Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(O)=O>CCO>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([NH:1][NH:2]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=1)#[N:7]
Reactant: CCOC(=O)/C=C/N(C)C
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C=C/NNc1cc(C#N)ccn1
Yield: 34.6 %

Procedure:
To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol, PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg, 3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture was heated under reflux conditions overnight. The reaction mixture was cooled and concentrated to dryness. The residue was adjusted to pH >8 with sat'd. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=5/1) to give the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'd for C11H12N4O2, 233. Found, 233.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].CC1C=CC(S(O[CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (161 mg, 0.5 mmol), (prepared as described in Example 49), 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine (222 mg, 0.6 mmol), (prepared as described for the starting material in Example 10), and potassium carbonate (188 mg, 1 mol) in DMF (1.6 ml) was heated at 100° C. for 2 hours. After cooling, water was added. The precipitate was collected by filtration, washed with water, and dried under vacuum over phosphorus pentoxide at 60° C. The solid was triturated with petroleum ether, collected by filtration, washed with a mixture of ether/petroleum ether (1/1) and dried under vacuum to give 6-methoxy-4(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (200 mg, 77%).
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]#[N:15])=[N:6]1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(O)(=O)C>[C:14]([C:7]1[C:8]2[C:9](=[N+:10]([O-:29])[CH:11]=[CH:12][CH:13]=2)[N:5]([CH2:4][CH2:3][C:2]([F:1])([F:20])[C:16]([F:17])([F:18])[F:19])[N:6]=1)#[N:15]
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2c1ccc[n+]2[O-]
Temperature: 75 °C
Reaction time: 6 h

Procedure:
1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile, as described in Step D of Example 158 (1.818 g, 6.26 mmol) and 3-chloroperbenzoic acid (7.1 g, 31.68 mmol, 77%) in acetic acid (20 mL) were stirred at 75° C. for 6 hours. The reaction was then evaporated under reduced pressure to remove acetic acid. To the residue was added a mixture of hexane/ethyl acetate (2/1, 200 mL total) and the pH adjusted to 7.0˜7.5 with aq. K2CO3 at 0° C. The water layer was extracted with hexane/ethyl acetate (2/1, 2×60 mL). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate eluent to give the desired product as a white solid. 1H NMR (500 MHz, CDCl3): δ 2.86 (m, 2H); 5.44 (t, J=7.3 Hz, 2H); 7.31 (t, J=8.2 Hz, 1H); 7.80 (d, J=8.4 Hz, 1H); 8.38 (d, J=5.1 Hz, 1H). m/z=307.02 (M+H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.CC(O)C>CS(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[C:21]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=3)[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: CC(C)(C)c1cc(Nc2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)no1
Temperature: 120 °C

Procedure:
To a slurry of (5-t-butyl-isoxazol-3-yl)-(2-chloro-pyrimidin-4-yl)-amine (Example 2, Step A) (0.120 mg, 0.47 mmol) in DMSO (0.120 mL) was added 3-aminobenzenesulfonamide (0.082 g, 0.47 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 1 h at which time TLC indicated the disappearance of starting material. IPA (5 mL) was added and the mixture was filtered and washed with IPA (2×1 mL) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C([O-])(=O)C.[Na+].[N+:15]([C:18]1[CH:27]=[CH:26][C:21](/[CH:22]=[CH:23]/[CH:24]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH:9]=[CH:24][CH:23]=[CH:22][C:21]2[CH:26]=[CH:27][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[N:3]=1
Reactant: O=C/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)nc(C=CC=Cc2ccc([N+](=O)[O-])cc2)c1
Yield: 50.6 %

Procedure:
2,4,6-Trimethylpyridine (2.24 mL, 16.9 mmol) and sodium acetate (0.92 g, 11.3 mmol) were added to a solution of trans-4-nitrocinnamaldehyde (1.0 g, 5.64 mmol) in acetic anhydride (20 mL). The reaction mixture was refluxed for 8 h, then brought to room temperature and quenched with 5% sodium bicarbonate solution (40 mL). The compound was extracted with ethyl acetate and the organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using 30% ethyl acetate in hexane as eluent to afford 2,4-dimethyl-6-[4-(4-nitro-phenyl)-buta-1,3-dienyl]-pyridine (800 mg, 51%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([O:19]C)=[O:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]([F:15])([F:14])[F:13])[CH2:8][CH2:7]2.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]([F:14])([F:15])[F:13])[CH2:8][CH2:7]2
Reactant: COC(=O)Cc1cc(Cl)c2c(c1)CCC(C(F)(F)F)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1cc(Cl)c2c(c1)CCC(C(F)(F)F)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
The compound (1.58 g) of Example 14 was added to a mixed liquor of aqueous solution (5 ml) containing sodium hydroxide (310 mg) with ethanol (5 ml) and the mixture was stirred at room temperature for 1 hour. Water (20 ml) was added and the reaction mixutre was brought to pH 4 with concentrated hydrochloric acid, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain aimed product (1.41 g) as white crystals. When recrystallizing from ethyl acetate-hexane, these give a melting point of 127°-128° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[CH:8]([OH:10])[CH3:9]>C(Cl)(Cl)Cl>[C:3]1([C@H:9]2[CH2:8][O:10]2)[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)O
Reactant: CCCCCC
Solvent: ClC(Cl)Cl
Product: c1ccc([C@H]2CO2)cc1
Yield: 69 %

Procedure:
Colorless oily substance, 69% yield, >99% ee (CHIRALCEL OD-H, hexane/iPrOH 99.9:0.1); [α]D23 +26.1° (c=0.48, CHCl3); 1H NMR (CDCl3): δ7.39-7.26 (m, 5H), 3.88-3.85 (dd, J=2.6, 4.0 Hz, 1H), 3.17-3.13 (dd, J=4.0, 5.6 Hz, 1H), 2.82-2.79 ppm (dd, J=2.6, 5.6 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=2)[O:8][N:7]=1)=[O:5])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:40][C:41]1[CH:50]=[CH:49][CH:48]=[C:47](O)[C:42]=1[C:43]([O:45][CH3:46])=[O:44].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:40][C:41]1[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:47]([CH:48]=[CH:49][CH:50]=1)[O:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(O)cccc1O
Reactant: CCOC(=O)c1cc(-c2cccc(CCCO)c2)on1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OCCCc1cccc(-c2cc(C(=O)O)no2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
To 5-(3-(3-hydroxy-propyl)-phenyl)-isoxazole-3-carboxylic acid ethyl ester (31 mg, 0.1 mmol) was added triphenylphosphine (29 mg, 0.11 mmol), methyl (2,6-dihydroxy)benzoate (20 mg, 0.12 mmol), then THF (1 mL). After the solids had dissolved, diethylazodicarboxylate (20 μL, 0.13 mmol) was added, and the reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo, and the residue was taken up in aqueous 2M NaOH (1 mL), along with enough methanol to make the solution homogeneous. After stirring for 10 minutes, the solvents were removed in vacuo, glacial acetic acid (4 drops)was added, and the product was purified by reverse phase HPLC, eluting with a acetonitrile/0.1% aq. trifluoroacetic acid gradient to provide the title compound (2.7 mg, 7%). 1H NMR (500 MHz, d6-DMSO) δ 9.94 (s, 1H), 7.79 (s, 1H), 7.76 (d, 1H, J=7.8 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.37 (d, 1H, J=7.5 Hz), 7.34 (s, 1H), 7.15 (t, 1H, J=8.3 Hz), 6.49 (dd, 2H, J=2.8, 8.4 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.79 (s, 3H), 2.78 (t, 2H, J=7.5 Hz), 2.01 (m, 2H); MS (ESI) m/z 398 (M+H), 415 (M+NH4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:29][CH2:28][CH2:26][OH:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCO)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethanolamine.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:5][CH:4]([NH2:6])[CH2:3]1.Cl.CCN(C(C)C)C(C)C.[F:18][C:19]([F:42])([F:41])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:40])[C:28]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([NH:37][CH3:38])=[CH:30][C:29]=2F)[CH2:22][CH2:21]1>CC#N>[F:18][C:19]([F:41])([F:42])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:40])[C:28]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([NH:37][CH3:38])=[CH:30][C:29]=2[NH:6][CH:4]2[CH2:5][C:2]([F:7])([F:1])[CH2:3]2)[CH2:22][CH2:21]1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: NC1CC(F)(F)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(NC2CC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of 3,3-difluoro-cyclobutylamine×HCl (49 mg, 0.34 mmol), DIPEA (0.26 ml, 1.5 mmol), N-(trans-4-trifluoromethyl-cyclohexyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (125 mg, 0.34 mmol, prepared according to WO2010/100249) and MeCN (5 mL) is stirred for 16 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: [Cu][C:2]#[N:3].[CH3:4][O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br>CN(C)C=O.O.[Fe](Cl)(Cl)Cl>[CH3:4][O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:2]#[N:3]
Reactant: N#C[Cu]
Reactant: COC(=O)Cc1ccccc1Br
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#N
Temperature: 25 °C

Procedure:
To a stirring solution of copper (I) cyanide (1.2 eq) in dimethylformamide (2.1 M) at room temperature was added slowly a solution of 2a in dimethylformamide (8.7 M). The reaction was heated to reflux overnight then cooled to room temperature. A solution of iron (III) chloride (1.2 eq) in H2O (0.3 M) was added slowly to the vigorously stirred solution. The resulting solution was extracted with ethyl acetate (3×). The organic phases were combined then washed with brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the product as a clear oil. (70%) 1H NMR (300 MHz, CDCl3) δ 6.09 (m, 1H), 5.98 (m, 1H), 5.79 (m, 2H), 2.29 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:33]=[CH:32][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:37])([F:36])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:41][NH:42][CH3:43]>CO>[CH2:1]([N:8]1[C:16]([C:17]2[CH:33]=[CH:32][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([N:42]([CH3:43])[CH3:41])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:36])([F:35])[F:37])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: COC(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
This compound was prepared from Example 912. Methyl 3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoate (49 mg, 0.0971 mmol) was dissolved in a 2M solution of dimethylamine in methanol (1.5 mL), 0.5 mg of sodium cyanide was added and the reaction mixture was stirred at 60° C. overnight. The solvent was evaporated, the residue dissolved in CH2Cl2 and washed with brine. The combined organic phases were dried, evaporated and the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 9 mg of analytically pure product.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[CH2:32](OCOCC)C>>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:32])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CCOCOCC
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12

Procedure:
1.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione is reacted analogously to Example 9 with formaldehyde diethylacetal, and worked up, thus obtaining 790 mg of 17,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[ClH:39].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[C:21]([NH:23][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:20]=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
40 mg (0.11 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-amino-1-benzothiophene-2-carboxamide dihydrochloride are dissolved in 2 ml of DMF, and 59.6 μl (0.43 mmol) of triethylamine are added. 30 mg (0.21 mmol) of benzoyl chloride are added. The reaction mixture is stirred at RT for 18 h and then separated by preparative HPLC. The product fraction is concentrated under reduced pressure, a mixture of acetonitrile and 1N hydrochloric acid is added, and the mixture is then again concentrated and dried under high vacuum. 32 mg (67.8% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].Cl.CN(C)CCCN=C=NCC.O>O1CCCC1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:6])=[CH:3][C:2]=1[Br:1]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of 3-bromo-4-(methoxycarbonyl)benzoic acid (Example 76; 1.60 g, 6.2 mmol) in tetrahydrofuran (30 mL) was cooled to 10° C. and N-hydroxysuccinimide (781 mg, 6.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 g, 6.5 mmol) were added. The solution was allowed to stir at room temperature overnight, then water was added and the solution was concentrated in vacuo to remove tetrahydrofuran. The mixture was extracted with ethyl acetate and the extracts were dried (MgSO4), filtered and evaporated under reduced pressure to furnish 2-bromo-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (2.20 g, quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([NH:7][CH3:8])[CH3:6].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([N:7]([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH3:8])[CH3:6]
Reactant: C=CC(=O)OC
Reactant: CNC(C)CC(=O)OC
Product: COC(=O)CCN(C)C(C)CC(=O)OC
Yield: 57.9 %

Procedure:
3-Methylamino-butyric acid methyl ester (7.6 g, 58 mmol, 1.0 equiv) was added neat to methyl acrylate (7.5 g, 87 mmol, 1.5 equiv). The resulting solution was refluxed for 16 h. The reaction was cooled and diluted with hexanes (200 mL) and an insoluble polymer separated out. The hexane solution was decanted and the polymer washed 2×100 mL hexanes with vigorous stirring. The combined hexane solutions were then concentrated in vacuo. The crude product was purified by flash chromatography on SiO2 using pure CH2Cl2 as an eluent. The pure product was isolated as a clear colorless oil (7.3 g, 58%); MS, m/z 218=M+1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (26%). mp 222° C.; LCMS: m/z=541.18 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.10 (s, 1H), 7.58 (s, 1H), 7.25 (m, 6H), 6.54 (m, 1H), 3.60 (m, 4H), 3.34 (s, 3H), 2.95 (d, 3H, J=4.8 Hz), 2.25 (m, 2H), 1.96 (m, 2H), 1.29 (s, 6H).
Reaction SMILES: Cl.C(O[C:5](=N)[CH2:6][CH2:7][CH3:8])C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1)([O-:12])=[O:11]>C(O)C>[CH2:6]([C:5]1[NH:20][C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:18]=[CH:17][C:16]=2[N:19]=1)[CH2:7][CH3:8]
Reactant: CCCC(=N)OCC
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Solvent: CCO
Product: CCCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 51.7 %

Procedure:
A mixture of ethyl-butyroimidate hydrochloride (7.6 g, 50 mmol) and 4-nitro-1,2-phenylenediamine (7.6 g, 50 mmol) in ethanol (100 mL) was refluxed for 18 hours. The ethanol was evaporated under vacuum. The sticky solid was suspended in H2O (100 mL). Separation of the yellow solid gave the title compound (5.3 g, 52% yield). 1H-NMR (DMSO-d6 ; 200 MHz) δ 12.9 (s, 1H), 8.4 (s, 1H), 8.0-8.05 (d, 1H), 7.6-7.64 (d, 1H), 2.8-2.85 (t, 2H), 1.7-1.85 (m, 2H), 0.9-1.0 ppm (t, 3H),
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[N:21]1[CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)N2CCCOCC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[F:10].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12]>CCO>[CH2:11]([N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[F:10])[CH2:14][CH3:15])[CH3:12]
Reactant: CCNCC
Reactant: Fc1cc(I)ccc1CBr
Solvent: CCO
Product: CCN(CC)Cc1ccc(I)cc1F
Yield: 93.3 %

Procedure:
A mixture of 1-(bromomethyl)-2-fluoro-4-iodobenzene (1.89 g, 6.0 mmol) and a solution of diethylamine (2.19 g, 30 mmol) in EtOH (60 mL) was stirred at rt overnight under N2, then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), and washed with water (100 mL×3) followed by brine (100 mL). The organic phase was concentrated in vacuo to give the title compound as colorless oil (1.72 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC1CCCC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 7.49 g (0.086 mol) of cyclopentylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C., then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 14.3 g (65.9%) of the title product as yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.