 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.5 g.), m.p. 144°-7°; ultra-violet absorption peak at 240 mμ (ε15,500); infrared absorption peaks at 2.94, 6.06, 6.23 μ.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.Br[CH2:33][CH2:34]Br>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([C:27]2([C:28]([O:30][CH3:31])=[O:29])[CH2:34][CH2:33]2)[CH:15]=[CH:16][C:17]=1[B:18]1[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: BrCCBr
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
Lithium bis(trimethylsilyl)amide (7.08 mL, 7.08 mmol) was added dropwise to methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1 g, 3.22 mmol) in THF (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 30 minutes and then 1,2-dibromoethane (0.305 mL, 3.54 mmol) was added to the reaction and was stirred at 0° C. for 5 minutes. The reaction mixture was quenched with saturated NH4Cl (50 mL) and was diluted with EtOAc (75 mL). The organic layer was separated and re-extracted with EtOAc (75 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (0.182 g, 16.79%) as a colourless gum.