Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:23][C:24](OC(C)=O)=[O:25]>C1COCC1.O.C1COCC1>[CH:1]1([C:4]2[N:8]([C:24](=[O:25])[CH3:23])[N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.4 %

Procedure:
To the solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (3 g, 7.44 mmol) in THF/H2O (50 mL/25 mL), a solution of Ac2O (1.5 g, 14.88 mmol, 2.0 equiv.) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered to afford compound 1-(5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (2.2 g, 66%). LC-MS (m/z): 446.0 [M+H]+.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH4+:8].[OH-:17].[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Product: [NH4+]
Temperature: 25 °C
Reaction time: 8 h
Yield: 1 %

Procedure:
tert-Butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.46 mmol, 203 mg) and Pearlman's catalyst were combined in methanol under a hydrogen atmosphere (1 atmosphere) stirred overnight at room temperature. Purged with nitrogen, filtered off the catalyst, and concentrated the filtrate to a yellow liquid. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (5% MeOH, 0.5% NH4OH in CH2Cl2, then 10% MeOH, 1% NH4OH in CH2Cl2) to provide the title compound. MS (DCI/NH3) m/z: 213 (M+H)+; 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.75 (br, 4H), 2.93 (d, 1H), 3.01 (d, 1H), 3.47 (d, 2H), 3.68 (d, 1H), 3.81 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[NH3:6].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(O)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: N
Product: O=C(c1ccc(O)cn1)N1CCCCC1
Yield: 5 %
Yield: 90 %

Procedure:
To a solution of 5-hydroxy-2-pyridine carboxylic acid (2.00 g, 14.0 mmol) and piperidine (1.5 mL, 15 mmol) in DCM (150 mL) was added HOBt (2.80 g, 21.0 mmol), EDC (4.00 g, 21.0 mmol), and N-methyl morpholine (8.5 mL, 84 mmol). After 18 h the reaction mixture was concentrated. Chromatography of the residue (SiO2; 5-10% 2 M NH3 in MeOH/DCM) gave the title compound as a solid (1.30 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N+:9]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: Cc1noc(N)c1Br
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: Cc1noc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1Br
Yield: 55 %

Procedure:
3-Nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 3-nitrobenzenesulfonyl chloride in 55% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 151-153° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:13]2[CH:14]=[CH:15][C:11]([C:10]([F:17])([F:16])[F:9])=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and 3-trifluoromethyl pyrazole (83 g, 0.61 mol) in dry N,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and the reaction was then heated to 110–125° C. over 48 hours. The reaction was cooled to 100° C. and filtered through Celite® diatomaceous filter aid to remove solids. N,N-Dimethylformamide and excess dichloropyridine were removed by distillation at atmospheric pressure. Distillation of the product at reduced pressure (b.p. 139–141° C., 7 mm) afforded the title product as a clear yellow oil (113.4 g). 1H NMR (CDCl3) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][O-:21].[Na+].CO>>[CH3:20][O:21][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: [Na+]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 89 %

Procedure:
A solution of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (100 mg, 0.31 mmol) in 1M sodium methoxide-methanol (30 mL) is stirred under reflux for 42 h. The resulting mixture is concentrated under reduced pressure, diluted with water and neutralized with dilute HCl to give 7-methoxy-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (92 mg, 89%) as a white solid. 1H NMR (DMSO) δ 10.22 (1H, brs), 9.57 (1H, s), 8.63 (1H, s), 8.19 (1H, s), 7.86 (1H, brd, J=7.9 Hz), 7.39 (1H, t, J=7.9 Hz), 7.35 (1H, dd, J=7.9, 1.5 Hz), 6.96 (1H, s), 4.00 (3H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([C:11]1[N:12]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]=[CH:14][C:15]=1[C:16](O)=[O:17])[CH3:10].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:10][C@@H:9]1[C:11]2[N:12]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:13]=[CH:14][C:15]=2[C:16](=[O:17])[NH:8]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@@H](C)N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2[C@@H](C)NC3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 105 %

Procedure:
To a slurry of (R)-2-(1-aminoethyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (702d; 22.83 g, 54.1 mmol) in 150 mL EtOAc at 0° C. was added DIPEA (28.2 mL, 162 mmol). A portion of the slurry seemed to dissolve. After 10 min, 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in EtOAc; Matrix Scientific; 35.0 mL, 59.5 mmol) was added and much of the solid dissolved. After 10 min, the still heterogeneous reaction was warmed to RT. After 4 h, the reaction was dark brown and homogeneous. The reaction was treated with 400 mL sat'd aq. NaHCO3 and transferred to a separatory funnel. The layers were separated and the organic layer was washed with 1× sat'd aq. NaHCO3 then 1× brine, dried over anhydrous Na2SO4, filtered through a glass frit and concentrated in vacuo to give (R)-6-methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (16.5 g, 56.8 mmol, quantitative yield) as a tan foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.70-7.77 (2H, m), 7.35 (2H, d, J=8.0 Hz), 7.16 (1H, d, J=3.3 Hz), 6.48 (1H, d, J=3.1 Hz), 5.75 (1H, br. s.), 4.68 (1H, q, J=6.5 Hz), 1.62 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 291.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:15][CH3:16])[C:13]#N.[OH-:22].[Na+].CI.[C:26](=O)([O-])[O-:27].[K+].[K+]>C(O)C.O>[CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:15][CH3:16])[C:13]([O:27][CH3:26])=[O:22]
Reactant: CCC(C#N)c1ccccc1COc1cc(C)ccc1C
Reactant: O=C([O-])[O-]
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CI
Product: CCC(C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]butyronitrile (0.67 g, 2.4 mmol) and 96% sodium hydroxide (0.73 g, 17.5 mmol) in ethanol (8 ml) was heated under reflux for 43 hours. The solvent was evaporated, and then water was added. The mixture was adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The crude product was dissolved in N,N-dimethylformamide (5 ml) and stirred at room temperature. Methyl iodide (0.50 g, 3.5 mmol) and potassium carbonate (0.50 g, 3.6 mmol) were added thereto in this order. After 1 hour, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=9/1) to give the desired compound methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]butyrate (0.62 g, 83%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:27])([CH3:26])[O:19][C:20]=3[C:21]([C:23](O)=[O:24])=[CH:22][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:26])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([C:33]([F:32])([F:41])[F:42])=[CH:35][CH:36]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)cc3)c3c(c21)CC(C)(C)O3
Yield: 7.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-49, 0.100 g, 0.2564 mmol), thionyl chloride (2.0 mL), 4-trifluoromethyl aniline (0.124 g, 0.769 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.47 (s, 3H), 3.56 (s, 2H), 7.17-7.01 (m, 1H), 7.21 (bs, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 9.92 (bs, 1H), 10.52 (bs, 1H): MS [M+H]+: 533.25.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:20]3=[O:34])[CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:19]([CH2:18][C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[C:16]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[C:20]1=[O:34]
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2ccn3C(=O)OC(C)(C)C)c2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
6-Chloro-4-[3-(2-methoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (570 mg 1.1 mmol) is dissolved in 2.5 mL of dichloromethane and 2.5 mL of trifluoroacetic acid is added. The reaction is stirred for one hour, and then the solvent evaporated in vacuo to give an oil. The oil is taken up 3× in methanol and evaporated in vacuo to give the desired compound (450 mg, 1.1 mmol, 100%)
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>S(=O)(=O)(O)O>[C:12]1([CH:11]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH:7]([CH3:9])[CH3:8])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)c1ccccc1C(C)c1ccccc1

Procedure:
Aralkylation of cumene with styrene was carried out in the presence of sulfuric acid catalyst. From the reaction product, a fraction mainly containing 1-phenyl-1-(isopropylphenyl)ethane was obtained by distillation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH:7](CC(O)=O)[C:8]([OH:10])=O.CN(C)[CH:17]=[O:18].C(Cl)(=O)C(Cl)=[O:22].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[O:10]=[C:8]1[CH2:7][SH:6]([C:17]([OH:18])=[O:22])[C:2]2[S:1][CH:5]=[CH:4][C:3]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CC(Sc1cccs1)C(=O)O
Reactant: CN(C)C=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C[SH](C(=O)O)c2sccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred suspension of 2-(2-thienylthio) succinic acid (75.5 g, 0.325 mol) in methylene chloride (500 ml) under a nitrogen atmosphere was added dimethylformamide (3 ml) followed by the dropwise addition of oxalyl chloride (70.7 ml, 0.81 mol) over a 1/2 hour period. The mixture was stirred at ambient temperature for 21/2 hours and the resulting solution was concentrated in vacuo to a brown oil. Then 1/2 of this oil was dissolved in methylene chloride (200 ml), cooled to about -78° C. and stirred as trifluoromethane sulfonic acid (50 g, 0.33 mol) was added dropwise over 5 minutes. After 1/4 hour at -78° C., the cooling bath was removed and the temperature was allowed to rise to room temperature. After 43/4 hours, the mixture was poured into ice and water. Methylene chloride (400 ml) was added and the mixture was filtered to obtain the product as a pale gray solid (4.1 g). The methylene chloride layer was separated, washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo to a black gum. The gum was dissolved in ethyl acetate (150 ml). This solution was extracted with 10×50 ml of 0.25N KOH. The individual extracts were acidified and solids were filtered and dried. Total product obtained was 19 g or 55% yield. Pure product melted at 182.5°-184° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C.O>[NH2:12][C:10]([C:3]1[C:2]([F:1])=[C:7]([CH:6]=[CH:5][C:4]=1[F:9])[O:8][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,6-difluoro-3-hydroxybenzenecarboxamide (1.2 g, 7 mmol, 1 equiv.), K2CO3 (2.87 g, 21 mmol, 3 equiv.) and methyl bromoacetate (0.69 ml, 7.35 mmol, 1.05 equiv.) in DMF (30 ml) was stirred at r.t. for 18 h. The mixture was diluted with water and extracted with EtOAc (4×80 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure. The product was used crude on the next step. HPLC-MS (method 1): m/z 246 [M+H]+, Rt=2.08 min.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C.O>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:23](=[O:25])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[Br:20])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
HOBt (4 g, 29.6 mmol) and DIEA (8.7 g, 67.7 mmol) were added to a stirred solution of 2-bromo benzoic acid (5.6 g, 28.3 mmol) in DMF (50 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (7.76 g, 40.48 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (5 g, 26.9 mmol) were added. Then reaction mixture was stirred at the room temperature overnight. Water was added and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4, and removed under reduced pressure to afford 9 g (90%) of 4-(2-bromo-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR: (DMSO-d6): δ 7.58 (d, 1H), 7.38 (t, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 3.85 (m, 1H), 3.7 (m, 1H), 3.55 (t, 2H), 3.5 (m, 1H), 3.3 (m, 3H), 3.15 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([O:9][CH:10]([C@H:13]1[O:22][C@@H:16]2[O:17][C:18]([CH3:21])(C)[O:19][C@@H:15]2[CH2:14]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24].S(=O)(=O)(O)O>C(O)(=O)C.C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:9][CH:10]([C@@H:13]1[CH2:14][C@@H:15]([O:19][C:18](=[O:17])[CH3:21])[CH:16]([O:26][C:23](=[O:25])[CH3:24])[O:22]1)[CH2:11][CH3:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(C)=O)C(OC(C)=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl benzoate (compound 26a, 6.73 g, 22.0 mmol) and acetic anhydride (11 mL) in acetic acid (44 mL) and chloroform (11 mL) was added concentrated sulfuric acid (200 uL) dropwise. After being stirred at room temperature overnight, the resulted mixture was diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:10 EtOAc in petroleum ether) to afford 5.1 g 1-[(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]propyl benzoate (compound 26b) as a viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:25][N:24]=1)([O-])=O>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Reactant: NCCCN(Cc1ccccc1)c1ccccn1
Solvent: c1ccncc1
Product: O=c1[nH]c(NCCCN(Cc2ccccc2)c2ccccn2)ncc1Cc1ccncc1

Procedure:
2-[N-(3-aminopropyl)-N-benzylamino)pyridine (1.0 g) and 2-nitroamino-5-(pyrid-4-ylmethyl)pyrimid-4-one (0.68 g) were heated together under reflux in pyridine (2.5 ml) for 23 hr. After stripping the residue was twice crystallized from ethanol/water to give 2-[3-(N-benzyl-N-pyrid-2-ylamino)propylamino]-5-pyrid-4-ylmethylpyrimid-4-one 1.6 H2O, 0.86 g (68%) m.p. 87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([F:26])[CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH3:23])[N:12]=[CH:11][C:10]([C:24]#[N:25])=[C:9]2[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:26]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1N
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A mixture of 500 mg (1.34 mmol) 4-[(4-chloro-2-fluorophenyl)amino]-7-methoxy-6-nitro-3-quinolinecarbonitrile, 20 ml ethanol and 1.52 ml (6.71 mmol) tin chloride dihydrate was heated to reflux under N2. At 3 hours, removed heat, added ice water and made basic with sodium bicarbonate. Stirred for several hours and extracted with chloroform. Dried organic layer with sodium sulfate, stripped solvent and dried in vacuo, giving 350 mg of green solid: mass spectrum (electrospray m/e): M+H=342.9, 344.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31](CC)CC)[CH3:30].BrCC#N>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:30][C:29]#[N:31])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: N#CCBr
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCN(CC#N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (522 mg) obtained in Example 23-4 was dissolved in DMF (10 ml) and added with triethylamine (372 μl) and bromoacetonitrile (139 μl) and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (469 mg) as a colorless oily substance.
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[CH2:21]([NH:25][OH:26])[CH:22]([CH3:24])[CH3:23]>CO.Cl>[C:1]([O:4][C:5]1[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][C:8]([CH:9]=[N+:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[O-:26])=[CH:7][C:6]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)CNO
Agent: Cl
Solvent: CO
Product: CC(=O)Oc1c(C(C)(C)C)cc(C=[N+]([O-])CC(C)C)cc1C(C)(C)C

Procedure:
To a solution of 4-acetoxy-3,5-di-tert-butylbenzaldehyde (17.0 g, 0.0615 mol) in methanol (250 mL) was added isobutylhydroxylamine (5.36 g, 0.0714 mol) and concentrated hydrochloric acid (10 drops ). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (Rf=0.23 for product and 0.84 for starting material using 3.1 hexanes/EtOAc) The solvent was removed in vacuo and the residue was a red oil which when triturated with hexanes it turned into solid. The solid was separated and washed completely with hexanes. The titled compound was isolated in 52.3% yield a a white solid, m.p. 176.8-180.4° C.