Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)=[N:4][CH:3]=1.Cl.Cl.[CH3:30][N:31]([CH3:36])[CH:32]1[CH2:35][NH:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[C:12]([N:34]3[CH2:35][CH:32]([N:31]([CH3:36])[CH3:30])[CH2:33]3)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Nc2cc(N3CC(N(C)C)C3)nc(Sc3ccc(NC(=O)C4CC4)cc3)n2)s1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
A suspension of N-(4-(4-(5-methylthiazol-2-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (138 mg, 0.33 mmol), 3-dimethylaminoazetidine dihydrochloride (178 mg, 1.0 mmol), N,N-diisopropylethylamine (0.34 ml, 1.98 mmol) in n-butanol (10 ml) was heated at 90° C. for 17 h. Reaction mixture was then allowed to cool to room temperature, concentrated in vacuo. The crude product was purified on HPLC to give the title compound as an off-white solid (106 mg, 58%). 1H NMR (DMSO) 0.82-0.81 (4H, m), 1.87-1.81 (1H, m), 2.07 (3H, s), 2.78-2.77 (6H, m), 4.20 (5H, s), 5.56 (1H, s), 6.94 (1H, s), 7.52 (2H, d), 7.76 (2H, d), 10.55 (1H, s) MS(ES+): 482.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOCC>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH2:16][C:17](=[O:19])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH2:1][C:8]=2[CH:13]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Solvent: CCOCC
Product: COc1ccc2c(c1)Cc1ccccc1C(=O)C2
Reaction time: 0.25 h

Procedure:
Finely powdered 2-benzyl-4-methoxyphenylacetic acid (3.26 g, 12.72 mmol) was added to well-stirred polyphosphoric acid (165 g) at 100-110° C. After 15 min, the reaction was poured onto ice (330 g). Et2O (330 mL) was added, and the mixture was stirred briskly for 15 min. The layers were separated, and the aqueous layer was extracted with Et2O (330 mL). The combined organic layers were washed with 5% NaHCO3 (2×80 mL) then with brine (80 mL), dried (MgSO4), and concentrated. The residue was reconcentrated from toluene, then was chromatographed (silica gel, 20% EtOAc/hexarnes). The title compound was obtained as a yellow solid (1.44 g, 48%): TLC Rf (20% EtOAc/hexanes) 0.46; 1H NMR (250 MHz, CDCl3) δ 8.07-8.15 (m, IH), 7.39-7.49 (m, 1H), 7.25-7.48 (m, 2H), 7.19 (d, J=8.3 Hz, 1H), 6.86 (d, J=2.6 Hz, 1H), 6.71 (dd, J=8.3, 2.6 Hz, 1H), 4.21 (s, 2H), 4.11 (s, 2H), 3.77 (s, 3H); FTIR (CCl4) 1680, 1501, 1282, 1270 cm-1 ; MS (ES) m/e 261 (M+Na)+, 256.0 (M+NH4)+, 239.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[C:8](=[O:9])[NH:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)=[N:5]1)([CH3:3])[CH3:2].C[Li].[CH3:20][C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1>O1CCCC1.C(OCC)C.C(Cl)Cl>[OH:27][CH:26]([C:15]1[C:10]([C:6]2[NH:7][C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:5]=2)=[N:11][CH:12]=[C:13]([CH3:16])[CH:14]=1)[C:24]1[S:25][C:21]([CH3:20])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C=O)s1
Reactant: Cc1ccc(C2=NC(C)(C(C)C)C(=O)N2)nc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(O)c2ccc(C)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
A stirred solution of 4-isopropyl-4-methyl-2-(5-methyl-2-pyridyl)-2-imidazolin-5-one (10.0 g, 0.043 mol) in anhydrous tetrahydrofuran (200 mL) is cooled to -78° C. and treated with a 1.5 molar solution of methyl lithium in diethyl ether (60.6 mL). The resultant suspension is stirred at -78° C. for 30 minutes and at 0° C. for 30 minutes. The reaction mixture is recooled to -78° C. and 5-methyl-2-thiophenecarboxaldehyde (15.35 g, 0.043 mol) is added dropwise. After 30 minutes, the cooling bath is removed and the reaction mixture is stirred at room temperature overnight then diluted with water. The aqueous mixture is acidified to pH 6 with acetic acid and extracted with diethyl ether. The combined organic extracts are washed with water, dried (Na2SO4) and concentrated in vacuo to obtain an orange oil. Chromatography of the oil using silica gel and a 20% diethyl ether in methylene chloride mixture gives a yellow oil which is triturated with diethyl ether to obtain the title product as a white solid (2.0 g, mp 147°-148° C.)
Reaction SMILES: [CH2:1]1[C:4]2([CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][NH:6][CH2:5]2)[CH2:3][O:2]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](OC(F)(F)F)[CH:26]=2)[N:21]=[C:20]([N:33]2[CH2:39][C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[S:36](=[O:45])(=[O:44])[CH2:35][CH2:34]2)[CH:19]=1.[CH:46]1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[O:44]=[S:36]1(=[O:45])[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[CH2:39][N:33]([C:20]2[CH:19]=[C:18]([N:6]3[CH2:7][CH:8]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[C:4]4([CH2:3][O:2][CH2:1]4)[CH2:5]3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:46])[CH:26]=3)[N:21]=2)[CH2:34][CH2:35]1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CNCC12COC2
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC(NC(=O)OC(C)(C)C)C4(COC4)C3)c2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 925.1 %

Procedure:
A mixture of tert-butyl 2-oxa-6-azaspiro[3.4]oct-8-ylcarbamate (459 mg, 2.0 mmol), 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (500 mg, 1.34 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,2-dioxide), tri(dibenzylideneacetone)dipalladium(0) (61.3 mg, 0.067 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl[1,1′-biphenyl]-2-amine (52.7 mg, 0.134 mmol), sodium tert-butoxide (192.2 mg, 2.0 mmol) and 1,4-dioxane (6 mL) was heated with stirring in a 20 mL of microwave process vial for 3 hours at 100° C. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 700 mg of the product as a white solid, which was used for next step without further purification.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:18])[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.C1COCC1.O>CO>[C:10]([NH:9][CH2:8][C:7]([OH:18])=[O:6])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CNC(=O)c1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
LiOH.H2O (73 mg, 1.74 mmol) was added to a solution of benzoylamino-acetic acid ethyl ester (90 mg, 0.43 mmol) in a mixture of MeOH (5 mL), THF (2 mL) and H2O (2 mL). The resulting mixture was stirred for 3 hrs at room temperature. The MeOH and THF were evaporated and the resulting residue was diluted with water (2 mL), acidified with citric acid and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford benzoylamino-acetic acid in 77% yield. LC-MS purity: 92%
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=O)(=[O:3])[CH3:2].I[CH3:15].[C:16](=[O:19])([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:15])([CH3:5])[C:16]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
A mixture of N-acetyl oxindole (2.0 g, 11.4 mmol), iodomethane (1.56 mL, 25.1 mmol) and potassium carbonate (3.1 g, 22.8 mmol) in DMSO (20 mL) was stirred at room temperature for 20 h. The reaction mixture was diluted with water. The resulting solids were filtered, washed with water and dried to give N-acetyl dimethyl oxindole as an orange solid (1.9 g, 84%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:16][CH:17]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isatin (2.5 g, 0.017 mol) in anhydrous DMF (50 ml) was cooled to 0° C. under a nitrogen atmosphere and treated with sodium hydride (0.5 g, 1.2 equivalents). A purple solution was formed which was stirred at 0° C. for 30 minutes and then warmed to room temperature. 4-Bromoanisole (2.13 ml, 1 equivalent) was added followed by copper iodide (6.46 g, 2 equivalents). The reaction was heated in an oil-bath at 145° C. for 7 hours. The reaction was then cooled to room temperature and diluted with an equal volume of ethyl acetate. This suspension was filtered and the filtrate was evaporated to dryness. TLC (1:4, ethyl acetate:hexanes) indicated a very clean reaction; Rf (product)=0.5. The crude material was used as such for the next reaction.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:18])[C@@H:10]([CH:11]=[C:12]([Br:14])[Br:13])[C@H:9]1[C:15](Cl)=[O:16].[O:19]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][OH:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:18])[C@@H:10]([CH:11]=[C:12]([Br:14])[Br:13])[C@H:9]1[C:15]([O:32][CH2:31][C:29]1[N:30]=[C:26]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:27][CH:28]=1)=[O:16]
Reactant: OCc1csc(Oc2ccccc2)n1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2csc(Oc3ccccc3)n2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
1.6 ml of pyridine was added dropwise at 0° C. to a solution of 1.7 g of (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylicacid chloride and 1 g of the product of Step B in 20 ml of benzene and the mixture was stirred for 2 hours at 20° C. and was poured into aqueous N hydrochloric acid solution. The decanted organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-ethyl acetate mixture to obtain 1.87 g of (2-phenoxy-4-thiazolyl)-methyl (1R,3R)2,2-dimethyl-3-(2,2-dibromoethenyl)-cyclopropane-1-carboxylate melting at ≃50° C. and having a specific rotation of [α]D20 =-9°±1° (c=1% in benzene).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[K+].[K+].[CH2:7]([NH:10][CH2:11][C:12]#[CH:13])[C:8]#[CH:9].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:20]([O:4][C:1](=[O:2])[N:10]([CH2:11][C:12]#[CH:13])[CH2:7][C:8]#[CH:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CCNCC#C
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Agent: [K+]
Solvent: O
Product: C#CCN(CC#C)C(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a cooled (5° C.) solution of K2CO3 (4 Kg, 29.0 mol) in water (17.5 L) and toluene (12.5 L) was added dipropargylamine (2.50 Kg, 26.88 mol). Benzyloxychloroformate (4.8 Kg, 28.14 mol) was added at a rate such that T<10° C. The solution was stirred at 5° C. for 10 mins and then allowed to warm to RT. The aqueous phase was separated and the organic phase was washed with 0.2M HCl (12.5 L), sat NaHCO3 (13.5 L) and brine (17 L) and the resultant solution used in step 7 (assayed to contain 6.23 Kg, 102% based on an evaporated portion).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([OH:13])=[C:7]([CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21])=[C:7]([CH3:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O)c(C)c(C(=O)O)c1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c(C)c(C(=O)O)c1Br
Temperature: 20 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 12.0 g of 2-bromo-5-hydroxy-3-methoxy-6-methyl-benzoic acid in 700 ml of acetonitrile were added at -5° C. 27.7 g of tert-butyldimethylchlorosilane and 18.5 g of triethylamine. The mixture was stirred for 30 min at -5° C. and for 16 h at 20° C. The solvent was evaporated in vacuo and the solid residue was washed with water and dried in vacuo. A solution of this material in 200 ml of ethanol was heated for 8 h to 80° C. The solvent was evaporated in vacuo and the residue was recrystallized from pentane to yield 12.0 g of 2-bromo-5-(tert-butyl-dimethylsilanyloxy)-3-methoxy-6-methyl-benzoic acid as white crystals, m.p. 120°-125° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.C([O:21][C:22](=O)[C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C>C(O)C>[OH:31][C:23]1[C:22](=[O:21])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=2)[C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: O=Cc1cccc(O)c1
Solvent: CCO
Product: O=C1C(O)=C(c2ccccc2)C(c2cccc(O)c2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3-Hydroxy-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethylester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[N:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[N:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nnn(-c3ccc(C(C)C)cc3)n2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)c1ccc(-n2nnc(-c3ccc(O)cc3)n2)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
4-Isopropylaniline (1.35 g) was added to a mixed solution of 50% ethanol (16 ml) and concentrated hydrochloric acid (2.6 ml). To the mixture was added a solution of sodium nitrite (0.69 g) in water (4 ml) over 10 min below 5° C. and stirring was continued for 10 min. To a solution of 4-methoxybenzaldehyde phenylsulfonylhydrazone (2.9 g) in pyridine (60 ml) was added dropwise the above solution of diazonium salt during 20 min at -10° C.~-15° C., and stirring was continued for 30 min at -10° C. and for 30 min at room temperature. The mixture was poured into ice water and extracted with ethyl acetate. The extract was washed succesively with 4 N hydrochloric acid, water, aqueous sodium carbonate,and water, dried, and evaporated to dryness. The residue was purified by column chromatography on silica gel with benzene-hexane (1/2-2/1) as an eluate to give 2-(4-isopropylphenyl)-5-(4-methoxyphenyl)tetrazole (1.6 g,54%). To a solution of 2-(4- isopropylphenyl)-5-(4-methoxyphenyl)tetrazole (1.3 g) in dichloromethane (10 ml) was added dropwise boron tribromide (10 ml,2.6M solution in dichloromethane) at -10° C. Stirring was continued for 1 h at -10° C. and for 1 h at room temperature. To the mixture was added water (20 ml), and the mixture was extracted with chloroform. The extract was washed with water, dried and evaporated to dryness. The residue was recrystallized from benzene to give 1.1 g (72%) of the title compound.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:13]([NH2:15])=[O:14])#[N:3].O>CO>[NH2:3][C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=2)[N:12]=[C:13]([OH:14])[N:15]=1
Reactant: CCc1ccc(NC(N)=O)c(C#N)c1
Agent: [Na]
Solvent: O
Solvent: CO
Product: CCc1ccc2nc(O)nc(N)c2c1
Yield: 93.5 %

Procedure:
To a solution of sodium metal (0.365 g) in dried methanol (300 ml) was added (2-cyano-4-ethylphenyl)urea (10 g) and the reaction mixture was heated under reflux for 5 hours and a half. The resultant mixture was concentrated under reduced pressure to give a residue, to which was added water. The resultant crystals were separated by filtration, washed with water and dried under reduced pressure to give crystalline 4-amino-6-ethyl-2-hydroxyquinazoline (9.35 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]2([CH3:24])[CH3:23])=[CH2:9].[OH-:25].[Na+].Cl.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:20][C:19]1[C:10]([C:8]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:30]=2[CH:29]=[CH:28][C:32]([OH:31])=[O:25])=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:22])[C:17]=2[CH:18]=1
Reactant: [OH-]
Reactant: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1I
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Product: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1C=CC(=O)O

Procedure:
A solution of the product of Example 5 (1.28 g, 3.2 mmol) and sodium hydroxide (1.3 g) in THF (50 ml) is refluxed for 6 h, acidified to pH 1 (concentrated HCl), extracted with ethyl acetate and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. and the product is washed with heptane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][CH:35]([NH2:38])[CH2:36][OH:37].[I-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:38][CH:35]([CH3:34])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(N)CO
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)CO)CC2)nc1N
Temperature: 150 °C
Yield: 65.2 %

Procedure:
The reaction mixture of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.198 mmol, Example 226), dl-2-amino-1-propanol (158 uL, 1.980 mmol, TCl) and sodium iodide (30 mg, 0.198 mmol) in tetrahydrofuran (4 mL) was heated at 150° C. for 1 hour using a Smith Creator microwave synthesizer. Upon cooling to room temperature, the solvent was removed and acetonitrile (3 mL) was added. The mixture was filtered and trifluoroacetic acid (0.25 mL) was added. Purification by reverse phase HPLC (Cl8, eluting with acetonitrile and water) gave (4-amino-2-[1-[3-(2-hydroxy-1-methyl-ethylamino)-propane-1-sulfonyl]-piperidin-4-ylamino]-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (70 mg, 65% yield) as off-white solids. HR-MS (ES, m/z) calculated for C23H33N6O5SF2[(M+H)+] 543.2196, observed 543.2202.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](N2CCNCC2)=[CH:31][CH:30]=1)(=[O:28])=[O:27].[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49]([OH:51])=O)[C:46]=1[CH3:47]>>[CH3:25][S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH:11]2[CH2:10][NH:15][CH2:14][CH2:13][N:16]2[C:49](=[O:51])[CH2:48][N:45]2[C:46]([CH3:47])=[C:42]([Cl:41])[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44]2)=[CH:33][CH:34]=1)(=[O:27])=[O:28]
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCNCC1c1ccc(S(C)(=O)=O)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methanesulfonyl-phenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.69 (d, 2H), 7.08 (d,2H), 5.38 (s, 2H), 3.59 (m, 4H), 3.49 (m, 2H), 3.38 (m, 2H), 3.09 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=465.1, found=465.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].[CH2:16]=[CH:17][CH:18]=[CH2:19].C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[CH:7]([N+:8]([O-:10])=[O:9])[CH2:19][CH:18]=[CH:17][CH2:16]2)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Reactant: C=CC=C
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OC)cc(C2CC=CCC2[N+](=O)[O-])c1
Temperature: -78 °C

Procedure:
A stainless steel pressure vessel was charged with 28.6 g. (0.137 mole) 3,5-dimethoxy-beta-nitrostyrene, 20 g. (0.378 mole) butadiene, 40 ml. toluene and a few crystals of hydroquinone. The vessel was cooled to -78° C. under a nitrogen atmosphere and sealed. The sealed vessel was heated at 100° C. for 48 hours, cooled and the reaction mixture concentrated under nitrogen. The residual solid was crystallized from methanol to afford 29.8 g. of title compound, M.P. 80.5°-82° C. J. Org. Chem., 27, 376 (1962) reported M.P. 73°-75° C. 1H-NMR (CDCl3) ppm (delta): 3.75 (s, 6H, OCH3), 4.95 (m, 1H, CHNO2), 5.75 (s, 2H, olefin), 6.40 (s, 3H, aromatic).
Reaction SMILES: C([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([Cl:28])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C.CO.C[O-].[Na+].O1CCCC1>O>[Cl:28][C:14]1[C:15]2[C@:20]([CH3:21])([CH2:19][O:18][C:17](=[O:27])[CH:16]=2)[C@@H:22]2[C@H:12]([C@H:11]3[C@:25]([CH3:26])([CH2:24][CH2:23]2)[C@@:5]([OH:4])([C:6](=[O:8])[CH3:7])[CH2:9][CH2:10]3)[CH:13]=1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 70 °C

Procedure:
A mixture of 116 mg iof 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione, 0.5 ml of an about 28% methanol solution of sodium methylate, 0.1 ml of tetrahydrofuran and 5 ml of methanol was heated at 70° C. for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a 30% aqueous solution of hydrogen chloride and then with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (19/1)] to give 70 mg of 6-chloro-17α-hydroxy-2-oxapregna-4,6-diene-3,20-dione.