Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:17])=[O:18])[CH:15]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 61 %

Procedure:
5-Chloro-2-methoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 5-chloro-2-methoxybenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 180°-184° C., yield 61%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1.O=[C:32]1C2(COC3C=C4C(=CC2=3)CCO4)C2[C:34](=CC=CC=2)[N:33]1CC1OC(C(O)=O)=CC=1>>[CH3:32][N:33]([CH3:34])[C:28]([C:26]1[N:27]=[C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])[O:24][CH:25]=1)=[O:29]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Product: CN(C)C(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 13.1 and making non-critical variations using 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid to replace 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(1′H)-yl)methyl]furan-2-carboxylic acid, N,N-dimethyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide was obtained (3.0%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.09 (s, 1H), 7.27-6.86 (m, 4H), 6.50 (s, 1H), 6.40 (s, 1H), 5.08 (ABq, 2H), 4.82 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.29 (s, 3H), 3.06 (s, 3H), 2.97 (t, J=8.6 Hz, 2H); MS (ES+) m/z 431.8 (M+1).
Reaction SMILES: [N+](C[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([O-])=O.[CH3:15][N:16]([CH2:18][CH2:19][OH:20])[CH3:17]>C1C=CC=CC=1>[C:5]([O:20][CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(=O)C[N+](=O)[O-]
Reactant: CN(C)CCO
Solvent: c1ccccc1
Product: CCCCCCCCC(=O)OCCN(C)C
Yield: 72 %

Procedure:
In accordance with practice of the process of this invention, ten parts of 1-nitro-2-decanone, 5.0 parts of dimethylaminoethanol, and 110 parts of dry benzene are admitted to a reaction vessel wherein they are refluxed for four hours. At the end of this time, there are distilled off from the reaction mixture 44 parts by weight of benzene solvent and 2.0 parts by weight of nitromethane. The remaining benzene is then distilled at atmospheric pressure and 80° C. Thereafter the residual dark oil is distilled at 106°-110° C, at 2mm Hg to yield 8.2 parts by weight of N,N-dimethylaminoethyl nonanoate, a pale yellow liquid having a boiling point of 106°-110° C/2mm and a refractive index ND24 1.4355. (Yield 72%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:38])[CH3:37])=[CH:31][C:30]=2[N:39]2[CH:43]=[CH:42][C:41]([CH3:44])=[N:40]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:38])[CH3:37])=[CH:31][C:30]=2[N:39]2[CH:43]=[CH:42][C:41]([CH3:44])=[N:40]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(CN(C)C)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(CN(C)C)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(4-((dimethylamino)methyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15]>C(OCC)C.[OH-].[Na+]>[S:1]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Reaction time: 4 h

Procedure:
A solution of tosyl chloride (20 g, 0.1 mol) in diethyl ether (100 ml) was added in drops at room temperature to a solution of D-valine (11.7 g, 0.1 mol) in 200 ml of 1N NaOH, and the two-phase mixture was stirred vigorously for 4 hours. Then, the diethyl ether phase was separated, the aqueous phase was washed twice more with diethyl ether and acidified at 0° C. by adding concentrated HCl. After 30 minutes, it was suctioned off, liberally rewashed with ice water and dried for several hours at 0.01 Torr. 18.1 g, (67%), of colorless crystals was obtained (melting point: 147° C.).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH2:31]([N:35]1[C:43]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:42][C:41]2[C:36]1=[N:37][C:38]([C:56]1[CH:57]=[N:58][C:59]([NH2:62])=[N:60][CH:61]=1)=[N:39][C:40]=2[N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[CH:32]([CH3:34])[CH3:33].[C:63](O)(=[O:66])[CH2:64][OH:65]>C(Cl)Cl.CO.CN(C)C=O>[NH2:62][C:59]1[N:60]=[CH:61][C:56]([C:38]2[N:37]=[C:36]3[C:41]([N:42]=[C:43]([N:44]4[CH2:49][CH2:48][N:47]([C:64](=[O:65])[CH2:63][OH:66])[CH2:46][CH2:45]4)[N:35]3[CH2:31][CH:32]([CH3:34])[CH3:33])=[C:40]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[N:39]=2)=[CH:57][N:58]=1
Reactant: O=C(O)CO
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)CO)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 21 h
Yield: 71.9 %

Procedure:
1-Hydroxybenzotriazole monohydrate (37.9 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (71.2 mg, 0.37 mmol), and triethylamine (51.7 μl, 0.37 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(isobutyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (108.5 mg, 0.25 mmol) and glycolic acid (22.6 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred for 21 hours and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (89.2 mg, 73%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:48])=[C:29]([CH:43]=[C:44]([C:46]#[N:47])[CH:45]=1)[O:30][CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:48][C:28]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:20][CH2:19]3)[CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[CH:45][C:44]([C:46]#[N:47])=[CH:43][C:29]=1[O:30][CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C#N)cc(N)c2Cl)C1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C(=O)OC(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 70 °C
Yield: 64.9 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(50 mg, 0.141 mmol), (+/−)-tert-butyl 3-(3-amino-2-chloro-5-cyanophenoxy)pyrrolidine-1-carboxylate (47.6 mg, 0.141 mmol), palladium(II) acetate (8.38 mg, 0.037 mmol), Xantphos (8.15 mg, 0.014 mmol), DPPF (7.81 mg, 0.014 mmol) and cesium carbonate (119 mg, 0.366 mmol) in dioxane (1 ml) was evacuated and back filled with nitrogen three time and was heated at 70° C. for 3 h. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g gold column, eluting with 0-40% ethyl acetate/dichloromethane). (+/−)-tert-butyl 3-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenoxy)pyrrolidine-1-carboxylate (60 mg) was obtained as a colorless oil which was carried as such to the next reaction.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(O)=O>C1(C)C=CC=CC=1>[C:24]([O:23][C:21](=[O:22])[NH:20][C@H:4]([CH:3]=[O:2])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)([CH3:25])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -78 °C
Yield: 70 %

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[4-(4-chloro-phenoxy)-phenyl]-propionic acid methyl ester (107 mg, 0.26 mmol, 1 eq.) in toluene (5 ml) was added dropwise diisobutylaluminium hydride (1 M in hexane, 0.6 ml, 2.3 eq.) by a syringe with stirring under Ar at −78° C. After the addition was complete, the mixture was stirred at the same temperature for 2 hr and then AcOH (0.2 ml) was added. The mixture was allowed to warm to room temperature overnight. The mixture was partitioned between water and ethyl acetate. EA layer was separated and aqueous layer was extracted with EA. The combined EA layers were dried over anhydrous MgSO4. After the volatile material was removed, the desired product was obtained (68 mg, 70% yield). The product thus obtained was forward to the next step without any further purification.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].[CH2:23]([NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:24]([CH3:26])[CH3:25]>C1COCC1>[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)CNCC(C)C
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)CN(CC(C)C)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Diisopropylcarbodiimide (13.8 ml, 1.2 eq) is added to 4-fluoro-3-nitrobenzoic acid (15 g, 1 eq) in solution in THF (150 ml). The mixture is stirred for 3 hours at a temperature of approximately 20° C. then diisobutylamine (12.9 ml, 1 eq) is added. After stirring for 15 hours at approximately 20° C., the reaction mixture is evaporated under reduced pressure at 40° C. The residue is taken up in dichloromethane (200 ml) and water (70 ml). After decantation and extraction, the combined organic phases are washed with salt water, followed by drying over Na2SO4 then evaporating under reduced pressure at 40° C. Purification of the compound by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2) produces the expected compound in the form of a yellow solid (13.8 g; 63% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:28]=2[NH:27][C:26]2[CH:25]=[N:24][CH:23]=[CH:22][C:21]3=2)[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9]1)=O)(C)(C)C.C(OC(=O)[NH:39][CH:40](C=O)[CH2:41][CH3:42])(C)(C)C>>[Cl:29][C:18]1[CH:19]=[C:20]2[C:28](=[C:16]([NH:15][C:14]([CH:13]3[CH2:12][O:11][C:10]([CH3:31])([CH3:32])[CH2:9][N:8]3[CH2:6][CH:40]([NH2:39])[CH2:41][CH3:42])=[O:30])[CH:17]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CCC(C=O)NC(=O)OC(C)(C)C
Product: CCC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
Method C was followed, using 5-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholine-4-carboxylic acid tert-butyl ester and the appropriate aldehyde, (1-formyl-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [I:1]I.N1C=CN=C1.O[CH2:9][C:10]1[N:11]=[C:12]([C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[O:13][CH:14]=1>C(Cl)Cl>[I:1][CH2:9][C:10]1[N:11]=[C:12]([C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[O:13][CH:14]=1
Reactant: II
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CO)co1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc(CI)co1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of TPP (873 mg, 3.33 mmol) in CH2Cl2 (10 mL), was added I2 (845 mg, 3.33 mmol), and stirred for 10 min. Imidazole (227 mg, 3.33 mmol) was added and stirred for an additional 10 min and then a solution of (R)-tert-butyl 1-(4-(hydroxymethyl)oxazol-2-yl)ethylcarbamate (537 mg, 2.22 mmol) in CH2Cl2 (15 mL) was added. After 2 h, the reaction mixture was washed successively with sat. aq. NaHCO3, aq. Na2S2O3, dried on Na2SO4 and concentrated under low pressure. The residue was chromatographed on silica gel (20% ethyl acetate/80% hexanes) to yield 84% of (R)-tert-butyl 1-(4-(iodomethyl)oxazol-2-yl)ethylcarbamate.
Reaction SMILES: [C:1]([C:4]1[C:9]2[N:10]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21](=[O:26])[C:11]3=[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:7](=[O:27])[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[N:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:47]Br.[Br-]>C1COCC1>[Br:47][CH2:2][C:1]([C:4]1[C:9]2[N:10]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21](=[O:26])[C:11]3=[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:7](=[O:27])[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[N:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CBr)c32)C1=O
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.50 g, 0.98 mmol) in anhydrous THF (20 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (1.08 mL, 1.08 mmol) in THF was added. After stirring at the same temperature for 15 minutes, bromine (0.24 g, 1.47 mmol) was added and the reaction was stirred at room temperature. The reaction was monitored by LC-MS. Additional solution of lithium bis(trimethylsilyl)amide and bromine were added to drive the reaction to completion. The bromide generated as a solution in THF was used in the following reaction without further workup or purification. ES MS M+1=587
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=[C:3]([Cl:12])[CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[C:16](=[O:28])[N:15]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[Cl:12][C:3]1[CH:2]=[CH:1][C:6](/[CH:7]=[CH:8]/[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]([CH2:20][CH:21]([O:22][CH2:23][CH3:24])[O:25][CH2:26][CH3:27])[C:16](=[O:28])[N:15]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: CCOC(Cn1ccc(N)nc1=O)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(Cn1ccc(NC(=O)/C=C/c2ccc(Cl)cc2)nc1=O)OCC
Temperature: 70 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
P-chloro cinnamic acid (1.84 g, 10 mM), 4-amino-1-(2,2-diethoxyethyl)-1H-pyrimidin-2-one (b, 3.00 g, 15 mM), 1-hydroxybenztriazolemonohydrate (2.30 g, 15 mM) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.90 g, 15 mM) were suspended in N,N-dimethylformamide (20 mL) and stirred at 70° C. for 5 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added and stirred at room temperature. The crystal precipitated from the reaction mixture was filtered to afford 2.48 g of the desired compound (E)-3-(4-chlorophenyl)-N-[1-(2,2-diethoxyethyl)-2-oxo-1,2-dihydropyrimidin-4-yl]-acrylamide (c) (yield 68%, colorless crystal).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH:22]2[CH2:24][O:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[OH:23][CH2:24][CH:22]([S:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[OH:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: Oc1ccc(O)c(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCC(Sc1cc(O)ccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 2-mercaptobenzene-1,4-diol (0.5 g) and potassium carbonate (0.49 g) in water (5 ml) was added 2-phenyloxirane (0.40 ml) under argon. The mixture was stirred at room temperature for 2.5 hours and then treated with 2 M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried and evaporated. The crude product was purified by column chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 8.94 (br s, 1H), 8.72 (br s, 1H), 7.24-7.37 (m, 5H), 6.62-6.65 (m, 2H), 6.47 (dd, 1H, J 8.6, 2.8 Hz), 4.97 (br s, 1H), 4.34 (m, 1H), 3.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][N:4]2[CH2:28][CH:25]2[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethyl-6-nitroindoline (450 mg) was dissolved in 20 mL of dichloroethane, N-boc-4-formylpiperidine (750 mg) was added to the mixture, followed by 2 g NaHB(OAc)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 9:1 Hexane:EtOAc to afford an orange oil. MS: 290 (M-99). Calc'd. for C21H31N3O4—389.5.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.ClCCl>S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[N+:24]([O-:9])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc2nccc(-c3c(F)cc(F)cc3F)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(-c1c(F)cc(F)cc1F)cc[n+]2[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
m-Chloroperbenzoic acid (425 mg) was added to a mixture of methyl 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate (710 mg) and dichloromethane (20 mL), followed by stirring at room temperature for 3 days. The reaction mixture was diluted with aqueous sodium thiosulfate solution, and extracted with chloroform. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain methyl 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate 1-oxide (680 mg).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([NH2:39])=[O:38])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN(C=O)C.CCOC(C)=O>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([NH2:39])=[O:38])[CH:17]=2)[C:13]([I:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2ccnc(N)n2)n1COCC[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2I)n1COCC[Si](C)(C)C
Temperature: 65 °C
Yield: 61.1 %

Procedure:
N-iodosuccinimide (720 mg, 3.2 mmol) was added to a solution of 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (1.39 g, 3.0 mmol) in dry DMF (6 mL). The reaction mixture was heated at 65° C. for 7 h, allowed to cool to room temperature and then diluted with EtOAc (30 mL), washed with water (2×20 mL) brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 97/3) to afford the title compound as yellow solid (1.07 g, 60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:9][Mg]Br>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH3:9])=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.9 %

Procedure:
4-Pyridinecarbaldehyde (1.00 ml, 10.5 mmol) in tetrahydrofuran (10 mL) was mixed with methylmagnesium bromide (0.97 M in tetrahydrofuran, 19.5 mL, 18.9 mmol) under cooling with ice and stirred at room temperature for 5 hours. After quenching by adding water under cooling with ice, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (283 mg, 22% yield).