Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl.C([O-])(=O)C.[Na+].II>>[CH3:1][N:2]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: CNc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Product: CN(Cc1cccc(Cl)c1)c1cccc(F)c1

Procedure:
N-methyl-N-m-chlorobenzyl-m-fluoroaniline was prepared from 17.5 grams (0.14 mole) of N-methyl-m-fluoroaniline, 23. grams (0.14 mole) m-chlorobenzyl chloride (Aldrich), 11.9 grams anhydrous sodium acetate and 0.12 grams iodine according to the procedure described in Example III. Yield 28.6 grams (83.7 percent), boiling point 172° C. at 0.07 mmHg.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1.Cl[C:14]([O:16][CH3:17])=[O:15]>>[CH3:17][O:16][C:14]([NH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1)=[O:15]
Reactant: COC(=O)Cl
Reactant: NCC1CNc2ccccc2C1
Product: COC(=O)NCC1CNc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The title compound is prepared from 3.1 g of 3(R,S)-aminomethyl-1,2,3,4-tetrahydroquinoline and 2.2 ml methyl chloroformate in an analogous manner to that described in Example 54) (stirring for 2 h at 0° C.) and is purified by chromatography over silica gel with a 1:2 mixture of hexane and ethyl acetate as the mobile phase: Rf (A)=0.25; FAB-MS: (M+H)+ =221.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCC(O)CO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(O)CO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1,2-propanediol (45 ml) and triethylamine (150 mg) were added to pyridine (500 mg), and the mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (60 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (107 mg) as a colorless powder.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[N:22]=[C:23]([NH2:42])[C:24]2[CH:30]=[C:29]([CH:31]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][CH:34]=3)[CH:28]=[N:27][C:25]=2[N:26]=1>>[NH2:20][C:21]1[N:22]=[C:23]([NH2:42])[C:24]2[CH:30]=[C:29]([CH:31]=[CH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:40])=[CH:35][CH:34]=3)[CH:28]=[N:27][C:25]=2[N:26]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Agent: Cl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OC(C)(C)C

Procedure:
Alternatively, 2.2 g (0.0074 mol) of di-tert-butyl L-glutamate hydrochloride were allowed to react with 1.5 g (0.0049 mol) of 2,4-diamino-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine, to yield di-tert-butyl N-(4-[2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate in a yield of 1.3 g (48%), mp>300° C. NMR (CDCl3 /CD3OD) delta 1.47, 1.52 (2s, 18H), 2.0-2.6(m, 4H), 4.5-7.0(m, 1H), 6.8(br, s, 2H), 7.35, 7.78(AB q, 4H, J=9 Hz), 8.38(s, 1H), 8.5(s, 1H); IR (Nujol) 3350, 3180, 1725, 1640, 1605 cm-1. MS: Calc'd.: for C29H36N6O5 : 548. Found: m/e 548, 446, 290.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Cl:28][S:29](O)(=[O:31])=[O:30]>ClCCl>[F:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([S:29]([Cl:28])(=[O:31])=[O:30])=[CH:24][CH:23]=2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CCOC(=O)c1cn2c3c(c(-c4ccccc4)c(F)cc3c1=O)OCC2C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(c(-c4ccc(S(=O)(=O)Cl)cc4)c(F)cc3c1=O)OCC2C
Temperature: 0 °C

Procedure:
A suspension of ethyl 9-fluoro-10-phenyl-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylate (0.4 g, 1.2 mmol) in dichloromethane (15 ml) was cooled to 0° C. with stirring. Chlorosulfonic acid (5 ml) was added dropwise over 5 minutes. The dark solution was stirred at 0° C. for 15 minutes, then it was warmed gradually to room temperature over 1.5 hour. The reaction mixture was poured onto ice water with stirring. Three extractions with chloroform, drying the combined organic layers over magnesium sulfate, filtration and removal of solvent in vacuo gave a yellow oil (0.5 g) which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.[H-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[O:10])[N:8]([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([CH3:31])=[CH:29][CH:28]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nn(Cc2ccc(C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 76 %

Procedure:
The alkylation of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with 4-methylbenzyl bromide was carried out as described in Example 3, Step A, except that no excess sodium hydride was used. After work-up, flash chromatography of the crude product on silica gel (eluting with 0.6% methanol in CH2Cl2) provided a 76% yield of the title compound as a clear oil, homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 437 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH:33]=O)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH2:33][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=CCc1ccc2c(c1)CCC[C@H]2NC(=O)C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C(C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)N[C@@H]1CCCc2cc(CCN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step E (63 mg, 0.116 mmol) and piperidine (20 mg, 0.23 mmol) in 1 mL of dichloroethane was added sodium triacetoxyborohydride (49 mg, 0.23 mmol). After stirring overnight at room temperature, the reaction solution was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vaco. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:10 to 100:12) afforded the title compound as a white solid. MS: 573.2 (M+1).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7](=O)[CH2:8][N+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.[NH2:24]O>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:7]2[N:24]=[C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]3[CH:8]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(C(=O)C[n+]2cccc3ccccc32)c1
Reactant: NO
Agent: Cl
Agent: [Br-]
Solvent: O
Product: COc1cccc(-c2cn3c(ccc4ccccc43)n2)c1

Procedure:
In a steel bomb having an internal glass coating, 9.34 g. of 1-(3-methoxyphenacyl)quinolinium bromide is heated at 130° C. for 24 hours together with 2.17 g. of hydroxylamine hydrochloride dissolved in 39 ml. of water. After cooling, the resulting solid precipitate is boiled with 60 ml. of water and recovered by filtration. The solid product is suspended in 50 ml. of water and concentrated ammonium hydroxide is added to the suspension. The mixture is extracted with dichloromethane and the organic extract is evaporated to dryness. By crystallization from methanol, 4.5 g. of the title product is obtained which melts at 129°-31° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23](=[O:24])[N:9]([CH:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chlorophenyl)amino]-1-piperidinecarboxylate (D28) (5.8 g) was dissolved in 100 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 10 ml) and triethylamine (5.6 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, dried over MgSO4, filtered and evaporated The product was crystallised from diethyl ether to yield the title compound, 5.7 g.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[Br:19])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:6]([O:5][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:20])=[CH:14][C:13]=1[Br:19])([F:11])[F:10])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CBr)cc1Br

Procedure:
A solution of [(2-bromo-4-methyl-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester (10.93 g, 30.6 mmol), N-bromosuccinimide (5.45 g, 30.6 mmol) and AIBN (100 mg) in benzene (300 mL) was refluxed for 18 h. The reaction mixture was concentrated in vacuo and redissolved in Ethyl acetate (200 mL). The solution was washed with H2O (50 mL), HCl (1 N, 50 mL), NaHCO3 (5%, 50 mL) and H2O (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (4:1) to provide a colorless oil (9.6 g, 80% purity with starting material as byproduct), which was taken on to the next step without further purification.
Reaction SMILES: Cl.[CH:2]([O:5][N:6]=[C:7]([C:28]1[N:29]=[C:30]([NH:33]C=O)[S:31][CH:32]=1)[C:8]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]>O1CCCC1.CO>[CH:2]([O:5][N:6]=[C:7]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:8]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 20.3 %

Procedure:
Conc. hydrochloric acid (1 ml) was added to a solution of 7-[2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(1.3 g) in a mixture of tetrahydrofuran (10 ml) and methanol (10 ml). The mixture was stirred for 3.5 hours at ambient temperature and then concentrated to dryness. Water was added to the residue and to the mixture was added sodium bicarbonate to give a solution. The solution was adjusted to pH 3.0 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)(0.25 g).
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH2:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)(C)CN
Solvent: C1CCOC1
Product: CC(C)(C)CNCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of neopentylamine (8.5 g, 98 mmol) in tetrahydrofuran (75 mL) was slowly added a solution of 1,3-propane sultone (11.5 g, 93 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×50 mL). The solid was suspended in EtOH (150 mL). The suspension was stirred at reflux for 15 minutes. The solid product was collected by filtration, washed with acetone (2×50 mL), and dried in vacuo, to afford compound DL (13.3 g, 69%). 1H NMR (D2O, 500 MHz) δ ppm 3.09 (t, 2H, J=7.3 Hz), 2.89 (t, 2H, J=7.3 Hz), 2.78 (s, 2H), 2.04 (m, 2H), 0.901 (s, 9H). 13C NMR (D2O, 125 MHz) δ ppm 59.44, 48.31, 47.83, 29.91, 26.42, 21.06. ES-MS 208 (M−1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C1COCC1.C(O)C>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:12][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:5]=1
Reactant: BrCc1ccncc1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)NCc1ccncc1
Reaction time: 24 h

Procedure:
4-Bromomethylpyridine (1 g) was suspended in THF:ethanol (5:1) and cooled to 0–5° C. Isopropylamine (1.01 ml) was added and the resultant mixture allowed to reach room temperature. After 24 h, the mixture was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with DCM:methanol 1:1, 3:7, 1:4 and methanol) to give an impure sample of the title compound. Further purification using SPE (silica, eluting with DCM, ethyl acetate, acetonitrile, methanol) gave the title compound (0.25 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH:23](C(OC(C)(C)C)=O)[CH2:24][CH3:25])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(F)cc2Cl)cc1

Procedure:
Using procedure 4, 2-chloro-4-fluorobenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 165-167° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:7][N:6]([CH3:20])[CH2:5][C:4]=2[N:3]=1.N(CC)CC.[CH2:26]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:27][C:28]#[CH:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]2[CH2:7][N:6]([CH3:20])[CH2:5][C:4]3[N:3]=[C:2]([C:29]#[C:28][CH2:27][CH2:26][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:11]=[CH:10][C:9]2=3)=[CH:13][CH:14]=1
Reactant: C#CCCN1CCCCC1
Reactant: COc1ccc(C2CN(C)Cc3nc(Cl)ccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C)Cc3nc(C#CCCN4CCCCC4)ccc32)cc1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A flask containing a mixture of 2-chloro-5-(4-methoxy-phenyl)-7-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine (0.080 g, 0.28 mmol), Et2NH (1.0 mL), 1-but-3-ynyl-piperidine (0.077 g, 0.56 mmol), CuI (5.3 mg, 27.8 umol), PPh3 (36 mg, 0.14 mmol), and Pd(PPh3)2Cl2 (0.020 g, 0.028 mmol) in DMF (0.5 mL) was evacuated and back-filled with N2 (3×). The mixture was heated at 105 C for 18 h, then was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with DCM. The combined organic layers were washed with H2O, dried, and concentrated. The residue was purified (SiO2; 0-6% 2 M NH3 in MeOH/DCM) to give the title compound (35 mg, 33%). MS (ESI): mass calcd. for C25H31N3O, 389.25; m/z found, 390.6 [M+H]+. 1H NMR (CDCl3): 7.15-7.08 (m, 2H), 7.06 (d, J=8.7, 2H), 6.83 (d, J=8.7, 2H), 4.23-4.17 (m, 1H), 3.91-3.85 (m, 1H), 3.79 (s, 3H), 3.66-3.59 (m, 1H), 3.05-2.99 (m, 1H), 2.76-2.62 (m, 4H), 2.56-2.46 (m, 5H), 2.45 (s, 3H), 1.68-1.58 (m, 4H), 1.49-1.40 (m, 2H).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[N:6]([CH2:24][C:25]2[N:34]=[C:33]([CH3:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[C:7](=[O:23])[C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:10]=[N:11][C:12]=2[N:13]=1.CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:9]2[C:8]3[C:7](=[O:23])[N:6]([CH2:24][C:25]4[N:34]=[C:33]([CH3:35])[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:5]4=[N:4][CH2:3][CH2:2][N:13]4[C:12]=3[N:11]=[CH:10]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cnc3nc(NCCO)n(Cc4nc(C)c5ccccc5n4)c(=O)c32)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cnc3c2C(=O)N(Cc2nc(C)c4ccccc4n2)C2=NCCN23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-(2-hydroxyethylamino)-7-(4-methoxybenzyl)-1-((4-methylquinazolin-2-yl)methyl)-1H-purin-6(7H)-one 12 (1.68 g, 3.56 mmol) in DCM (66 ml) was added Et3N (1.50 ml, 10.7 mmol) and MsCl (0.55 ml, 7.1 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with DCM, washed with water, NaHCO3 and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (MeOH/DCM) to afford 3-(4-methoxybenzyl)-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 13. 1H NMR S 8.03 (d, J=7.81, 1H), 7.87 (d, J=7.81, 1H), 7.78 (t, J=7.03, 1H), 7.55 (t, J=7.03, 1H), 7.46 (s, 1H), 7.28 (d, J=8.59, 2H), 6.85 (d, J=8.59, 2H), 5.60 (s, 2H), 5.38 (s, 2H), 4.20 (d, J=9.37, 2H), 3.78 (d, J=9.37, 2H), 3.78 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[O:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=O)COCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2coc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 42.9 %

Procedure:
To a solution of 2-Benzyloxy-acetamide (1.40 g, 8.56 mmol) in 4 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (2.0 g, 8.56 mmol) and the reaction mixture was heated at 130° C. for 6 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (1.1 g, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]=[C:9]([C:13]#[N:14])[C:8]2=O.O(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]#[N:14]
Reactant: ClOCl
Reactant: COc1cccc2c(=O)c(C#N)c[nH]c12
Solvent: CN(C)C=O
Product: COc1cccc2c(Cl)c(C#N)cnc12
Yield: 91 %

Procedure:
A mixture of 3.8 g (19 mmol) of 1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarbonitrile and 40 mL of phosphorous oxochloride and 5 drops of DMF was refluxed for 0.5 hours. The mixture was evaporated to dryness and diluted with hexanes. The solid was collected and mixed with cold dilute sodium carbonate solution and extracted several times with ethyl acetate. The organic layer was dried over sodium sulfate and filtered through a pad of silica gel. Removal of the solvent gave 3.8 g of 4-chloro-8-methoxy-3-quinolinecarbonitrile as an off white solid in 91% yield, mass spectrum (electrospray, m/e): M+H 219.1.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C1N2CCN(CC2)C1>O1CCOCC1.O>[N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[C:16](=[CH2:17])[C:15]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)OC)C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2,4-Dinitrobenzaldehyde was dissolved in dioxane and water, methyl acrylate and triethylenediamine were added thereto at room temperature, and the whole was stirred to obtain methyl 2-[(2,4-dinitrophenyl) (hydroxy)methyl]acrylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(F)cc2F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 60 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1.2 g) is alkylated using 1-bromomethyl-2,4-difluoro-benzene (0.6 ml; 4.6 mmol) and K2CO3 (1.8 g; 13 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated using hydrochloric acid (60 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(2,4-difluoro-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.95 g) is obtained and used without further purification.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=O>>[CH2:1]([NH:3][CH2:10][C:6]1[N:5]([CH3:4])[CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN
Reactant: Cn1cccc1C=O
Product: CCNCc1cccn1C

Procedure:
prepared by reaction of ethylamine with 1-methyl-1H-pyrrole-2-carbaldehyde