Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[Cl:28][CH2:29][CH2:30][CH2:31]I>C1COCC1.CCCCCCC.CCOC(C)=O>[Cl:28][CH2:29][CH2:30][CH2:31][C:12]1[O:11][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccco1
Reactant: ClCCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CCCCl)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 2-(t-butyldimethylsilyloxymethyl)furan (5 g, 0.023 mol) in THF (48 mL) was dried over 3 {acute over (Å)} molecular sieves. After the sieves were removed, an additional 10 mL THF was added along with TMEDA (3.47 mL, 0.023 mol), and the solution was cooled to 0° C. in an ice bath. A solution of BuLi (10.1 mL of 2.5M in hexane, 0.025 mol) was added dropwise over 25 minutes. The mixture was allowed to stir for 1 hour. 1-chloro-3-iodopropane (5.64 g, 0.028 mol) was injected rapidly. After 2 hours TLC indicated completion. The solvent was evaporated, and the material was partitioned between ether (100 mL) and 5% citric acid (100 mL). The ether layer was washed with water (50 mL) and then brine (50 mL). The ether solution was dried with sodium sulfate, filtered, and evaporated. The resulting material was flashed on silica using 20/1 heptane/EtOAc. Appropriate fraction were combined and evaporated to yield 4.9 g (75% yield). TLC: Rf 0.6 (Heptane/EtOAc 5/1) 1H NMR: (CDCl3) δ 0.00 (s, 6H), 0.83 (s, 9H), 2.01 (p, 2H), 2.71 (t, 2H), 3.48 (t, 2H), 4.51 (s, 2H), 5.88 (d, 1H), 6.04 (d, 1H)
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Ic1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a stirred solution of 1-(5-iodopyridin-2-yl)piperazine (CAS number 219635-89-9, 5.083 g, 17.6 mmol), and triethylamine (4.91 mL, 35.2 mmol) in CH2Cl2 (75 mL) at 0° C. was added methane sulfonyl chloride (2.04 mL, 26.4 mmol) dropwise and the resulting suspension stirred for 30 mins at room temperature. The reaction mixture was diluted with CH2Cl2 (200 mL) and washed twice with water (2×200 mL). The organic phase was washed with saturated brine solution (1×200 mL), dried (MgSO4), filtered and concentrated in vacuo to give a dark yellow solid. This was triturated with ether, filtered and dried to give 1-(5-iodopyridin-2-yl)-4-(methylsulfonyl)piperazine as a yellow solid (5.378 g, 83%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl[C:21]([O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][CH2:24][CH:25]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.02 h

Procedure:
To a solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3 mg, 36 μmol) in 10 mL of dichloromethane at ambient temperature was added 9-fluorenylmethyl chloroformate (8 mg, 30 μmol) as a solid. The mixture was vortexed at room temperature for about 1 min., becoming slightly cloudy. Aminomethylpolystyrene (ca. 90 mg, 0.64 meq/g, 100-200 mesh, Bachem) was added to quench excess chloroformate, and after a few minutes the mixture was filtered through a short plug of silica gel, eluting with 10:1 dichloromethane-methanol to isolate the product as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.87 (d, J=7.6 Hz, 2H), 7.65 (m, 3H), 7.50 (t, J=7.6 Hz, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.3 (m, 4H), 7.15 (bs, 2H), 4.62 (t, J=7 Hz, 2H), 4.27 (d, J=7 Hz, 2H), 4.17 (t, J=7 Hz, 1H), 3.03 (q, J=7 Hz, 2H), 1.84 (quintet, J=7 Hz, 2H), 1.45 (quintet, J=7 Hz, 2H), MS (APCI) m/e 478.28 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:48]1N=N[C:50]2[CH:51]=CC=C[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:48][CH2:49][CH2:50][CH3:51])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCN
Product: CCCNC(=O)c1cc(F)c(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and propylamine (6.78 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.7 mg, 58%). LC-MS m/z 581 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[C:26](N)[CH:25]=[CH:24][C:23]=1[CH3:29])([CH3:19])[CH2:9][C:8]2=[O:30])(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:35].[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38]>CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH2:38][CH:37]([Cl:35])[C:36]([O:40][CH2:41][CH3:42])=[O:39])[CH:25]=[CH:24][C:23]=1[CH3:29])([CH3:19])[CH2:9][C:8]2=[O:30])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1cc(N)ccc1C)CC2=O
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(C)c(OCC2(C)CC(=O)c3cc(OC(C)=O)c(C(C)(C)C)cc3O2)c1

Procedure:
Following the same procedure as described in Preparation 25, 5.53 g of 6-acetoxy-2-(5-amino-2-methylphenoxymethyl)-7-t-butyl-2-methylchroman-4-one (prepared as described in Preparation 41), 1.2 g of sodium nitrite, 2.4 ml of concentrated hydrochloric acid, 14 ml of ethyl acrylate, 190 ml of cuprous oxide and 50 ml of acetone were reacted, to give the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].O>O1CCCC1.C(Cl)Cl>[CH2:1]([C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1c(C(=O)O)cccc1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCc1c(CO)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.4 %

Procedure:
To a stirred solution of 2-ethyl-[1,1'-biphenyl]-3-carboxylic acid (2.1 g, 0.0093 mole) in 50 ml of tetrahydrofuran was added dropwise borane-tetrahydrofuran complex (1.6 g, 0.0186 mole). The reaction mixture was stirred at room temperature for approximately 18 hours. Water (6 ml) was slowly added to the reaction mixture and the solvent removed under reduced pressure to give a residue. The residue was dissolved in methylene chloride; the solution was washed with 1 N aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 2-ethyl-[1,1'-biphenyl]-3-methanol (2.1 g) as an oil. The ir and nmr spectra were consistent with the named compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[CH:15][CH:16]=[N:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[N:17]1[C:18]2[C:13](=[C:12]3[C:21](=[CH:20][CH:19]=2)[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][CH:5]=2)[S:8](=[O:10])(=[O:9])[NH:11]3)[N:14]=[CH:15][CH:16]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2nccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3nccnc23)-c2ccccc21
Yield: 16.4 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-quinoxalin-5-yl-benzenesulfonamide (Intermediate 304) (440 mg, 1.4 mmol), t-butyl nitrite (0.27 ml, 2.19 mmol), AcOH (4.5 ml) and THF (4.5 ml) gave the title compound (65 mg, 16%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([CH2:10][C:11](O)=O)#[N:9].C=O.[C:16](=O)=O>O.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:16][C:10](=[CH2:11])[C:8]#[N:9])[CH2:4][CH2:3]1
Reactant: O=C=O
Reactant: CN1CCNCC1
Reactant: N#CCC(=O)O
Agent: C=O
Solvent: O
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCN(C)CC1

Procedure:
0.5 Mole of N-methylpiperazine are added to 0.5 mole of cyanoacetic acid in 150 cc. of dioxan at a temperature kept at around 0° C. This is followed by the addition of 1 mole of formaldehyde in the form of a 30% aqueous solution. After the heat effect has abated, the mixture is stirred until there is no further evolution of carbon dioxide gas (approximately 2 hours). 200 cc. of water are then added, the product extracted with ether, dried over sodium sulphate and the ether removed in vacuo, followed by distillation.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)O)=[CH:13][CH:12]=1.O>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1
Reactant: OCCCl
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1

Procedure:
A mixture of 20 parts of 2-chloroethanol, 3 parts of sulfuric acid and 16 parts of benzene was heated on a water-bath. Then there were added dropwise 35 parts of 4-fluoro-α-(4-fluorophenyl)benzenemethanol dissolved in 32 parts of benzene. After the addition was complete, the whole was stirred and refluxed for 4 hours. After cooling the reaction mixture was poured into water. The benzene layer was separated, dried over calcium chloride and evaporated. The residue was distilled in vacuo, yielding 35 parts of 1,1'-[(2-chloroethoxy)methylene]bis[4-fluorobenzene]; bp. 164°-166° C. at 1.5 mm. pressure; nD20 : 1.5462; d2020 : 1.2290 (intermediate 1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:15])=[O:14])=[C:9]([CH3:25])[CH:8]=2)[N:5]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([O:37][C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:34]=[CH:33][C:32]=1[NH2:45].C1C[O:49][CH2:48]C1>ClCCCl>[C:26]([C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH:45][C:32]2[CH:33]=[CH:34][C:35]([O:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=3)=[CH:36][C:31]=2[F:30])=[O:49])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)(=[O:15])=[O:14])=[C:9]([CH3:25])[CH:8]=2)[N:5]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(-n2nc(C(C)(C)C)cc2N)ccc1S(=O)(=O)NCCN1CCOCC1
Reactant: C1CCOC1
Reactant: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: ClCCCl
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(S(=O)(=O)NCCN4CCOCC4)c(C)c3)c(F)c2)ccn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzenesulfonamide (150 mg, 0.36 mmol) in anhydrous DCE (1 mL) was added CDT (64 mg, 0.39 mmol, 1.1 eq), and the reaction was stirred under nitrogen at 50° C. for 18 h. A solution of 2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenylamine (86 mg, 0.39 mmol, 1.1 eq) in anhydrous THF (1 mL) was added to the reaction, and the solution was stirred under at 50° C. for 3 days. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The crude product was purified by HPLC and recrystallized from DCM/hexane to give 55 mg (23%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 8.92 (d, J=14.4 Hz, 2H), 8.30 (d, J=5.7 Hz, 1H), 8.07 (t, J=9 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.68 (t, J=6 Hz, 1H), 7.58 to 7.51 (m, 2H), 7.25 (dd, J=11.4, 2.4 Hz, 1H), 6.97 to 6.92 (m, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.74 to 6.70 (m, 1H), 6.41 (s, 1H), 3.45 (t, J=4.5 Hz, 4H), 2.93 (q, J=6H, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.25 (t, J=6.9 Hz, 2H), 2.20 to 2.17 (m, 4H), 1.27 (s, 9H); MS LC-MS [M+H]+=666, RT=2.26 min.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O1CCCC1>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1
Reactant: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCOC1
Solvent: O=CO
Product: C=CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 82.9 %

Procedure:
A solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 8.7 g.), 50% formic acid (42.5 ml.) and tetrahydrofuran (42.5 ml.) was stirred at 60° C. for 40 minutes. After concentrating the resultant solution in vacuo, the residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the resultant solution in vacuo, the residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn, to give ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.7 g.), mp. 102° to 104° C.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, 88 mg of isoamyl nitrite was added dropwise to a mixture of 0.24 g of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate, 99 mg of copper(I) chloride, 0.20 g of copper(II) chloride, and 2.5 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]-acetate (compound a-6).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].FC(F)(F)S(O)(=O)=O>ClCCl>[I:34][C:9]1[C:5]2[NH:6][C:7](=[O:8])[C:2]([CH3:16])([CH3:1])[O:3][C:4]=2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(I)c2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a suspension of 2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(1), 1.00 g) in dichloromethane (50 mL) was added bis(pyridine)iodonium tetrafluoroborate (1.68 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were further added bis(pyridine)-iodonium tetrafluoroborate (0.84 g) and trifluoromethanesulfonic acid (1.2 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. The resultant residue was diluted with ethyl acetate, tetrahydrofuran and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution, an aqueous 15% sodium thiosulfate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was triturated in n-hexane/ethyl acetate to give 5-iodo-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (0.90 g) as a pale brown powder.
Reaction SMILES: C([NH:4][C@@H:5]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)(O)=O.CN(C)CCCN.C([NH:30][C@H:31]([C:47]([O:49]C(=O)[C@H](CCCCNC(OCC1C=CC=CC=1)=O)NC(O)=O)=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])(O)=[O:28]>ClCCCl>[CH2:13]([CH:7]([C:8]([OH:9])=[O:28])[CH2:6][C@@H:5]([C:11]([OH:10])=[O:12])[NH2:4])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH2:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]([C:47]([OH:49])=[O:48])[NH2:30])=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)N[C@H]1CC(Cc2ccccc2)C(=O)OC1=O
Reactant: O=C(O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)O
Agent: CN(C)CCCN
Solvent: ClCCCl
Product: N[C@@H](CC(Cc1ccccc1)C(=O)O)C(=O)O
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 1,2-dichloroethane (10 ml) was added N-carboxy-γ-benzyl-L-glutamic acid anhydride (1.00 g, 3.80 mmol), and the mixture was cooled to 0° C. N,N-Dimethyl-1,3-propanediamine (0.48 μl, 3.8 μmol) was added as an initiator, and the mixture was stirred at 25° C. for 1 day and cooled again to 0° C. Nα-Carboxy-Nε-benzyloxycarbonyl-L-lysine anhydride (1.16 g, 3.80 mmol) was added, and the mixture was stirred at 25° C. for 3 days to give a γ-benzyl-L-glutamic acid-Nε-benzyloxycarbonyl-L-lysine block copolymer (high molecular weight copolymer). The weight average molecular weight, Mw, of the copolymer was measured by Measurement Method 1 described below. In addition, the composition of the copolymer was measured by Measurement Method 2 described below.
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][NH:19][CH2:18][CH2:17][NH:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]1[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:30]=1>>[CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:16][CH2:17][CH2:18][N:19]([C:29]4[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]5[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=5)[N:30]=4)[CH2:20]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CN(c1ccc([C@H]2CNCCN2)cc1)C1CCCCC1
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCN2)cc1)C1CCCCC1
Reaction time: 4.5 h
Yield: 85.9 %

Procedure:
To a solution of (S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl) piperazine (50 mg, 0.183 mmol) and triethylamine (0.077 mL, 0.55 mmol) was added 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (37 mg, 0.17 mmol) at room temperature. After stirring for 4.5 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(3-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (67 mg, 88%) as a oil, which was dissolved in ethyl acetate and treated with 4 N hydrogen chloride in ethyl acetate to yield its trihydrochloride.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][NH:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C1COCC1.O>[Cl:9][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([N:13]([CH3:12])[CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[C:7]=1[F:8]
Reactant: CSc1nc(Cl)c(F)c(Cl)n1
Reactant: CNCc1nccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(Cl)c(F)c(N(C)Cc2nccs2)n1
Reaction time: 8 h
Yield: 103.5 %

Procedure:
4,6-Dichloro-5-fluoro-2-(methylthio)pyrimidine (see Intermediate E) (0.3313 g, 1.563 mmol), N-methyl-1-(1,3-thiazol-2-yl)methanamine (0.200 g, 1.5625 mmol), and triethylamine (0.26 mL, 1.8654 mmol) were dissolved in THF (5 mL) and left to stir overnight. Then the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce 6-chloro-5-fluoro-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a yellow oil (0.4928 g). LCMS: (M+H)+=305.0.
Reaction SMILES: [OH-].[Na+].COC([N:7]1[C:17]2[CH2:16][CH:15]3[N:18]([S:19]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:11]([CH2:12][N:13]([C:29]([O:31][CH3:32])=[O:30])[CH2:14]3)[C:10]=2[CH:9]=[N:8]1)=O>C1COCC1.C(Cl)Cl.O>[CH3:32][O:31][C:29]([N:13]1[CH2:12][CH:11]2[N:18]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]([CH2:16][C:17]3[NH:7][N:8]=[CH:9][C:10]=32)[CH2:14]1)=[O:30]
Reactant: COC(=O)N1CC2Cc3c(cnn3C(=O)OC)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Aqueous sodium hydroxide (3 N, 0.39 mL, 1.18 mmol) was added to a stirring solution of 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-5,10-dicarboxylic acid dimethyl ester (270 mg, 0.594 mmol) in THF (1 mL). The reaction mixture was stirred for 3 h at room temperature and subsequently diluted with methylene chloride (10 mL) and water (5 mL). The phases were separated and the aqueous layer was extracted with methylene chloride (2×5 mL). The organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid methyl ester as a white solid. Retention time (min)=1.435, method [1], MS(ESI) 397.13 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 5.21 (s, 1H), 4.41 (s, 1H), 4.19-4.01 (m, 1H), 3.90 (d, J=13.2 Hz, 1H), 3.60-3.40 (m, 3H), 3.35-3.14 (m, 2H), 2.85-2.80 (m, 1H), 2.71 (d, J=17.6 Hz, 1H).