Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]3[CH:27]=2)[CH:6]=[CH:7][CH:8]=1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:28]1([C:31]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]4[CH:27]=3)[CH:6]=[CH:7][CH:8]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C(C)(C)F
Reactant: O=C(O)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CNC(=O)C4CC4)c3)cc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68, 15 mg, 0.041 mmol), cyclopropanecarboxylic acid (3.40 μl, 0.041 mmol) and triethylamine (8.49 μl, 0.061 mmol) in DMF (0.5 mL) was added BOP (17.96 mg, 0.041 mmol) and the resulting mixture was stirred at rt for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (9.6 mg, 53%). HPLC (condition J): retention time=2.140 minute. LC/MS (M+H)+=438.2. 1H NMR (500 MHz, MeOD) δ ppm 8.08 (1 H, s), 7.86 (1 H, d, J=1.7 Hz), 7.50-7.57 (2 H, m), 7.35 (1 H, t, J=7.6 Hz), 7.19 (1 H, d, J=7.5 Hz), 7.09 (1 H, d, J=1.7 Hz), 4.39-4.49 (3 H, m), 1.54-1.61 (1 H, m), 1.51 (3 H, d, J=3.6 Hz), 1.44-1.48 (6 H, m), 0.89-0.95 (2 H, m), 0.72-0.78 (2 H, m).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1.CCOCC>ClCCl>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:25][CH:24]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
N-phenyl-1,2-phenylenediamine (1.84 g, 10 mmol) and 30 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was then added, and the mixture was cooled to 0° C. 4-Fluoro-benzoyl chloride (1.58 g, 10 mmol) was dissolved in 30 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(4-fluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=2.3 g, 80%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OC(C)C)(C)C.C(O)C>[ClH:1].[C:8]1([CH:6]2[O:5][N:4]=[C:3]([CH2:2][N:24]3[CH2:23][CH2:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=4)([OH:27])[CH2:26][CH2:25]3)[CH2:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: ClCC1=NOC(c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: OC1(c2ccc(Cl)cc2)CCN(CC2=NOC(c3ccccc3)C2)CC1
Reaction time: 6 h

Procedure:
3-Chloromethyl-5-phenyl-4,5-dihydroisoxazole (5.87 g), 6.3 g of 4-(4-chlorophenyl)-4-hydroxypiperidine, 4 g of potassium carbonate and 50 ml of ethanol are heated to 60°-70° C. with stirring for 6 hours. The reaction mixture is filtered and the filtrate is condensed by distillation under reduced pressure. To the residue are added 200 ml of ethyl acetate and 100 ml of water. The organic layer is separated off, washed with water, dried on magnesium sulfate and evaporated under reduced pressure. The residue thus obtained is dissolved in isopropyl ether and alcoholic hydrochloric acid is added to the solution. The crystals thus formed are filtered and then recrystallized from isopropyl alcohol, giving 1-(5-phenyl-4,5-dihydroisoxazol-3-ylmethyl)-4-(4-chlorophenyl)-4-hydroxypiperidine hydrochloride. Melting point: 175°-176° C. (decomposition)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(I)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(Br)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[4-(2,4-Dichloro-phenyl)-2-(4-iodo-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (3.2 g, 5 mmol) was treated as described in general procedure G using 4-bromophenylboronic acid (2.0 g, 10 mmol) to give 5-{4-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]1[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2C(=O)CCC2CCC(=O)OCc2ccccc2)cc1
Temperature: 55 °C

Procedure:
A solution of 50 g of 5-oxo-2-pyrrolidinepropanoic acid benzyl ester in 800 ml of tetrahydrofuran is treated with 28.3 g of 4-methoxybenzoyl chloride. The mixture is heated to 55° C. and a solution of 20 g of triethylamine in 400 ml of tetrahydrofuran is added dropwise over a two hour period. The mixture is stirred and heated at 55° C. for 16 hours. The warm mixture is filtered through filter aid to remove triethylamine hydrochloride and concentrated at reduced pressure. Chromatography over silica using a Waters Prep 500 HPLC apparatus yielded 1-(4-Methoxybenzoyl)-5-oxo-2-pyrrolidinepropanoic acid benzyl ester mp 80°-83° C. After concentration and crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][CH:10]=[C:9]([CH:13]=O)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]([NH:18][NH2:19])(=[O:17])[CH3:16].C(Cl)Cl.O>C(O)C>[C:15]([NH:18]/[N:19]=[CH:13]/[C:9]1[CH:10]=[N:11][CH:12]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:17])[CH3:16]
Reactant: CCOC(=O)c1c(Cl)cncc1C=O
Reactant: CC(=O)NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(Cl)cncc1/C=N/NC(C)=O
Reaction time: 2 h
Yield: 8.7 %

Procedure:
To ethyl 3-chloro-5-formylisonicotinate (2 g, 9.36 mmol) in 60 mL of ethanol was added acetohydrazide (0.832 g, 11.24 mmol) at room temperature. The reaction mixture was stirred for 2 h. Then, the reaction mixture was mixed with DCM and water. The organic phase was washed with brine, dried and concentrated. The crude title compound was purified by chromatography (eluent: DCM/methanol) to give 220 mg (8.7%) of the title compound as orange oil.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][N:26]6[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]6)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:26]1([CH2:25][CH2:24][O:23][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:15]=2[C:14]2[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]34)[CH:11]=[CH:12][CH:13]=2)[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2cccc4c2n3C(c2ccccc2)CO4)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C2COc3cccc4c5c(OCCN6CCNCC6)cccc5n2c34)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a mixture of tert-butyl 4-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}-1-piperazinecarboxylate (0.406 g, 0.79 mmol) in CH2Cl2 (2 mL) is added trifluoroacetic acid (2 mL). The mixture is stirred at room temperature for 1 h then partitioned between CH2Cl2 and water. The organic layer is washed with saturated potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica) using CH3OH/CH2Cl2 (8/92) with 2 drops per 100 mL of NH4OH gave 0.133 g (35%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl 2-(1-piperazinyl)ethyl ether; mp 72° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.C(I)CC>CN(C=O)C>[CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH:23]([CH2:40][CH2:39][CH3:43])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OCC)c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of ethyl [2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.491 g; 1.25 mmol) in dry DMF (5 mL) at −10° C. was added a 1N solution of LHMDS in THF (1.38 mL; 1.38 mmol) and 1-propyliodide (0.183 mL; 1.88 mmol). The reaction mixture was allowed to warm up to room temperature and the stirring was carried on for 3 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford 0.322 g (59%) of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[NH2:12][O:13][CH2:14][CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 40(f), 0.18 ml of 4'-chloroacetophenone was reacted with 400 mg of 5-[4-(2-aminooxyethoxy)benzyl]-thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was mixed with a mixture of diethyl ether, diisopropyl ether and hexane, and the mixture was then stirred. The resulting precipitate was collected by filtration, to give 360 mg of the title compound, melting at 118-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][CH2:28][NH2:29]>>[NH2:26][CH2:27][CH2:28][NH:29][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Reactant: NCCN
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCN)nc21

Procedure:
The product of Example 44, and 1,2-diaminoethane were reacted by the procedure of Example 60 to afford 2-(2-amino-ethylamino)-4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (ride)=386 (MH-F). Rt=1.54 min
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([CH:8]2[O:12]CCO2)[CH:5]=[CH:4][C:3]1=O.[CH3:14][N:15]1C=CC=C(C2OCCO2)C1=O.Cl>O1CCCC1>[C:14]([C:3]1[N:2]=[CH:7][C:6]([CH:8]=[O:12])=[CH:5][CH:4]=1)#[N:15]
Reactant: Cn1cc(C2OCCO2)ccc1=O
Reactant: Cn1cccc(C2OCCO2)c1=O
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)cn1
Reaction time: 12 h
Yield: 100 %

Procedure:
The 73:27 mixture (933 mg, 5.15 mmol) of 1-methyl-5-(1,3-dioxolan-2-yl)-2(1H)-pyridone and 1-methyl-3-(1,3-dioxolan-2-yl)-2(1H)-pyridone was dissolved in tetrahydrofuran (10.0 mL). To this, 1N hydrochloric acid (10.0 mL) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 12 hours. Then, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and thereby 6-cyano-3-pyridinecarboxaldehyde (364 mg, yield: 100%) was obtained. The residue was purified by preparative thin-layer chromatography (ethyl acetate) to give 1-methyl-5-formyl-2(1H)-pyridone (309 mg, yield: 45%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)C(=O)[O:18][N:17]=2)=[N:13][O:14][N:15]=1.[S:30](N)([NH2:33])(=[O:32])=[O:31].N1C=CC=CC=1.[OH-].[Na+]>C(O)(=O)C>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]([C:12]2[C:11]([CH2:10][CH2:9][NH:8][S:30](=[O:32])(=[O:31])[NH2:33])=[N:15][O:14][N:13]=2)=[N:17][OH:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: NCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of 3-[4-(2-aminoethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4h)-one trifluoroacetate (23.0 mg, 53.0 mmol), sulfamide (15.0 mg, 160 mmol) and pyridine (1.0 mL) was heated at 120° C. for 3 min in a microwave. To the reaction solution was added 0.5 mL 1 N NaOH and stirred for 30 min. The reaction solution was then acidified with acetic acid and purified by preparative LCMS to give the desired product (12 mg, 46%). MF═C11H12ClFN6O4S; LCMS calculated for C11H13ClFN6O4S(M+H)+: m/z=379.0. 1H NMR (400 MHz, DMSO-d6): d 11.52 (s, 1H), 10.45 (s, 0.1H), 9.05 (s, 0.1H), 8.98 (s, 1H), 7.95 (m, 0.1H), 7.32 (m, 0.2H), 7.15 (t, J=9.0 Hz, 1H), 7.00 (dd, J=6.5 Hz, 2.7 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.65 (m, 1H), 6.59 (s, 2H), 3.29 (m, 2H), 3.07 (t, J=7.2 Hz, 2H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:49]2[N:50]=[C:51]([NH2:53])[S:52][C:48]=2[C:47]([N:54]([CH3:61])[CH:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[CH:46][CH:45]=1>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:53][C:51]1[S:52][C:48]2[C:47]([N:54]([CH3:61])[CH:55]3[CH2:56][CH2:57][O:58][CH2:59][CH2:60]3)=[CH:46][CH:45]=[C:44]([O:43][CH3:42])[C:49]=2[N:50]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(N(C)C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(N(C)C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 7 h
Yield: 62 %

Procedure:
To a stirred solution of 103 mg (0.51 mmol) 2-bromo-isonicotinic acid in 3 ml THF were added 204 mg (0.53 mmol) HATU and 0.11 ml (1.02 mmol) N-methylmorpholine and stirring continued at 30° C. for 7 h. 75 mg (0.26 mmol) 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-yl)-benzothiazole-2,7-diamine was then added and stirring continued at 40° C. for 16 h. The reaction mixture was then diluted with ethyl acetate and washed sequentially with saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane) followed by trituration in ether/pentane afforded 77 mg (63%) 2-bromo-N-{4-methoxy-7-[methyl-(tetrahydro-pyran-4-yl)-amino]-benzothiazol-2-yl}-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 479 (M{81Br}+H+, 100), 477 (M{79Br}+H+, 95).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[SH2:12].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:12])[NH2:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(C(N)=S)ccc1O
Temperature: 70 °C

Procedure:
A solution of 4-hydroxy-3-methoxybenzonitrile (15.0 g, 0.1 mol) in DMF (150 mL) was treated with a slow flow of gaseous hydrogen sulfide for 30 minutes at rt. Diethyl amine (15.6 mL, 11.0 g, 0.15 mol) was added and the solution was heated at 70° C. for 4 h. The solution was cooled to rt and the residual H2S was removed by passing argon through the solution for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica, followed by washing with EtOAc. Removal of the solvent resulted in a crude brown oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH3:14])[C:5]([CH2:7][CH2:8]C(O)=O)=[O:6])[CH2:2][CH3:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:22])C=CC=CC=1.C([N:34]([CH2:37]C)CC)C>C1C=CC=CC=1>[CH2:12]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][CH2:8][N:34]=[C:37]=[O:22])=[O:6])[CH2:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: CCCN(CCC)C(=O)CCC(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCCN(CCC)C(=O)CCN=C=O

Procedure:
The reaction of 3-(N,N-dipropylcarbamoyl)propionic acid and diphenylphosphoryl azide in a solution of triethylamine and benzene provided a solution comprising 2-(N',N'-dipropylcarbamoyl)ethyl isocyanate (I.R.: 2280 cm-1), which was reacted with 5-fluorouracil to provide 1-[N-[2-(N',N'-dipropylcarbamoyl)ethyl]carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.
Reaction SMILES: N1C2C=CC=CC=2NC1=[O:10].[Cl:11][CH:12]([CH3:24])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[NH:20][C:16]=2[CH:15]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)CC)C>C(#N)C>[Cl:11][CH:12]([CH3:24])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[NH:20][C:16]=2[CH:15]=1.[ClH:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][N:36]([CH:12]([CH3:24])[C:13]([C:14]2[CH:23]=[CH:22][C:17]3[NH:18][C:19](=[O:21])[NH:20][C:16]=3[CH:15]=2)=[O:10])[CH2:35][CH2:34]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: CC(Cl)Cc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C(C)C(=O)c2ccc3[nH]c(=O)[nH]c3c2)CC1
Product: Cl
Reaction time: 3 h

Procedure:
5-(2-chloropropyl)-1H-benzimidazol-2-one was prepared from 1H-benzimidazol-2-one according to the synthetic and working-up method of general procedure B. 5-(2-chloropropyl)-1H-benzimidazol-2-one (2.47 g, 0.011 mol) and 2-methoxyphenyl piperazine (1.92 g, 0.01 mol) were dissolved in 100 ml of acetonitrile, and triethylamine (3.04 g, 0.03 mol) was added. A reaction under refluxing was allowed to proceed for 3 hours at an elevated temperature. Working up according to general procedure B gave 3.73 g of 5-(2-(4-(2-methoxy phenyl)piperazin-1-yl)propanoyl)-1H-benzo[d]imidazol-2(3H)-one hydrochloride. The yield was 89.5%.
Reaction SMILES: C(OC1C=C(C(F)=CC=1Cl)[NH2:8])C=C.[CH2:14]1[CH:19]2[C:20](O[C:23](=[O:24])[CH:18]2[CH2:17][CH:16]=[CH:15]1)=[O:21].C(O)(=O)C>O>[C:23]1(=[O:24])[NH:8][C:20](=[O:21])[C:19]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1=2
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2CC=CCC12
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C2=C1CCCC2
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 19A, 6.8 g of THPA and 100 mL of glacial acetic acid was heated at reflux temperature for 4 hours. The resulting mixture was cooled to room temperature, poured into 450 mL of water and extracted with ether. The extract phase was washed with water, dried (Na2SO4), and filtered, and the solvent was evaporated from the filtrate. The residue was flash-chromatographed on silica gel, with a 15:85 v:v mixture of ethyl acetate and hexane as eluent, to give N-(3-allyloxy)-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide (19B), as an orange oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH:35]([NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[NH:43][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (210 mg, 0.563 mmol) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 78 supra) (611 mg, 2.25 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to 4:1) to afford crude (2-(3-chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester. (Yield 150 mg). LC-MS: [M+H]+ 564.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[Br:12]N1C(C)(C)C(=O)N(Br)C1=O.C1(C(OO)=O)C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cccc2nccnc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OO)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2nccnc12
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 10 parts of 5-methylquinoxaline, 10 parts of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, 1.7 parts of benzenecarboperoxoic acid and 318 parts of tetrachloromethane was stirred for 16 hours at reflux temperature under 2 lamps of 250 Watt. The reaction mixture was cooled and the organic layer was decanted. The product was filtered off and dried, yielding 15.5 parts (100%) of 5-(bromomethyl)quinoxaline (interm. 1).