Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[C:9]([C:12](=[O:15])[CH2:13]Br)[CH:10]=2)[C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3]1.[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[C:21]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:18])([CH3:17])[CH:4]([CH3:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:7][C:8]=2[CH3:16])=[O:15])[CH2:32][CH2:31]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(=O)CN1CCC(NC(=O)c3ccccc3)CC1)C(C)(C)CC(C)C2(C)C
Yield: 24.1 %

Procedure:
A mixture of 1,1,3,4,4,6-hexamethyl-7-bromacetyl-1,2,3,4-tetrahydronaphthalene (7 g.), 4-benzamidopiperidine (4.27 g.) and triethylamine (3.5 g.) was refluxed in100 ml. EtOH for 2 hours. The resulting yellow solution was cooled, whereupon the product crystallised. This was recrystallised twice from EtOH/water to give the title compound (2.3 g.) as a pale yellow solid, m.p. 153°(dec.). Analysis Calculated for C30H40N2O2 ; C, 78.22%; H, 8.75%; N, 6.08%. Found: C, 78.29%; H, 8.92%; N, 6.14%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1.Cl>CCOCC.[Cl-].[Cl-].[Zn+2]>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[O:18])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: O=C(O)C=CC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
Freshly fused ZnCl2 (82 g, 0.6 mole) was dissolved in dry Et2O (400 ml) and added dropwise to the Grignard reagent prepared from 4-bromobenzotrifluoride (112.5g, 0.5 mole) and Mg (12.2 g, 0.5 g-atom) in Et2O (600 ml). Maleic anhydride (44 g, 0.45 mole) in Et2O (400 ml) was added over 30 minutes with stirring at reflux. After 2 hours, the mixture was cooled and acidified to pH 2 with 10% HCl. The Et2O layer was separated and dried (MgSO4), and the Et2O evaporated. The residue was recrystallized from C6H6 (x3) to yield the title compound, 24.5 g (21%), mp 149°-151°. Anal. (C11H7F3O3) C, H, F. An alternative procedure is as follows. A mixture of 4-trifluoromethylacetophenone (18.8 g) glyoxylic acid monohydrate (18.8 g), Ac2O(20 ml) and a drop of Et3N was heated to 135°, internal temperature. More Et3N (2 ml) was added, and the mixture was held at 135° for 20 minutes. The mixture was cooled and evaporated to dryness in vacuo. The solid residue was digested with H2O, filtered, dried and recrystallized from C6H6 to give the title compound, 12.2 g (50%), mp 149°-151°.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24].Cl>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(C)cc2)cc1

Procedure:
A solution of 4-(4′-methylphenoxy)phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g, 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford 4-(4′-methylphenoxy)phenyl allyl ether.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C1SC=C(C(O)=O)N=1.[F:19][C:20]1[CH:21]=[C:22]([CH:36]([OH:38])[CH3:37])[CH:23]=[C:24]([F:35])[C:25]=1B1OC(C)(C)C(C)(C)O1.Br[C:40]1[N:45]=[C:44]([C:46]([O:48]C)=[O:47])[CH:43]=[CH:42][C:41]=1[F:50]>>[F:35][C:24]1[CH:23]=[C:22]([CH:36]([OH:38])[CH3:37])[CH:21]=[C:20]([F:19])[C:25]=1[C:40]1[N:45]=[C:44]([C:46]([OH:48])=[O:47])[CH:43]=[CH:42][C:41]=1[F:50]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: CC(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (Intermediate 106) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:13][Si:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[CH:20]1.C(OCC)(=O)C>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:24]([C:22]2[N:21]=[CH:20][N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:27])([CH3:26])[CH3:13])[CH:23]=2)[OH:25])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C[Si](C)(C)CCOCn1cnc(C=O)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cnc(C(O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-bromopyridine (1.0 g, 6.33×10−3 mol) was cooled to −78° in a dry ice/acetone bath. To this solution, BuLi (3.48 mL, 6.96×10−3 mol, 2M solution in cyclohexane) was added dropwise and the reaction was stirred for 15 minutes. A solution of 1-(2-trimethylsilanylethoxymethyl)-1H-imidazole-4-carbaldehyde (0.955 g, 4.22×10−3 mol) in ether (5 mL) was added dropwise to the reaction and the solution was stirred for 1 hour at −78 C. The reaction was quenched with sat. NaHCO3 (10 mL) and allowed to warm to room temperature. Ethyl acetate was added (100 mL) and the organic layer was washed with water (3×50 mL), dried over MgSO4, filtered and solvent was removed under reduced pressure. The crude product was purified by silcagel column chromatography eluting with a gradient of ethyl acetate:hexane (1:3) to ethyl acetate to ethyl acetate:methanol (9:1). The pure product was isolated as a mixture of isomers (yellow oil, yield 778 mg, 40%). Rf 0.5 (ethyl acetate); 1H-NMR (CDCl3) δ−0.09-0.11 (m, 9H), 0.86-0.99 (m, 2H), 3.41-3.57 (m, 2H), 5.22 & 5.26 (2×s, 2H), 5.89 & 6.05 (2×s, 1H), 6.63 & 6.80 (2×s, 1H), 7.25-7.39 (m, 1H), 7.53 & 7.58 (2×s, 1H), 7.79-7.90 (m, 1H), 8.53 & 8.57 (d, 1H), 8.64 & 8.69 (2×s, 1H); ESMS Calcd (C10H18N2O2Si): 226.11, found 227.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[N:24][C:23]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]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>ClCCl>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[N:24][C:23]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]4[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=3)=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([O:12][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cnc(NCc3ccc4ccccc4c3)cn2)cc1)C(=O)O
Reactant: OCCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(-c2cnc(NCc3ccc4ccccc4c3)cn2)cc1)C(=O)OCCN1CCOCC1
Reaction time: 8 h
Yield: 4.3 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid (48 mg, 0.090 mmol), 4-(2-hydroxyethyl)morpholine (12 mg, 0.090 mmol), triethylamine (18 mg, 0.180 mmol), and benzotriazole-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 18 mg, 0.090 mmol), in dichloromethane (3.0 ml) were stirred at room temperature for 5 hours. Additional triethylamine (18 mg, 0.180 mmol) and BOP (18 mg, 0.090 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated and purified via prep HPLC to give 2 mg of the captioned compound.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[CH2:20]([O:19][C:18]([NH:17][CH:13]1[CH:2]2[CH:3]([C:4](=[O:11])[C:5]3[C:10]([C:1]2=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH:15]=[CH:14]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=CC=CNC(=O)OCc1ccccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1C=CCC2C(=O)c3ccccc3C(=O)C12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
3.16 g of 1,4-naphthoquinone, 4.48 g of benzyl N-butadienylcarbamate and 50 mg of hydroquinone were dissolved in 100 ml of toluene and stirred at 25° C. for 8 hours and the solution was then concentrated in vacuo. The residue was taken up in chloroform, the solution was filtered through silica gel and the filtrate was concentrated in vacuo. 7.12 g of 1-benzyloxycarbonylamino-1,4,4a,9a-tetrahydroanthraquinone (93% pure; 92% of theory) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:61]1[C:66](=[O:67])[CH2:65][CH2:64][C:62]1=[O:63])=[N+](C)C)C>C1COCC1>[O:63]=[C:62]1[CH2:64][CH2:65][C:66](=[O:67])[N:61]1[O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)ON2C(=O)CCC2=O)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
4-(14-tert-Butoxycarbonyl tetradecyloxy) isophthalic acid 3-tert-butyl ester (0.15 g, 0.28 mmol) was dissolved in THF (2 ml). DIEA (58 μl, 0.34 mmol) was added, and the solution was cooled to 0° C. TSTU (0.10 g, 0.28 mmol) was added. The reaction was stirred at 0° C. for 30 min and then at rt for 16 h. The sample was concentrated under vacuum to near dryness. AcOEt (20 ml) was added and the solution was washed with 0.2 N HCl and sat. NaHCO3 (3×5 ml each), dried over MgSO4 and concentrated to yield a residue (0.18 g). The residue was purified by flash chromatography (silica: AcOEt/heptane 3:7 (0.5 l), 1:1 (0.2 l)) yielding an oil with white solids (55 mg, 31%).
Reaction SMILES: [CH3:1][C:2](=[CH:7]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]([O:5][CH3:6])=[O:4].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:7]/[C:2](=[CH:1]\[O:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)=COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C(C)=C/Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.2 %

Procedure:
To a solution of 6.98 g (25.8 mmol) of methyl 2-methyl-3-(p-toluenesulfonyloxy)-2-propenoate in 30 ml of DMF was added 2.67 g (28.3 mmol) of phenol and 10 g (30.6 mmol) of cesium carbonate and stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with tert-butyl methyl ether (twice). The combined organic layer was washed sequentially with a 1N aqueous NaOH solution, water, and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 657 mg of (E)-methyl 2-methyl-3-phenoxy-2-propenoate.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 868 mg (4.59 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 1.64 g (8.58 mmol) of EDC and 773 mg (5.72 mmol) of HOBT are dissolved in 24.5 ml of DMF. After 15 min, 2.39 ml (17.2 mmol) of TEA and 1.64 g (2.86 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 12 ml of DMF are added. After 20 hours, the mixture is concentrated by evaporation, and water and methylene chloride are added to the residue; the aqueous phase is separated off and extracted 2× more with methylene chloride. The organic phases are washed with 10% citric acid solution, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Digestion from DIPE yields the title compound: HPLC20-100: tRet=18.6; FAB MS (M+H)+=743.
Reaction SMILES: O1CCCC1.[CH:6]1([OH:10])[CH2:9][CH2:8][CH2:7]1.[H-].[Na+].[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40]Br>O>[Br:13][C:14]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:17]2[CH:18]=[N:19][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21](=[O:22])[C:16]=2[C:15]=1[CH2:40][O:10][CH:6]1[CH2:9][CH2:8][CH2:7]1
Reactant: OC1CCC1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc2c(c(COC3CCC3)c(Br)n2COCC[Si](C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To 10 ml of dehydrated tetrahydrofuran solution containing 0.89 g (12 mmol) of cyclobutanol was added 0.25 g (6.2 mmol) of sodium hydride (60% dispersed material in mineral oil) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. To the mixture was further added 0.70 g (1.2 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Reference example 25-(a), and the mixture was stirred at 45° C. for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 561 mg of the title compound as a pale yellowish oil. (Yield: 82%)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][S:6]([C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[Cl:26])=[C:11]([Cl:27])[CH:10]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.[Br:28][C:29]1C=CC(CN)=[CH:31][CH:30]=1>>[Br:28][C:29]1[CH:3]=[CH:2][C:1]([CH2:4][NH:5][S:6]([C:9]2[CH:10]=[C:11]([Cl:27])[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[Cl:26])=[C:13]([Cl:15])[CH:14]=2)(=[O:8])=[O:7])=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)NCC3CC3)cc2Cl)c(Cl)c1
Reactant: NCc1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)NCc3ccc(Br)cc3)cc2Cl)c(Cl)c1

Procedure:
This compound was prepared according to the procedure for the preparation of 120 using 4-bromobenzylamine resin in place of the cyclopropylamino methyl resin.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:22]([OH:25])[C:23]#[CH:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:24]#[C:23][CH:22]([C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[OH:25])=[CH:4][N:3]=1
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reactant: Nc1ncc(I)c(N)n1
Product: COc1cc(C(O)C#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 77.8 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-ol (444 mg) as per the general procedure to afford 3-(2,4-Diaminopyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)-prop-2-yn-1-ol as a yellow powder (257 mg, 78%): Rf=0.12 (9:1, CHCl3:MeOH); mp=203-205° C.; 1H NMR (DMSO-d6) δ 7.84 (s, 1H), 6.83 (s, 2H), 6.34 (s, 2H), 6.01 (d, J) 5.6 Hz, 1H), 5.50 (d, J) 5.4 Hz, 1H), 3.78 (s, 6H), 3.65 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.3, 158.2, 152.7, 138.3, 136.7, 109.3, 103.6, 96.3, 79.3, 63.4, 60.0, 55.8; Anal. (C16H18N4O4) C, H, N.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[N:28]1([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:38][CH:39]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Nc1ccc(Cn2ccnc2)cn1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(Cn4ccnc4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-imidazol-1-ylmethyl-pyridin-2-ylamine (Step 120.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 3 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 503.1 [M+H]+; tR=3.76 min (System 1); TLC: Rf=0.47 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][CH:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:29](=O)[CH3:30])[C:25]([O:27][CH3:28])=[O:26].CC(O)=O>CCO>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([NH:1][CH:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8][CH2:9]1)[CH3:3])[CH3:30]
Reactant: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)C(C(C)=O)c1ccccc1Br
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C(=C(C)NC(C)C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1Br
Temperature: 85 °C
Yield: 49.1 %

Procedure:
To a round bottomed flask was added (R or S)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (9.35 g, 40.9 mmol), EtOH (75 mL), and methyl 2-(2-bromophenyl)-3-oxobutanoate (7.40 g, 27.3 mmol) (from Step 4). To this solution was added AcOH (1.563 ml, 27.3 mmol) and the reaction was heated overnight at 85° C. before cooling to room temperature and concentrating. The crude residue was purified via silica gel chromatography (330 g, 100% hexanes to 25% EA in hexanes) to afford the title compound (6.45 g, 13.40 mmol, 49.1% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[C:25]([CH:34]=O)[CH:24]=1)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([C:23]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:26]=[C:25]([CH2:34][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1-c1ccccc1
Yield: 79.3 %

Procedure:
Compound 53 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C(CN1CCC[C@H]1C(N(CC1C=CC=CC=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=O)(O)=O.C(N1CC[O:33]CC1)C.ClC(OCC(C)C)=O.CC1CCCCN1>C(#N)C>[NH2:12][C@H:11]([C:10]([OH:17])=[O:33])[C@H:13]([CH2:15][CH3:16])[CH3:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CC1CCCCN1
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)O
Temperature: 22 °C
Yield: 115.1 %

Procedure:
A -5° C. solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (202 mg, 0.53 mmol, 1.0 eq), N-ethylmorpholine (82 uL, 0.64 mmol, 1.20 eq) in acetonitrile (8 mL) was treated with isobutyl chloroformate (80 uL, 0.62 mmol, 1.15 eq) followed by 2-methylpiperidine (0.106 g, 1.07 mmol, 2.0 eq). The solution was warmed to 22° C., concentrated to a residue, and purified by flash chromatography to provide 80 mg (32%) of L-isoleucine, N-[1-[2-(N-(2-methylpiperidine))-2-oxoethyl]-L-prolyl] benzylamide as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[H-].[Na+].[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([NH:15][C:13]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=[C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:19])[N:3]=[C:2]([CH3:1])[N:7]=2)[CH:14]=1)=[O:26]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1cc(Nc2cc(N)c([N+](=O)[O-])cn2)nc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)c([N+](=O)[O-])cn2)nc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a cooled (0° C.) solution of N-(2,6-dimethylpyrimidin-4-yl)-5-nitropyridine-2,4-diamine (0.348 g, 1.337 mmol) in anhydrous N,N-dimethylformamide (10 mL) under nitrogen was added sodium hydride (0.064 g, 2.67 mmol, 60% dispersion in mineral oil) in one portion. The reaction mixture was stirred at 0° C. for 15 mins and then a solution of 2,6-dichlorobenzoyl chloride (220 uL, 1.5 mmol) in DMF (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3.5 hours and then quenched with water (60 mL). The mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20-80% ethyl acetate/heptane) to give 2,6-dichloro-N-(2-(2,6-dimethylpyrimidin-4-ylamino)-5-nitropyridine-4-yl)benzoamide (0.57 g, yield: 100%). LCMS (ESI) m/z: 433.1 [M+H+].