Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]([CH3:27])[C:15](=[O:26])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([OH:25])[CH3:24])[C:17](=[O:18])[C:12]=2[C:11](=[O:28])[CH:10]=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49](O)(=[O:51])[CH3:50].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:49]([O:25][C@@H:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17](=[O:18])[C:12]2[C:11](=[O:28])[CH:10]=[C:9]([CH3:29])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:13]=2[N:14]([CH3:27])[C:15]1=[O:26])(=[O:51])[CH3:50]
Reactant: CC(=O)O
Reactant: Cc1cc(=O)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2n1Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(=O)cc(C)n(Cc3ccccc3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a mixture of (R)-8-benzyl-1,7-dimethyl-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.26 g, 3.18 mmol), triphenylphosphine (2.50 g, 9.52 mmol), acetic acid (0.54 ml, 9.52 mmol) and tetrahydrofuran (20 ml), cooled in an ice bath, was added diethylazodicarboxylate (1.5 ml, 9.5 mmol) dropwise. After stirring at room temperature for 4hours, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-hexanes to afford (S)-3-(5-acetoxyhexyl)-8-benzyl-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.2 g, 86% yield) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.30-1.75 (m, 6H), 2.02 (s, 3H), 2.49 (s, 3H), 3.67 (s, 3H), 4.03 (t, 2H), 4.88 (sextet, 1H), 5.30 (s, 2H), 6.56 (s, 1H), 7.30-7.56 (m, 5H).
Reaction SMILES: N(CC(O)=[O:5])C.[CH:7]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8]1.[OH:14][C:15]1[C@H:24]2[C@H:19]([C@H:20]3[CH2:25][C@@H:23]2[CH2:22][CH2:21]3)[N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:31])[C:16]=1[C:32]1[NH:37][C:36]2[CH:38]=[CH:39][C:40](I)=[CH:41][C:35]=2[S:34](=[O:44])(=[O:43])[N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[CH:7]1([S:10]([OH:12])(=[O:5])=[O:11])[CH2:9][CH2:8]1.[OH:14][C:15]1[C@H:24]2[C@H:19]([C@H:20]3[CH2:25][C@@H:23]2[CH2:22][CH2:21]3)[N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:31])[C:16]=1[C:32]1[NH:37][C:36]2[CH:38]=[CH:39][C:40]([NH:13][S:10]([CH:7]3[CH2:9][CH2:8]3)(=[O:12])=[O:11])=[CH:41][C:35]=2[S:34](=[O:44])(=[O:43])[N:33]=1
Reactant: CNCC(=O)O
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Reactant: NS(=O)(=O)C1CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)C4CC4)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Product: O=S(=O)(O)C1CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
A reaction flask was charged with copper (I) iodide (20 mg, 0.11 mmol), sarcosine (N-methyl glycine) (14.7 mg, 0.17 mmol), cyclopropanesulfonamide (125 mg, 1.04 mmol), (1R,2S,7R,8S)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(3-methyl-butyl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 34, 115 mg, 0.21 mmol) and potassium phosphate (176 mg, 0.83 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (5 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 3 h, and then allowed to cool to 25° C. The mixture was passed through a plug of Celite and rinsed with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cyclopropanesulfonic acid {3-(1R,2S,7R,8S)-[6-hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-amide (25 mg, 0.046 mmol, 22%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.92-0.98 (10H, m), 1.20-1.64 (9H, m), 2.52 (1H, m), 2.62 (1H, s), 2.68 (1H, m), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, m), 3.61 (1H, d, J=10.4 Hz), 3.66 (1H, m), 7.50-7.59 (3H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C25H32N4O6S2 548.18, found 549.4 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]1=[O:30].[C:31](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1([CH3:31])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:15]1=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CCN2C(=O)c3ccccc3C2=O)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC(C)(C)OC(=O)N1C(=O)C(C)(CCN2C(=O)c3ccccc3C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
To a mixture of tert-butyl 3-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2-oxoindoline-1-carboxylate (1.00 g, 2.46 mmol) and potassium carbonate (679 mg, 4.92 mmol) in DMF (5 mL) was added iodomethane (524 mg, 3.69 mmol) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 16 h. The resulting mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether to afford the title compound (700 mg, 1.66 mmol, 67% yield) as a brown solid. MS (ESI) m/z 421.1 [M+H]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:26])([O:3][CH3:4])=[O:2].[H-].[Na+].Cl[CH2:30][O:31][CH3:32]>CN(C)P(=O)(N(C)C)N(C)C>[C:1]([C:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]=1[O:26][CH2:30][O:31][CH3:32])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CCC1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOC1=C(C(=O)OC)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Reaction time: 4.5 h
Yield: 44.5 %

Procedure:
A solution of 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one (1.0 g, 2.8 mmol) and sodium hydride (80% dispersion in mineral oil, 0.09 g, 3.1 mmol) in dry hexamethylphosphoric triamide (8 mL) was stirred under an argon atmosphere at room temperature for 0.5 h. Chloromethylmethyl ether (0.26 mL, 3.4 mmol) was added and stirring was continued for 4.5 h. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, was extracted three times, the organic layer was dried (sodium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 3:1 hexanes/ethyl acetate, to provide a white solid (0.5 g, 44%): m.p. 98°-99° C.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[Si:48]([O:65][CH:66](O)[C:67]#[C:68][CH3:69])([C:61]([CH3:64])([CH3:63])[CH3:62])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1(C)C=CC=CC=1.O1CCCC1>[Si:48]([O:65][CH2:66][C:67]#[C:68][CH2:69][N:4]1[C:3](=[O:8])[C:2]([CH3:1])([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:7])([C:61]([CH3:62])([CH3:63])[CH3:64])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Reactant: CC#CC(O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Yield: 54.7 %

Procedure:
5-Methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (248 mg), triphenylphosphine (655 mg) and a solution of ethyl azodicarboxylate in toluene (2.2 mol/L, 1.00 mL) were added to a mixed solution of t-butyl-diphenylsilyloxy-2-butyn-1-ol (326 mg, 1.00 mmol) in tetrahydrofuran (10 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 303 mg of the title compound (yield: 55%) as a colorless oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C@H:19]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[CH:45]=[C:44]([Br:49])[CH:43]=3)[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:33][CH2:32][N:31](OC(C)(C)C)[C:30](=C=O)[CH2:29]4)[CH2:24][CH2:23]3)=[O:21])=[O:17])[CH2:12][CH2:11]2)[CH2:8][CH2:7][C:6]2[CH:50]=[CH:51][CH:52]=[CH:53][C:5]=2[NH:4]1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[O:2]=[C:3]1[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C@H:19]([CH2:41][C:42]3[CH:47]=[C:46]([Br:48])[CH:45]=[C:44]([Br:49])[CH:43]=3)[C:20](=[O:21])[N:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH2:24][CH2:23]3)=[O:17])[CH2:12][CH2:11]2)[CH2:8][CH2:7][C:6]2[CH:50]=[CH:51][CH:52]=[CH:53][C:5]=2[NH:4]1
Reactant: CC(C)(C)ON1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Br)cc(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O[C@H](Cc1cc(Br)cc(Br)c1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 mL HCl (3.2 M) were added to a solution of 180 mg (0.21 mmol) of (R)-1-(3,5-dibromo-benzyl)-2-[4-(1-tert-butoxy-carbonyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 64) in 2 mL water and the reaction mixture was stirred for 3 h at RT. The mixture was combined with 25 mL EtOAc and 20 mL 17% Na2CO3 solution, the organic phase was separated off, the aqueous phase was extracted again with 25 mL EtOAc, the combined organic phases were washed with 10 mL saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was suspended in diethyl ether, the organic phase was decanted off and the residue was dried.
Reaction SMILES: BrCCO[Si](C(C)(C)C)(C)C.Cl[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:13][N:30]2[CH2:31][CH2:32][N:28]([C:26]3[S:25][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([CH3:22])[CH:27]=3)[C:29]2=[O:33])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(CCl)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: CC(C)(C)[Si](C)(C)OCCBr
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(C#N)cc3)C2=O)cc1C
Yield: 86 %

Procedure:
Following the procedure as described in Example 50, making variations as required to replace (2-bromoethoxy)(tert-butyl)dimethylsilane with 4-(chloromethyl)benzonitrile to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a cream solid in 86% yield: 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 6.18 (s, 1H), 4.53 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.89-3.81 (m, 2H), 3.52-3.43 (m, 2H), 2.50 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[CH2:30][Mg:31][Br:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:37]1([C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[CH2:45]Br)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:22]1([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[CH2:30][Mg:31][Br:32])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[C:43]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH2:45][C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[OH:15]
Reactant: O=C(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Reactant: BrCc1ccccc1-c1ccccc1
Agent: Br[Mg]Cc1ccccc1-c1ccccc1
Product: OC(Cc1ccccc1-c1ccccc1)(C1CCOCC1)C1CN(Cc2ccccc2)CCO1
Reaction time: 8 h

Procedure:
Compound 55 is prepared from 8 (0.56 g, 1.94 mmol) and 2-phenyl benzyl magnesium bromide solution (0.25 M solution in diethyl ether, 9.31 mL, 2,33 mmol, 1.2 eq) following General Procedure 2. 2-Phenylbenzyl magnesium bromide is prepared from commercially available (Aldrich) 2-phenylbenzyl bromide following General Procedure 5. Further 2-phenyl benzyl magnesium bromide solution (1 mL) is added and the reaction left under stirring overnight. Purification by ion exchange chromatography gives 55 as an off-white foam-like solid (0.37 g, 68%). MW 457.62; C30H35NO3; LCMS. (6 minute method): m/z 458 [M+H]+, RT 3.58 min.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])=[CH:14][CH:13]=1)=O.C([O-])(O)=O.[Na+].[C:41]([NH:48][CH2:49][CH2:50][NH2:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>O.CC#N>[C:44]([O:43][C:41]([NH:48][CH2:49][CH2:50][NH:51][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][CH2:22][CH:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:14][CH:13]=1)=[O:8])=[O:42])([CH3:45])([CH3:46])[CH3:47]
Reactant: O=C(Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A solution of N-{4-[(2,5-dioxoazolidinyloxy)carbonylamino]phenyl}(fluoren-9-ylmethoxy)carboxamide (16.10 g, 34.15 mmol, 1.0 eq) in H2O/CH3CN (1/1, v/v, 360 mL) is reacted at room temperature with NaHCO3 (2.86 g, 34.15 mmol, 1.0 eq) and N—BOC-ethylenediamine (5.47 g, 34.15 mmol, 1.0 eq). After stirring overnight at room temperature, the reaction mixture is filtered to afford 16.36 g of the expected crude product as a white solid.
Reaction SMILES: C(N(CC)CC)C.CN(C)C=O.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.Cl.[C:24]1([NH2:31])[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([NH2:31])=[CH:25][CH:26]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(Nc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triethylamine (35 ml) was added into dimethylformamide (50 ml) including 2-chloro-5-nitropyridine (1) (9.5 g, 60 mmol) and para-phenylenediamine hydrochloride (10.9 g, 60 mmol), and stirred at the room temperature for 14 hours. After the reaction having been completed, the solution was poured into water, and the resultant solid was filtered and then N-(5-nitropyridin-2-yl) para-phenylenediamine was obtained as a brown solid. This solid was dissolved in ethanol (800 ml) and added with 5%-palladium carbon (2 g) so as to cause a hydrogen substitution, and then reduced at 70° C. under the normal pressure for 6 hours. After the reaction having been completed, the celite filtering was applied to remove the palladium carbon, and then it was washed by using a mixed solvent of ethyl acetate and hexane, thus obtained N-(5-amino-pyridin-2-yl) para-phenylenediamine (8.8 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])/[C:4](/[N:10](C)[NH2:11])=[CH:5]\[C:6](OC)=[O:7].[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=CC=1.[C:25]1([CH3:32])C(C)=CC=C[CH:30]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([OH:7])[N:11]([CH3:14])[N:10]=1)=[O:13].[CH:25]([O:2][CH:14]([CH3:19])[CH3:24])([CH3:32])[CH3:30]
Reactant: Cc1ccccc1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)/C=C(\C(=O)OC)N(C)N
Product: CC(C)OC(C)C
Product: COC(=O)c1cc(O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of (E)-2-(N-methyl-hydrazino)-but-2-enedioic acid dimethyl ester (12.2 g, 65 mmol) in xylene (65 mL) was added para-toluenesulfonic acid (0.9 g, 4.7 mmol) and the resulting mixture heated at reflux for 6 h. After cooling to room temperature the mixture was stirred overnight and the resulting solid was filtered off and dissolved in ethyl acetate and the organic extract washed with sodium hydrogen carbonate, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (7.49, 74%) as a light brown solid after trituration with diisopropylether. MS: m/e=157.2 [M+H]+.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:44][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:43][CH:42]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(CN4CCN(C)CC4)cc3)nn12
Yield: 24.7 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.3789 mL, 0.002175 mol) and 4-(4-Methyl-piperazin-1-ylmethyl)-phenylamine (0.179 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (0.500 mL, 0.00512 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 46.12 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine as a lyophilized powder. (M+H)=429.07. 1H NMR (400 MHz, DMSO, d6) δ 9.55 (s, 1H), 8.97 (s, 1H), 7.79 (dd, 1H, J=1.64, 5.97 Hz), 7.73 (d, 2H, J=8.36 Hz), 7.48 (m, 1H), 7.22 (d, 3H, J=7.96 Hz), 7.12 (t, 1H, J=7.45 Hz), 6.95 (m, 2H), 3.85 (s, 3H), 3.72 (m, 6H), 3.40 (m, 4H), 2.76 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O.O>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][CH:24]=[CH2:23])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:16])[NH:10]2)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Oc1ccc(O)c2c1CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(OC(C)=O)c2c1NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 Grams of 5-acetoxy-3,4-dihydro-8-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of dimethylformamide (DMF), to this solution were added 52 g of potassium carbonate powder and 50 ml of allyl bromide, the mixture thus obtained was stirred at room temperature for 8 hours. To this reaction mixture was diluted with 500 ml of water, extracted with 2 liter of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol, there was obtained 70 g of 5-acetoxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone as brown needle-like crystals.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:10]=[CH2:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Si](O/C(=C\C1C=CC(F)=CC=1)/C=C)(C)C)(C)(C)C.[C:39]([O:48][CH2:49][CH3:50])(=[O:47])/[CH:40]=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43]>>[Si:5]([O:8][C:9]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:40]([C:39]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:11][CH:10]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:7])[CH3:6]
Reactant: C=CC(=Cc1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)/C=C/C(=O)OCC
Agent: C=C/C(=C/c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 37 g (˜80% pure, 133.1 mmol, 1 equiv.) of 1E and 1Z-tert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane (Example 1, step C) and 17 mL (18 g, 104.6 mmol) diethyl (2E)-but-2-enedioate in 200 mL xylenes under nitrogen atmosphere was heated at 160° C. for 5 hr then cooled to RT. The solvent was evaporated under vacuum to give an oil which was used without further purification.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH3:4][O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])N.[CH3:13][C:14]1[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH3:4][O:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])[NH:1][C:2]([O:21][CH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=1)=[O:3]
Reactant: Cc1cccc(CO)n1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: [N-]=C=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(=O)OCc1cccc(C)n1)C(C)C

Procedure:
To a solution of the isocyanate derived from Valine methyl ester (17.9 mmol) dissolved in toluene was added 6-methyl-pyridine-2-methanol (2.42 g, 1.1 equivalent). The solution was heated at reflux for 2 hours. After concentration in vacuo and purifiction by silica gel column chromatography, (6-methylpyridin-2-yl)methoxycarbonyl-Valine methyl ester (2.8 g) was obtained. Hydrolysis of the methyl ester using aqueous lithium hydroxide provide the title compound upon recrystallization from hot ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[C:4](O)=[N:5][CH:6]=[CH:7][N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nccnc1O
Product: CCc1nccnc1Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
3-Ethyl-2-hydroxypyrazine (5 g) was heated with phosphorus oxychloride (15 ml) at reflux for 3 hours. The reaction was allowed to cool to ambient temperature and then poured onto 200 g of crushed ice. The mixture was extracted with dichloromethane (3×150 ml) and the combined extracts were dried (MgSO4). Volatile material was removed by evaporation to give a brown oil. The oil was purified by chromatography on silica gel, eluting with dichoromethane, to give 2-chloro-3-ethylpyrazine as a colourless oil (5.64 g, 98%); 1H MNR (d6 -DMSO, 200 MHz): 1.25 (t,3H), 2.93 (q,2H), 8.36 (d,1H), 8.59 (d,1H); mass spectrum (+ve CI): 143 (M+H)+.