Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[CH2:12][O:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([O:13][CH2:12][C:11]([F:20])([F:10])[F:21])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(OCC(F)(F)F)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.00 g, 5.45 mmol) in THF (10 ml) at room temperature was added 5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-amine (986 mg, 5.45 mmol) and triethylamine (606 mg, 6.0 mmol) and the reaction mixture was stirred at 40° C. overnight. The suspension was filtered and washed with water and dried to give the desired product as a white solid. MS: 328 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:31]=[C:30]([NH2:32])[CH:29]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:28][O:27][C:25](=[O:26])[C:24]1[CH:29]=[C:30]([NH:32][S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:31]=[C:22]([C:21]([O:20][CH3:19])=[O:33])[CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Benzyloxy-benzenesulfonyl chloride (7.35 g, 26.0 mmol) was added in small portions to a suspension of 5-amino isophtalic acid dimethyl ester (5.23 g, 25.0 mmol) in DCM (100 ml) and pyridine (10 ml). The resulting clear yellow solution was stirred for 2 hours at room temperature, the volatile solvents were removed under reduced pressure, the solid residue was suspended in MeOH (125 ml) and the mixture was heated to reflux for 10 minutes. The off white solid was filtered off, washed with water and cold MeOH and dried under high vacuum. Yield 10.93 g (96%).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1/[O:5][C:6]([CH3:8])([CH3:7])[C:2]([C:24]2[CH:25]=[N:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:3]/1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(F)nc1
Temperature: 65 °C
Yield: 47 %

Procedure:
To a mixture or 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (3.24 g, 10.0 mmol), 6-fluoropyridin-3-ylboronic acid (1.8 g, 12 mmol) in THF (150 mL), was added a solution of potassium carbonate (13.8 g, 100 mmol) in water (20 mL). The resulting mixture was deoxygenated by bubbling nitrogen through the reaction mixture for 3 minutes and palladium(0)tetrakis(triphenylphosphine) (578 mg, 5 mol %) was then added. The reaction mixture was heated at 65° C. for 18 hours. The reaction was cooled to room temperature and ethyl acetate (500 mL) added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated to give the crude product, which was purified first by silica gel column chromatography (5% CH3OH/CH2Cl2 elution) and then by titration with ethyl acetate. The resulting product was isolated by filtration and dried under vacuum to provide 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.6 g, yield 48%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([F:44])=[C:39](B(O)O)[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([F:44])=[C:37]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)[CH:36]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ncc(C3CCOCC3)cc12
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+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cc(Cl)ccc3F)ccc1Oc1ncc(C3CCOCC3)cc12
Reaction time: 1.5 h

Procedure:
A vial was charged with (S)-2′-amino-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (70.0 mg, 0.144 mmol), 5-chloro-2-fluorophenylboronic acid (75 mg, 0.433 mmol), potassium carbonate (100 mg, 0.721 mmol), and Pd(PPh3)4 (8.33 mg, 7.21 μmol). The vial was flushed with Ar (g), then Dioxane (721 μL) and water (0.3 mL) were added in sequence. The vial was sealed and placed in an 80° C. for 1.5 hours. The mixture was diluted with brine (20 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 24-g Redi-Sep Gold column with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-7-(5-chloro-2-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: C(=O)C1C=CC=C(OC)C=1.[CH3:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[N:31](CC3C=CC(OC)=CC=3)[CH:32]=[CH:33][N:34]=2)=[N:24][N:23]=1.C1(OC)C=CC=CC=1.Br>C(O)(=O)C>[CH3:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[NH:34][CH:33]=[CH:32][N:31]=2)=[N:24][N:23]=1
Reactant: COc1ccc(Cn2ccnc2Cc2nnc(NCCSCc3nc[nH]c3C)[nH]c2=O)cc1
Agent: Br
Agent: COc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: Cc1[nH]cnc1CSCCNc1nnc(Cc2ncc[nH]2)c(=O)[nH]1

Procedure:
Substitution of 1-(4-methoxybenzyl)-2-imidazole carboxaldehyde for m-anisaldehyde in the general procedure of Example 1 leads to the production of 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(1-(4-methyoxybenzyl)-2-imidazolylmethyl)-1,2,4-triazin-5-one, which when treated with anisole and hydrogen bromide in acetic acid gives 3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-6-(2-imidazolylmethyl)-1,2,4-triazin-5-one
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH2:35])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1CCCN
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 47 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[2-[(diethylamino)methyl]-piperidin-1-yl]propanamine in a yield of 47% of theory. Colourless crystals, m.p. 160°-161° C. (acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH3:10])=[O:4].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH2:10][Br:12])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1scc(Br)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1scc(Br)c1CBr
Yield: 56.7 %

Procedure:
4-Bromo-3-methyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 12.8 mmol), example 31-a, N-bromosuccinimide (2.33 g, 13.1 mmol), and benzoyl peroxide (310 mg, 1.28 mmol) were suspended in 32 mL of benzene and heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to produce 2.28 g of a yellow solid. NMR (CDCl3, 200 MHz): δ=7.48 (s, 1H), 4.91 (s, 2H), and 3.94 (s, 3H).
Reaction SMILES: [CH:1]([CH:4]([C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:18][C@H:16]2[CH2:15][C@H:14]([CH:4]([CH:1]([CH3:2])[CH3:3])[C:5]([CH:11]([CH3:12])[CH3:13])([CH:8]([CH3:9])[CH3:10])[O:6][SiH3:7])[CH2:17]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: CC(C)C([C@H]1C[C@@H](O)C1)C(O[SiH3])(C(C)C)C(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C([C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 100 mL flask with cis-3-(triisopropyl-siloxyethyl)cyclobutanol (0.64 g, 2.3 mmol), 4-nitrobenzoic acid (0.79 g, 4.6 mmol) and Ph3P (1.29 g, 4.83 mmol) inside, dry THF 10 mL was added under argon to give a colorless solution. This was cooled to 0° C. and DIAD (1.0 mL, 4.83 mmol) was added drop by drop. After 15 hr, the volatile materials were evaporated and the crude mixture was purified by silica gel flash chromatography (Hexane: EtOAc=20:1 to Hexane: EtOAc=12:1) to give yellow oil contaminated with some DIAD (0.96 g, 97.4%, Rf=0.48 (Hexane: EtOAc=12:1)). 1H NMR (CDCl3, 400 MHz): δ 1.02-1.07 (m, 21H), 1.74-1.79 (m, 2H), 2.24-2.33 (m, 2H), 2.35-2.42 (m, 2H), 2.48-2.60 (m, 1H), 3.67-3.71 (t, J=6.4, 2H), 5.30-5.38 (m, 1H), 8.19-8.28 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 12.13, 18.19, 25.97, 34.87, 39.08, 61.95, 70.81, 123.66, 130.85, 136.01, 150.65, 164.39. MS (FAB): expected for C22H35NO5Si (M+H)+ 422.60. Found 422.23608. IR (neat) νmax 2942, 2865, 1725, 1608, 1530, 1463, 1349, 1276, 1103, 882, 720, 681.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[C:42]([CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:48][CH2:49][CH:44]([C:42]([C:34]3[NH:33][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)=[O:43])[CH2:45][CH2:46]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1 H-benzoimidazole-2-carbonyl)-piperidine hydroiodide salt to give the title compound: mp; 108.0-111.0° C.; Rf=0.28 (silica gel, 5/1 ethyl acetate/methanol) Elemental Analysis calculated for C35H40N4O5·0.30 H2O: C 69.82; H 6.80; N 9.30; Found: C 69.90; H 6.79; N 9.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][C:15]=2[CH:14]=[C:13]([O:32][CH3:33])[CH:12]=1.[CH3:34][NH2:35]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH:35][CH3:34])[CH2:16][C:15]=2[CH:14]=[C:13]([O:32][CH3:33])[CH:12]=1
Reactant: COc1ccc(OC)c(-c2cc(OC)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Reactant: CN
Product: CNCC1Cc2cc(OC)cc(-c3cc(OC)ccc3OC)c2O1

Procedure:
The title compound was prepared (0.032 g, 27%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.152 g, 0.32 mmol) and methylamine (0.100 g, 3.2 mmol). mp 144-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([N:24]=[C:25]=[S:26])=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C.O.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:25]2[S:26][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Reactant: S=C=Nc1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(Nc2nc3cccnc3s2)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3-(Benzyloxy)-5-bromopyridin-2-amine (10.0 g, 35.83 mmol) was added to a mixture of 2-chloro-3-isothiocyanatopyridine (6.112 g, 35.83 mmol) in DMF. The reaction was stirred at 80° C. for an hour, then at 110° C. for two hours. The reaction was cooled, diluted in water (200 mL) and 2N NaOH (35 mL), stirred for 30 minutes, and then filtered. The wet solids were washed with water, then dissolved in dichloromethane (300 mL) dried over MgSO4, and filtered. Hexane (300 mL) was added to the combined filtrates, the mixture was concentrated to 500 mL, and then mixture stirred for 30 minutes. The mixture was filtered to afford the first crop of the title compound. The mother liquor was concentrated to 500 mL (until most of the dichloromethane was removed), filtered, washed with hexanes to afford a second crop of the title compound. The two crops combined afforded the title compound (10.2 g, 68.7%) as light yellow crystals: 1H NMR (CDCl3) δ 5.14 (s, 2H), 7.30-7.33 (m, 2H), 7.42-7.48 (m, 5H), 7.87 (d, 1H), 8.10 (s, 1H), 8.40 (d, 1H), 8.67 (bs, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=1>CC#N>[Cl:9][C:10]1[C:15]([Cl:1])=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH:11]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
N-chloro-succinimide (NCS, 79.45 g, 0.6 mol) was added to a solution of compound 7 (25.8 g, 0.12 mol) in dry CH3CN (300 mL). The resulting suspension was heated at reflux for 2 hours and then cooled to room temperature. After washing with 10% aqueous NaOH (2×150 mL), then water (2×200 mL), the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid. This solid was recrystallized from EtOH to give 28.7 g (95%) of compound 8 as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]1[C:31]([C:36]#[N:37])=[N:32][CH:33]=[CH:34][N:35]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:36]([C:31]1[C:30]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:35][CH:34]=[CH:33][N:32]=1)#[N:37]
Reactant: N#Cc1nccnc1Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nccnc2C#N)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0506 g, 0.132 mmol) and 3-chloropyrazine-2-carbonitrile (0.0338 g, 0.242 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.80 (s, 1H), 8.50 (d, J=2.2, 1H), 8.21 (d, J=8.7, 2H), 8.15 (d, J=2.2, 1H), 7.50 (d, J=8.7, 2H), 6.30 (t, J=5.5, 1H), 4.86 (s, 2 H), 4.00 (s, 2H), 3.74 (d, J=4.3, 4H), 3.49 (d, J=4.2, 4H), 3.12 (dt, J=13.8, 7.1, 3H), 2.85 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+486.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1.[SH:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.C(OCC)C>CO>[CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:20]([CH2:24][S:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:21]([OH:23])=[O:22])=[O:14])[C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH2:3][CH2:2]1
Reactant: Sc1cccs1
Reactant: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Solvent: CO
Solvent: CCOCC
Product: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CSc1cccs1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-[1-(1 -Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-acrylic acid (4.40 g, 12.4 mmol) was dissolved in methanol (10 ml) and placed under a blanket of argon prior to addition of 2-mercaptothiophene (4.5 ml). The mixture was stirred overnight at 60° C. under argon with the exclusion of light. The solvent was removed under reduced pressure to leave an oil to which was added cold diethyl ether (200 ml). The product precipitated on standing in an ice bath and was removed by filtration and washing with thoroughly with cold diethyl ether. The product was further purified by trituration with hot ethyl acetate and column chromatography (silica gel, gradient elution, 0-20% methanol in dichloromethane). Fractions were combined and evaporated to yield the title compound as an pale yellow solid (6.95 g, including minor impurities). 1H-NMR (CDCl3, partial deuterium exchange); δ 8.10 (1H, m), 7.85 (1H, d, J=9.2 Hz), 7.35 (1H, m), 7.03 (1H, m), 6.88 (1H, m), 4.06 (1H, d, J=9.2 Hz), 2.85 (1H, m), 2.67 (2H, m), 2.51 (1H, m), 1.53 (1H, m), 1.25 (1H, m), 1.02 (1H, m), 0.87 (9H, s), 0.76 (3H, d, J=6.4 Hz), 0.71 (3 H, d,J=6.5 Hz), 0.61 (2H, m) and 0.32 (2H, m).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][OH:33])[CH2:29][CH2:28]2)[CH:25]=[CH:24]3.C1C=CC=CC=1>CCOCC>[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][O:33][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:29][CH2:28]2)[CH:25]=[CH:24]3
Reactant: C1=COCCC1
Reactant: C[C@H](CO)[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
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[C@H](COC1CCCCO1)[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
Reaction time: 1 h
Yield: 65 %

Procedure:
1.8 ml. of 3,4-dihydro-2H-pyran and 20 mg of anhydrous p-toluenesulphonic acid were added to a solution of 2.45 g of (20S)-1α,2α-epoxy-21-hydroxy-20-methyl-pregna-4,6-dien-3-one in 125 ml. of absolute benzene. After standing at room temperature for 1 hour, the solution was diluted with ether, washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and concentrated in a water-jet vacuum. The residue was chromatographed on 30 g of silica gel using hexane/ether (4:1) for the elution, there being obtained 2.0 g (65%) of (20S)-1α,2α-epoxy-20-methyl-21-tetrahydropyranyloxy-pregna-4,6-dien-3-one. After recrystallisation from hexane, the product melted at 101°-102° C. and was shown by thin-layer chromatography, mixed melting point and IR spectrum to be identical with the compound prepared as described in Example 7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NC1CCCCC1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NC1CCCCC1
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with cyclohexylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19](=[O:21])[CH3:20].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@H:10]([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:11][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccccc2[C@H](Nc2ccccc2)C[C@@H]1C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2[C@H](N(C(=O)c2ccco2)c2ccccc2)C[C@@H]1C
Temperature: 90 °C
Yield: 40 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-(2-methyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-ethanone (0.163 g, 0.58 mmol, 1.0 equiv) and 2-furoyl chloride (0.285 mL, 2.9 mmol, 5.0 equ), pyridine (1.0 equiv.) and dry toluene (3 mL). The solution was heated to 90° C. for 15 h. The reaction mixture was evaporated in vacuo. The residue was purified by Biotage flash system (50% hexane/50% ethyl acetate) to yield the cis isomer 40% yield.