Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[C:26](O)(=[S:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)[CH2:3]1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OC(=S)c1cccnc1
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSCc4cccnc4)[C@@]3(C)CC(=O)[C@@H]12
Yield: 67.2 %

Procedure:
Treatment of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (240 mg) in acetone (15 ml) with thionicotinic acid (150 mg) for 4 hrs. in similar manner to that described in Example 27 gave title compound (220 mg) as a white foam [αD ] + 55.6° (c 1.01).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18].CC1C=CC=CC=1C=O.CNC>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:16]([N:17]([CH3:18])[CH3:19])[C:15]1[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=1[CH3:13])[CH3:2]
Reactant: Cc1ccccc1C=[N+](C)C
Reactant: CCc1cccc2cc[nH]c12
Agent: CNC
Agent: Cc1ccccc1C=O
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3C)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (2-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C4C(C=CC=3OC2)=NON=4)C1=O.Br[CH2:45][C:46]1[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=1.C(OC1C=CC(CCl)=NC=1)C1C=CC=CC=1>>[O:22]=[C:2]1[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:45][C:46]1[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: ClCc1ccc(OCc2ccccc2)cn1
Agent: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Product: CCOC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 9.67 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one, and ethyl 4-(bromomethyl)benzoate to replace 5-(benzyloxy)-2-(chloromethyl)pyridine, ethyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.21-7.16 (m, 2H), 7.03 (t, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H), 4.67 (d, J=8.7 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.22-4.19 (m, 2H), 4.15-4.12 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 458.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[N:34]1([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCCCCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)azepane. MS (ESI): mass calcd. for C22H23FN4O2S, 426.15; m/z found, 427.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=7.9, 1H), 7.96 (t, J=8.2, 1H), 7.66 (m, 1H), 7.60-7.55 (m, 1H), 7.38 (d, J=6.5, 1H), 7.31-7.24 (m, 2H), 1.63-1.52 (m, 12H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To 3.00 g of the 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 2 in Synthetic Example 2 in 30 ml of N,N-dimethylformamide, 4.13 g of potassium phthalimide was added, and the mixture was stirred at 80° C. for 3 hours and then at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 150 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was mixed with 40 ml of a mixture of diisopropyl ether and hexane (1:1), the insolubles were filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 15:85 to 25:75) as the eluent to obtain 0.32 g of the desired product as a dark brown resinous substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH2:11][OH:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CO)(CC1CCCCC1)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(COS(C)(=O)=O)(CC1CCCCC1)C(=O)OCC
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of 2-cyclohexylmethyl-2-hydroxymethyl-malonic acid diethyl ester (1.31 g, 4.13 mmol) in methylene chloride (20 mL) and triethyl amine (1.16 mL, 8.00 mmol) was cooled to −40° C. A solution of methylsulfonyl chloride (0.402 mL, 5.2 mmol) in methylene chloride (4 mL) was added to the reaction mixture over 5 minutes. The reaction mixture was warmed to −10° C. over 1 hour and then poured into cold dilute aqueous HCl. The product was extracted with ethyl acetate, the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give 2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester (1.505 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:13]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 3-(4-tert-butoxycarbonylaminophenyl)propanol (2.66 g, 10.6 mmol), methanesulfonylchloride (1.33 g, 11.6 mmol), triethylamine (1.18 g, 11.7 mmol) and ethyl acetate (10 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with hexane-ethyl acetate (3:1) to give 3-(4-tert-butoxycarbonylaminophenyl)propyl methanesulfonate as colorless crystals (2.75 g, 79%).
Reaction SMILES: C([O:5][C:6](=[O:21])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[C:11]1=[O:20])[CH2:8][CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C:12]1[C:11](=[O:20])[N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([OH:21])=[O:5])[CH:15]=[CH:14][CH:13]=1)(=[O:19])[CH3:18]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(C)=O)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C(=O)O)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of (S)-2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (569 mg, 1.93 mmol) in dichloromethane (5 mL) was cooled to 0° C. Trifluoroacetic acid (5 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 2 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the title product as a white solid (327 mg, 71%); 1H NMR (400 MHz, d6-DMSO) δ 0.78 (3H, t), 2.02-2.17 (5H, m), 4.98 (1H, dd), 6.29 (1H, t), 7.35 (1H, d), 8.21 (1H, d), 9.30 (1H, s), 13.07 (1H, vbr s).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[NH:5][C:6]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Al]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:21]([O:20][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][CH3:10])=[C:6]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1cc(C#N)c(=O)[nH]c1COCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: c1ccccc1
Product: CCc1cc(C#N)c(OCc2ccccc2)nc1COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a partial suspension of 3-cyano-5-ethyl-6-benzyloxymethyl-2(1H)-pyridinone (1.36 g, 5.08 mmol) in dry benzene (20 mL) was added benzyl bromide (0.80 mL, 6.7 mmol) and then silver carbonate (1.43 g, 5.2 mmol). This mixture was covered with aluminum foil and allowed to stir at room temperature. After 24 hours, the reaction was estimated to be ~80% complete. Additional silver carbonate (0.40 g, 1.45 mmol) was added and the mixture was stirred for another 24 hours until complete. The silver salts were removed by filtration, rinsed with benzene and the combined benzene washings were evaporated to give the pure product as an oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[N:13]=[CH:12][C:11]=1[NH2:20])[CH2:2][CH2:3][CH3:4].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:21]1[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCCNc1c(N)cnc2cccnc12
Reactant: CCCCC(=O)Cl
Product: CCCCOCCCn1c(CCCC)nc2cnc3cccnc3c21
Yield: 63.1 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) was reacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resulting amide intermediate was cyclized to provide 2.9 g of 1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine as a colorless oil. A small portion was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide a pure sample as a white powder, m.p. 56.5-57.5° C. Analysis: Calculated for C20H28N4O: %C, 70.56; %H, 8.29; %N, 16.46; Found: %C, 70.48; %H, 8.25; %N, 16.61. 1H NMR (300 MHz, CDCl3): δ 9.32 (s, 1H), 8.90 (dd, J=4.3,1.6 Hz, 1H), 8.49 (dd, J=8.5,1.6 Hz, 1H), 7.57 (dd, J=8.5,4.3 Hz, 1H), 4.94 (t, J=7.0 Hz, 2H), 3.45-3.39 (m, 4H), 3.04 (t, J=7.9 Hz, 2H), 2.26 (pentet, J=6.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.62-1.48 (m, 4H), 1.45-1.33 (m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=1.ClC1C(OC2N=CC=CN=2)=CC(N2C(=O)N3CCCCN3C2=S)=C(F)C=1>>[Cl:1][C:2]1[C:7]([O:8][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][CH2:18][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: O=c1cc2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCC2
Reactant: FC(F)(F)c1cccnc1Cl
Agent: O=c1n(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(=S)n2n1CCCC2
Product: O=c1cc2n(c(=O)n1-c1cc(Oc3ncccc3C(F)(F)F)c(Cl)cc1F)CCC2
Yield: 90 %

Procedure:
This was synthesized from 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-6,7-dihydro-pyrrolo-[1,2-c]pyrimidine-1,3(2H,5H)-dione and 2-chloro-3-trifluoromethylpyridine in 90% yield under similar conditions described below for the preparation of 2-[4-chloro-2-fluoro-5-(2-pyrimidyloxy)phenyl]hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.3) (compound (8-29).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:56])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[O:50][CH:51]=[CH:52][CH:53]=4)[O:46][C:47]=3[CH3:48])=[C:37]([O:54][CH3:55])[CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[O:50]1[CH:51]=[CH:52][CH:53]=[C:49]1[C:45]1[O:46][C:47]([CH3:48])=[C:43]([CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:35]([C:34]([NH:33][C:23]3[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:24]=3)=[O:56])=[CH:36][C:37]=2[O:54][CH3:55])[N:44]=1
Reactant: COc1cc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (277 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 38 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added a solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzamide (400 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v), then methanol-ethyl acetate (0:1 to 0.5:9.5, v/v) to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless amorphous form (380 mg, yield 75%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]O)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][Cl:21])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The alcohol 2.2 (15 g, 59.5 mmol) was dissolved in anhydrous DCM (100 mL). Thionyl chloride (10 mL) was slowly added dropwise to the above solution. The resulting mixture was stirred at room temperature for 24 hours. The organic solvent was removed under vacuo. The residue was chromatographed (SiO2 gel 60, eluted with 20% DCM in hexanes). Fractions containing the desired product 2.3 were combined and concentrated to a white solid (14.0 g). 1H NMR (400 MHz) (CDCl3) δ 7.73 (4H, s); 7.65 (1H, s); 7.58 (1H, s); 7.52-7.28 (2H, m); 4.69 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: COC(OC)OC
Reactant: Nc1ccc(Cl)cc1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC(n2cnc3ccc(Cl)cc3c2=O)C(=O)N1
Yield: 74 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide (0.31 g, 1.1 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (50 mg) was heated to 150° C. in a microwave oven for 10 minutes. The suspension was filtered and washed with ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (230 mg, 74% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.01 min (100%); mp: 302-305° C.; 1H NMR (DMSO-d6) δ 2.13-2.20 (m, 1H, CHH), 2.62-2.93 (m, 3H, CH2, CHH), 5.52 (br, 1H, NCH), 7.76 (d, J=9 Hz, 1H, Ar), 7.91 (dd, J=2, 9 Hz, 1H, Ar), 8.10 (d, J=2 Hz, 1H, Ar), 8.41 (s, 1H, CH), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.39, 30.87, 56.29 (br), 122.56, 125.05, 129.47, 131.59, 134.82, 146.19, 147.75, 158.73, 169.68, 172.39; LCMS: MH=292, 294; Anal Calcd for C13H10N3O3Cl: C, 53.53; H, 3.46; N, 14.41. Found: C, 53.43; H, 3.21; N, 14.27.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:23]=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CCCCO>[Br:1][C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:23]=[N:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cnc2ccccc2n1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cnc5ccccc5n4)c23)C1
Temperature: 155 °C
Yield: 11.4 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide (0.240 g, 0.621 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.373 g, 1.86 mmol) were placed in n-BuOH (3 mL) and heated to 155° C. for 48 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase HPLC (5:75 water:ACN gradient, Gilson system) to give (R)-tert-butyl 1-(5-bromo-3-(quinoxaline-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.040 g, 11% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].IC.[C:25]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:25])=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCOc1ccc(OC)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.69 g, 2.34 mmol), iodomethane (0.58 mL, 9.34 mmol) and K2CO3 (1.61 g, 11.68 mmol) in acetone (20 mL) was stirred, and refluxed for 3 hours, cooled. The solution was filtered, dried with silica gel powder (10 g). 30% Ethyl acetate in hexanes (2 L) was used to run flash chromatography. The title compound was obtained (377 mg, 52%). MS (APCI) m/z 310 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([CH2:29][CH2:30][C:31](O)=[O:32])=[CH:27][O:26][N:25]=2)=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:28]2[C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[N:25][O:26][CH:27]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2conc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.76 g), 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.66 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.49 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (1.14 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–90° C.