Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[I:24]N1C(=O)CCC1=O>O>[I:24][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:16])[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(=O)c2cc(I)ccc2-c2ccccc21
Temperature: 35 °C
Reaction time: 36 h
Yield: 75.4 %

Procedure:
Into a 200 mL volume eggplant-shaped flask, 10.0 g of 9,10-phenanthrenequinone, 54.8 g of trifluoroacetic acid, and 21.6 g of N-iodosuccinimide were added at room temperature, heated to 35° C., and then stirred for 36 hours in an argon atmosphere. The reaction mixture was poured into icy water. The solid precipitate was collected by filtration and recrystallized with tetrahydrofuran, thereby to give 12.1 g of 2-iodo-phenantrene-9,10-dione (yield 75%) as an orange-colored solid.
Reaction SMILES: [CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH2:45][OH:46])([CH3:44])[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:58]1[CH:63]=[CH:62][CH2:61][CH2:60][CH2:59]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(Cl)Cl>[CH2:1]([N:8]([C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:25]([N:27]([CH:41]([CH3:42])[CH3:43])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:29]3)=[O:26])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[O:14][C:13]([CH3:44])([CH2:45][O:46][CH:59]2[CH2:60][CH2:61][CH2:62][CH2:63][O:58]2)[C:12]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(CO)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(COC1CCCCO1)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-(2-{benzyl[(benzyloxy)carbonyl]amino}ethyl)-2-(hydroxymethyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate in methylene chloride (4.0 ml) were added 3,4-dihydro-2H-pyran (86 μl) and pyridinium p-toluenesulfonate (6.3 mg), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added water (3 ml), and the mixture was extracted with methylene chloride (5 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (440 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([C:15]([NH2:17])=[O:16])=[C:6]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](OC)=[O:26])=[CH:21][C:20]=1[CH3:29].[BH4-].[Li+].O.C(O)(=O)C>O1CCCC1>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][C:7]=2[C:15]([NH2:17])=[O:16])=[C:20]([CH3:29])[CH:21]=1
Reactant: COC(=O)c1ccc(Nc2c(C(N)=O)cnc3cc(OC)c(OC)cc23)c(C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccc(CO)cc3C)c2cc1OC
Reaction time: 24 h
Yield: 43.5 %

Procedure:
6,7-Dimethoxy-4-(4-methoxycarbonyl-2-methylanilino)-3-quinolinecarboxamide (0.080 g, 0.20 mmol) was dissolved in tetrahydrofuran (25 ml, dried over 4 A molecular sieves). Lithium borohydride (0.15 mg, 6.8 mmol) was added. The mixture was stirred for 24 h and additional lithium borohydride (0.050 g, 2.2 mmol) was added. The reaction mixture was stirred for additional 25 h and then poured into a cooled mixture of water (20 ml) and acetic acid (0.5 ml). Acetic acid (2 ml) was added and the mixture was evaporated under reduced pressure. The residue was suspended in water, filtered and the precipitate was washed with water and re-crystallized from aqueous methanol to give the title compound (32 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11]
Reactant: C1=COCCC1
Reactant: Cc1c(Br)ccc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)ccc2c1ncn2C1CCCCO1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-4-methyl-1H-benzo[d]imidazole (1.0 g, 4.74 mmol, CASRN 952511-48-7) and 3,4-dihydro-2H-pyran (2.0 g, 23.70 mmol) in THF (10 mL) was added p-TsOH.H2O (90 mg, 0.47 mmol). The mixture was heated at 80° C. overnight, cooled and the solvent was removed in vacuo. The residue was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to dryness in vacuo. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (10 to 50% EtOAc) to afford 800 mg (57%) of 5-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (254) as light yellow solid: MS (ESI) m/z=295.1 [M+1]+.
Reaction SMILES: C(OC1C=CC=CC=1C[N:12]([C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH:18]=[CH2:19])[C:13](=[O:15])[CH3:14])(=O)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:26][C:22]1[CH:21]=[C:20]([C@@H:17]([CH:18]=[CH2:19])[C@H:16]([NH:12][C:13](=[O:15])[CH3:14])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@@H](c1ccc(Cl)cc1)N(Cc1ccccc1OC(C)=O)C(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C)=O)c1ccc(Cl)cc1

Procedure:
A solution of 1.05 g (2.18 mmol) of 2-((N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamido)methyl)phenyl acetate (Example 115, Step C) and toluenesulfonic acid monohydrate (1.66 g, 8.71 mmol) in toluene (15.0 mL) was heated to reflux for about 2 h. 120 ml of ethyl acetate was added, and the combined organics were washed consecutively with NaHCO3 solution and sat. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The crude mixture was purified by preparative HPLC to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([CH3:29])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:14][OH:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 0.94 g (2.244 mmol) [2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 15 ml dry tetrahydrofuran was added 98 mg (2.356 mmol) lithium aluminum hydride at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was poured on 50 ml 10% aqueous sodium potassium tartrate solution and 50 ml ethyl acetate. The layers were separated and the aqueous layers were extracted again with 50 ml ethyl acetate. The combined organic layers were washed with 50 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) to give the title compound as a light yellow solid (57%). MS (Turbo Spray): m/z=405.4 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)=[CH:5][N:4]=1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1.C(NC(C)C)(C)C>C(Cl)Cl.CC(=O)OCC>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][S:16][C:13]3[NH:14][CH:15]=[C:10]([CH2:9][C:6]4[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=4)[C:11](=[O:17])[N:12]=3)=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(Oc2ccc(CCl)cc2)cc1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 60 °C
Yield: 55.5 %

Procedure:
A mixture of 5-((2-methoxypyrimidin-5-yl)methyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2.75 g, 10.99 mmol), 1-(chloromethyl)-4-(4-fluorophenoxy)benzene (2.6 g, 10.99 mmol) and diisopropylamine (3.34 g, 33.0 mmol) in DCM (50 mL) was heated at 60° C. overnight. After cooling to room temperature, the mixture was washed with brine, the organic phase was dried over Na2SO4, filtered and concentrated to leave the crude product, which was slurred in EA (20 mL) for 10 min, filtered, washed with EA and concentrated in vacuo to afford the title compound (2.75 g, 51.4% yield) as white solid. LCMS: rt=1.47 min, [M+H+]=451.0
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:21])[N:10]3[CH2:20][CH2:19][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:21])[N:10]3[CH2:20][CH2:19][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: S
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 48 h
Yield: 35 %

Procedure:
A stream of hydrogen sulphide was conducted for 1 hr. through a solution of 11.3 g (0.0396 mol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile in 230 ml of pyridine and 2.3 ml of triethylamine. The green solution was left to stand for 48 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and extracted. The pale yellow product was recrystallized in tetrahydrofuran and subsequently in methanol. There were obtained 4.44 g (35%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide as pale yellow crystals; m.p. 250-253° and [α]D20 =-330.6° (DMF, c=1%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:18])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>CN(C=O)C.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>[Br:18][C:8]1[C:7]([CH:21]=[CH2:22])=[C:16]([CH3:17])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ncccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2ncccc2c1Br
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate (230 mg, 0.62 mmol), tributyl(vinyl)stannane (200 μL, 0.68 mmol), lithium chloride (78 mg, 1.86 mmol) and PdCl2(PPh3)2 (43 mg) in DMF (10 mL) was heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to provide 5-bromo-7-methyl-6-vinylquinoline. LCMS-ESI+ (m/z): 248.2, 250.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.CC([O-])(C)C.[K+].[OH-].[Na+]>CN(C=O)C>[N:18]1([C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c2ccccc2c(-n2ccnc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 10-chloro-9-anthraldehyde (Aldrich, 15 g, 0.062 mol), imidazole (Aldrich, 10.2 g, 0.15 mol) and DMF (300 mL) was warmed to 55° and treated with KOtBu (MCB, 7.9 g, 0.07 mol) and stirred for 30 min. The reaction mixture was poured into 0.1N NaOH (1.5 L). The precipitate was filtered and then chromatographed on a plug of SiO2 (500 g) using CH2Cl2 (3 L) as the initial eluting solvent to remove starting material and byproducts. The yellow product band was then eluted with EtOAc (2 L) to yield, after removal of solvent and drying, 12.29 g (73%) of 10-(1H-imidazol-1-yl)-9-anthracenecarbaldehyde mp 194°-196°, (C, H, N), (EtOAc).
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13]N1C(=O)C2=CC=CC=C2C1=O.N(OCCCC)=O.S(=O)(=O)(O)O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCCCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCCCON=O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Cyclododecane (3.32 g; 19.8 mmol), N-hydroxyphthalimide (0.8 mmol), and acetic acid (4 ml) were placed in a flask, n-butyl nitrite (4 mmol) was added to the mixture in four installments of 1 mmol each once every 30 minutes with stirring at 70° C. in an atmosphere of argon gas for a total of 2.5 hours. The resulting mixture was further treated with sulfuric acid having a concentration of 98% by weight (200 mg) with stirring at 70° C. for 15 minutes. The reaction mixture was then neutralized with sodium hydroxide and was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 41%, 6%, and 6%, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>N1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3F)cn2)CC1
Temperature: 0 °C
Yield: 6.7 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol), 2-fluorophenol (1.1 g, 10.0 mmol), copper (650 mg, 10.0 mmol) and cesium carbonate (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120 0° C. in a sealed tube overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 20:1) to give tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 6%) as a yellow solid. MS (ES+) C19H23FN4O3 requires: 374, found: 397 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].P(Cl)(Cl)(Cl)=O>CN(C)C=O.O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 2.1 g.) was dissolved in a solution of N,N-dimethylformamide (0.8 ml.) and tetrahydrofuran (7.6 ml). To the solution was added a solution of N,N-dimethylformamide (0.78 ml) and phosphorus oxychloride (0.9 ml) in tetrahydrofuran (0.7 ml) all at once at -5+ C., and stirred at the same temperature for 30 minutes and at 22° C. for 30 minutes. The resultant solution was poured into ice water. The precipitates were washed with water (50 ml) and diisopropyl ether (25 ml) and dried over phosphorus pentoxide to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 1.37 g.). The mother liquid was extracted with ethyl acetate (100 ml.). The extract was washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo and the precipitates were pulverized with diisopropyl ether to give the same objective compound (syn isomer, 0.2 g.). Similar result was obtained by using SOCl2 in stead of POCl3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([O:20][CH:21](OCC)[CH3:22])[CH3:19])=[CH:12][CH:11]=2)[CH:3]=1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[OH-].[Na+]>ClCCl.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([O:20][CH:21]=[CH2:22])[CH3:19])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CCOC(C)OC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: C=COC(C)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(1-ethoxyethoxy)propoxy)benzyl)-benzene (550 mg, 1.3 mmol) in dichloromethane (10 mL) at 0° C. under argon was added triethylamine (0.2 mL, 2.2 mmol), followed by trimethylsilyltrifluoromethane sulfonate (240 mg, 2.2 mmol). After 1 h, 1.0 M sodium hydroxide (4 mL) was added, followed by diethyl ether (20 mL). The organic phase was separated, dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography (PE/EA=10:1) to obtain intermediate DA (290 mg, yield 59%).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52].Cl>CN(C=O)C.C(Cl)CCl>[C:56]([O:55][C:53](=[O:54])[C@@H:51]([NH:50][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH3:52])([CH3:59])([CH3:58])[CH3:57]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
To a solution of 500 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 186 mg HOBt, 232 mg EDC, 0.50 ml DIPEA and 220 mg L-Ala-OtBu×HCl. After stirring for 12 h it was concentrated and the residue dissolved in ethyl acetate. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.
Reaction SMILES: [ClH:1].Cl.NC[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)=[CH:7][CH:6]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C(OCC)(=O)C.[CH3:52][N:53]([CH:55]=O)[CH3:54]>CO.C(OCC)(=O)C.O.C(N(CC)CC)C>[ClH:1].[ClH:1].[CH3:54][N:53]([CH2:55][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)[CH3:52]
Reactant: CN(C)C=O
Reactant: Cc1cccc(Nc2nc(Nc3ccc(CN)cc3)ncc2C(N)=O)c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(Nc3ccc(CN(C)C)cc3)ncc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 7 ml portion of DMF solution containing 685 mg of 2-{[4-(aminomethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide dihydrochloride was mixed with 0.45 ml of triethylamine, 420 mg of 35% aqueous formalin and 1.09 g of sodium triacetoxy borohydride, followed by stirring overnight at room temperature. The reaction mixture was mixed with water, concentrated and then purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain crude crystals. This was dissolved in a methanol-ethyl acetate mixed solution and mixed with 1 ml of 4 M hydrogen chloride/ethyl acetate solution, and the thus precipitated crystals were collected by filtration and further recrystallized (methanol-water) to obtain 164 mg of 2-({4-[(dimethylamino)methyl]phenyl}amino)-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide dihydrochloride as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)=[CH:2]1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[N:13]=2)=[CH:2]1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1NCc1csc2ccccc12
Product: Oc1cccc(Nc2ncc(F)c(NCc3csc4ccccc34)n2)c1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDCl3): δ 4.45 (br, 1H), 4.95 (dd, J=1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J=1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J=8.1 Hz, 1H), 7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J=1.2 and 5.1 Hz, 1H), 7.84 (d, J=3.3 Hz, 1H), 7.92 (m, 1H); 19F NMR (282 MHz, CDCl3): 6-168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%; MS (m/e): 366.96 (MH+).