Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25][N:24]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:27]=4[CH:26]=[CH:25][N:24]=[CH:23]5)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1cccc2cnccc12
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc5cnccc45)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and isoquinoline-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(isoquinolin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (7 mg, 5%): m/z (ES+) 416 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=2)[CH:12]=[C:11]1[C:42](=O)[CH:43]([CH3:45])[CH3:44])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Si:25]([O:24][CH2:23][C:15]1[C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:18]2[N:10]3[CH2:9][CH2:8][N:7]=[C:42]([CH:43]([CH3:45])[CH3:44])[C:11]3=[CH:12][C:13]=2[CH:14]=1)([C:38]([CH3:41])([CH3:39])[CH3:40])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate (250 mg, 0.37 mmol) in CH2Cl2 (5.0 mL) was added trifluoroacetic acid (1.0 mL) and the mixture was allowed to stir at rt for 1 h. The excess amount of TFA was removed by azeotropic evaporation with toluene under reduced pressure. The residue was redissolved in CH2Cl2 (5 mL) and Et3N (0.5 mL) was added. The reaction mixture was stirred at rt for 45 min and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with CH2Cl2/methanol (98/2) to provide 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (135 mg, 65% yield). LC-MS m/z 559 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)[OH:18]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1cccnc1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A stirred solution of 5-fluoroindole (4 g, 30 mmol) in methanol is treated with 3-pyridine carboxaldehyde (2.79 ml, 30 mmol), cooled to 0° C., treated with 50% NaOH (3.25 ml), stirred at 0° C. for 1 hr, warmed to room temperature, stirred for 3 hr, treated with water and extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The residue is treated with ethyl acetate and filtered. The filtrate is further concentrated and filtered. The filtercakes are combined and dried to afford the title compound as a pale orange solid 5.2 g (73%) mp 131-133° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]2[C:10]([CH3:20])=[C:11]([OH:19])[C:12]([C:15](OC)=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1>O1CCCC1>[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]2[C:10]([CH3:20])=[C:11]([OH:19])[C:12]([C:15]([NH:1][OH:2])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)c(C)c1O
Reactant: NO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(F)cc2)cnc(C(=O)NO)c1O

Procedure:
5.0 mL of hydroxylamine solution (50 wt. % in water) was added to a solution of 0.169 g of methyl 5-(4-fluorobenzyl)-3-hydroxy-4-methylpicolinate 7c (0.615 mmol, 1 eq) in 5.0 mL of tetrahydrofuran. The reaction mixture was stirred at reflux overnight.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C.CC(C)=O>[CH3:17][O:16][C:3]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[CH:15][C:6]2[C:7]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Reactant: COc1cc2oc(=O)cc(C(C)C)c2cc1O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: COc1cc2oc(=O)cc(C(C)C)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 85 %

Procedure:
Method D (2.5 h at 85° C.); starting materials: 6-hydroxy-7-methoxy-4-(1-methylethyl)-2H-1-benzopyran-2-one (example 105) and 1-(3-chloropropyl)-4-phenyl-piperidine; yield 85%; fusion point 62°-65° C. (from TBME). Fumarate: method E; yield 65%; fusion point 155°-157° C. (from acetone, boiled out with TBME).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:26])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:50]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])(=[O:53])[CH:51]=[CH2:52].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:55]([O:54][C:50](=[O:53])/[CH:51]=[CH:52]/[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][C:16]=2[CH3:26])[CH:3]=1)([CH3:58])([CH3:57])[CH3:56]
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(C)c(CC(=O)Nc3cc(/C=C/C(=O)OC(C)(C)C)ccc3C(=O)O)c2c1
Temperature: 110 °C

Procedure:
To methyl 4-bromo-2-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}benzoate (20 mg) was added palladium acetate (2 mg), tri-o-tolylphosphine (3 mg), t-butyl acrylate (33 μl), triethylamine (32 μl) and dimethylformamide (1 ml). After heating at 110° C. for 18 h, the solvent was removed in vacuo and the residue diluted with dichloromethane (10 ml) and washed with 5% citric acid (5 ml). Purification by SPE eluting with dichloromethane, chloroform, and chloroform: ether mixtures afforded the title compound (5 mg), MH+ 465; MH− 463; TR 4.47 min.
Reaction SMILES: OC1C(C)=C(OCC2ON=C(CC3C=CC=C(I)C=3)N=2)C=CC=1C(=O)C.[Cl:27][C:28]1[C:29]([OH:38])=[C:30]([C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][C:33]=1[OH:34].Cl[CH2:40][C:41]1[O:45][N:44]=[C:43]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([I:53])=[CH:49][CH:48]=2)[N:42]=1>>[Cl:27][C:28]1[C:29]([OH:38])=[C:30]([C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][C:33]=1[O:34][CH2:40][C:41]1[O:45][N:44]=[C:43]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([I:53])=[CH:49][CH:48]=2)[N:42]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: ClCc1nc(Cc2ccc(I)cc2)no1
Agent: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone, employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone and 5-Chlormethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole. LC-MS (m/e): 485 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([NH2:13])[CH2:6][CH2:5]2.[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([N:13]=[C:14]=[S:15])[CH2:6][CH2:5]2
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC1CCc2cc(F)c(F)cc2C1
Solvent: CCOC(C)=O
Product: Fc1cc2c(cc1F)CC(N=C=S)CC2
Yield: 79.1 %

Procedure:
A mixture of (-)-6,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (0.56 g, 3.06 mmol), prepared as in Example 8, and 1,1'-thiocarbonyldiimidazole (0.82 g, 4.59 mmol) in 15 mL of ethyl acetate was stirred until the reaction was complete. The solvent was removed by evaporation. Purification of the residue by column chromatography on silica gel (elution: 5% acetone/methylene chloride) gave (-)-6,7-difluoro-2-isothiocyano-1,2,3,4-tetrahydronaphthalene (0.55 g, 2.42 mmol). [α]D25 -15.5°, (C=1.0, CH3OH).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[CH2:26]([O:29][N:30]=[C:31]([C:35]1[N:36]=[C:37]([NH:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[S:38][CH:39]=1)[C:32](O)=[O:33])[C:27]#[CH:28].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH2:26]([O:29][N:30]=[C:31]([C:35]1[N:36]=[C:37]([NH:40][C:41](=[O:46])[C:42]([F:45])([F:43])[F:44])[S:38][CH:39]=1)[C:32]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:33])[C:27]#[CH:28]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Yield: 87.1 %

Procedure:
7-Amino-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (1.93 g) and 2-(2-propynyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn isomer) (1.61 g) were reacted in the presence of Vilsmeier reagent prepared from dimethylformamide and phosphorus oxychloride to give 7-[2-(2-propynyloxyimino)-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.0 g).
Reaction SMILES: NC1C=CC(O)=C(F)C=1.FC1C=CC(CC(SC#N)=O)=CC=1.[F:23][C:24]1[CH:25]=[C:26]([NH:43][C:44]([NH:46][C:47](=[O:56])[CH2:48][C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[S:45])[CH:27]=[CH:28][C:29]=1[O:30]C1C2=C(C)C(OC)=CN2N=CN=1.CCOC(C)=O>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([NH:43][C:44]([NH:46][C:47](=[O:56])[CH2:48][C:49]2[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=2)=[S:45])[CH:27]=[CH:28][C:29]=1[OH:30]
Reactant: COc1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Agent: N#CSC(=O)Cc1ccc(F)cc1
Agent: Nc1ccc(O)c(F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 4-amino-2-fluorophenol (50 mg, 0.3 mmol, Indofine Chemical Co.) in CH2Cl2 (5 mL) was added a 0.25 M solution of 2-(4-fluorophenyl)-1-thiocyanatoethanone (prepared using a similar procedure for the synthesis of Compound A of Example 2) in EtOAc (1.6 mL, 0.4 mmol). The reaction was stirred at room temperature for 20 minutes, concentrated in vacuo and purified by silica gel flash chromatography (eluted with 1–25% EtOAc/CH2Cl2) to give the title compound (100 mg, 95%) as a white solid.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[C:7](Cl)=[C:8]([Cl:12])[CH:9]=[CH:10][CH:11]=1>C(O)=O>[Cl:12][C:8]1[CH:9]=[C:10]([Cl:1])[CH:11]=[C:6]([Cl:5])[CH:7]=1
Reactant: Clc1cccc(Cl)c1Cl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O=CO
Product: Clc1cc(Cl)cc(Cl)c1

Procedure:
To carry out the process according to the invention, the formic acid and the aluminum trichloride are added to the trichlorobenzene which has initially been introduced, and the mixture in the reactor is warmed to the desired temperature in the absence of moisture. The reaction mixture is worked up by filtering it off from the catalyst, washing the residue neutral with water, and distilling the filtrate in the customary manner to isolate the pure 1,3,5-trichlorobenzene. The non- isomerized trichlorobenzenes, which are obtained, for example, as a distillation residue, can be recycled to the isomerization. By this measure, the yield of 1,3,5-trichlorobenzene can be further increased.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: ClCCCn1cnc2ccccc21
Reactant: Fc1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(N2CCN(CCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
1-(3-chloropropyl)-1H-benzimidazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-fluorophenyl piperazine (6.91 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.4 g compound (I-8) with a yield of 63.1%. ESI-MS [M+H]+: m/z 339.2.
Reaction SMILES: NC1NC=NC=1C(N)=O.[N+:10](=[C:12]1[NH:16][CH2:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11].[CH3:20][N:21]=[C:22]=[O:23]>ClCCl>[CH3:20][N:21]1[N:11]=[N:10][C:12]2[N:16]([CH:15]=[N:14][C:13]=2[C:17]([NH2:19])=[O:18])[C:22]1=[O:23]
Reactant: [N-]=[N+]=C1NCN=C1C(N)=O
Reactant: CN=C=O
Agent: NC(=O)c1nc[nH]c1N
Solvent: ClCCl
Product: Cn1nnc2c(C(N)=O)ncn2c1=O

Procedure:
In this process, 5-amino-1H-imidazole-4-carboxamide (A) is converted into 5-diazo-1H-imidazole-4-carboxamide (B), which is then cyclized with methylisocyanate in dichloromethane to provide a high yield of clinical-grade Temozolomide. However, this process requires isolation of the unstable and potentially dangerous 5-diazo-1H-imidazole-4-carboxamide (B). Moreover, methylisocyanate is a difficult reagent to handle and ship, especially on the industrial scale, and indeed is better avoided in industrial manufacture. Furthermore, the cycloaddition of methylisocyanate requires a very long reaction time: Table I in J. Med. Chem. 1984, 27, 196-201, suggests 20 days.
Reaction SMILES: [CH2:1]([Li])[CH:2]=[CH2:3].[CH3:5][O:6][C:7](=[O:26])[CH:8]=[CH:9][CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:18])[N:12]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH3:24][C:22]([CH3:23])([O:21][C:19]([N:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]1[CH2:10][CH:9]([CH2:3][CH:2]=[CH2:1])[CH2:8][C:7]([O:6][CH3:5])=[O:26])=[O:20])[CH3:25]
Reactant: COC(=O)C=CCC1CCCCC(=O)N1C(=O)OC(C)(C)C
Reactant: [Li]CC=C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CC(=O)OC)CC1CCCCC(=O)N1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Four equivalents of allyl lithium are added to a stirring suspension of 2 equivalents copper (I) iodide in THF at -50° C. under argon. After the mixtures becomes homogeneous (approx. 20 minutes.), a solution of the title ester of Example 209 (1 equivalent) in THF is added to the cold mixture and stirred below -50° C. for approx. 30 minutes. The mixture is poured into saturated ammonium chloride solution and stirred vigorously for 15 minutes. The mixture is then partitioned between ether and water and the organic layer is washed with water and brine before it is dried (Na2SO4). The mixture is then filtered and stripped of all solvent. The title material is then purified by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:16][C@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H]3CO3)c2n1
Solvent: O
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)CN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
In a mixed solvent (16 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2R)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (Reference Example 77; 400 mg, 1.62 mmol) and 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 402 mg, 1.62 mmol), and the suspension was stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 288 mg (36%) of the title compound in the form of a yellowish solid.
Reaction SMILES: COC1C=CC(CC(O)=O)=CC=1.[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([C:37]([O-:39])=[O:38])[S:35]C=2)=[CH:28][CH:27]=1.[OH-].[Na+]>O1CCOCC1.CO>[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]1[S:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=1[C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccccc1Cl
Reactant: COc1ccc(-c2csc(C(=O)[O-])c2)cc1
Agent: COc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(C(=O)O)sc2-c2ccccc2Cl)cc1
Temperature: 55 °C

Procedure:
5-(2-Chlorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid is prepared, according to the procedure used in stages 1A)-1E), from (4-methoxyphenyl)acetic acid and methyl 2-chlorobenzoate. In the final stage of this procedure, 5 g of methyl 542-chlorophenyl)-4-(4-methoxyphenyl)-2-thiophenecarboxylate and 1.11 g of sodium hydroxide pellets are added to 30 ml of methanol and 3 ml of dioxane. The reaction medium is heated at 50-60° C. for 5 hours. It is evaporated to dryness, water is added and the impurities are extracted with ether. The aqueous phase is acidified and the expected compound is extracted with ether. After drying and evaporating, 3.5 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
To a solution of 2-amino-5-hydroxybenzoic acid (6.1 g, 0.04 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was added, dropwise, bromoacetyl bromide (8.0 g, 3.5 mL, 100 mol %) while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~20 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice-water. The light precipitate which formed was filtered and then dried in a vacuum oven for 20 h at 40°-45° C., giving 7.8 g (72%) of the title compound: mp 213°-215.3° C.; 1H NMR (DMSO-d6) δ13.56 (bs, 1H, OH), 11.19 (s, 1H, NH), 9.68 (s, 1H, OH), 8.19 (d, 1H, J=8.8), 7.36 (d, 1H, J=3.2), 7.01 (dd, 1H, J=3.2, J=9.2), 4.19 (s, 2H); 13C NMR (DMSO-d6) δ168.88, 164.32, 153.08, 131.69, 122.21, 120.79, 119.00, 116.60, 30.66; MS (EI, m/z) 273 (M+), 275 (M+2+). HRMS (EI) calcd for C9H8NO4Br 272.9637, found 272.9634.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([C:40](Cl)=[O:41])[CH:37]=[N:38][CH:39]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[O:41])[CH:37]=[N:38][CH:39]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (300 mg) and triethylamine (0.33 ml) in 1,4-dioxane (10 ml) was added 5-bromo-3-pyridylcarbonyl chloride·hydrochloride (304 mg). The mixture was stirred at room temperature for 15 minutes, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-[3-[(5-bromo-3-pyridyl)carbonylamino]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (256 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[CH2:25]([Mg]Br)[CH3:26]>C1COCC1.CN1C(=O)CCC1>[CH2:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1)[CH3:26]
Reactant: CC[Mg]Br
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCc1nc(SC)ncc1-c1ccnc(Nc2ccc(C#N)cc2)n1
Yield: 26.7 %

Procedure:
4-(4′-Chloro-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (35) (205 mg, 0.526 mmol) and ferric acetylacetonate (18.57 mg, 0.053 mmol) were dissolved in THF (3305 μl) and NMP (248 μl), then ethylmagnesium bromide (789 μl, 0.789 mmol) was added dropwise under nitrogen. The reaction was quenched with 1N HCl, then was extract with EtOAc. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was dry-loaded onto silica gel and purified by Biotage™ silica gel chromatography [25 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain 49 mg of the desired product (21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.58 Hz, 3H) 2.59 (s, 3H) 2.95 (q, J=7.58 Hz, 2H) 7.25 (d, J=5.05 Hz, 1H) 7.68-7.78 (m, 2H) 7.95-8.03 (m, 2H) 8.67-8.75 (m, 2H) 10.33 (s, 1H). MS (ES+): m/z=349.5 [M+1] (100). HPLC: tR=1.57 minutes over 3 minutes. Purity: 93% [HPLC (LC/MS) at 220 nm].