Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:9]([OH:28])[CH2:10][N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][CH:8]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:9]([OH:28])[CH2:10][N:11]([CH2:24][CH:25]([CH3:26])[CH3:27])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The wet crystals of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester were suspended in ethanol (around 950 L), and then hydrogenated in the presence of 10 wt % palladium carbon at around 5-30° C. After the resulting reaction mixture was filtered to remove the palladium-carbon, the filtrate was concentrated under reduced pressure to give a solution of (1-Benzyl-2-hydroxy-3-[isobutyl-(4-amino-benzenesulfonyl)-amino]-propyl)-carbamic acid tert-butyl ester in ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=O)[CH:19]([CH3:21])[OH:20].Cl.N>>[CH2:1]([O:8][C:9]1[C:10]2[N:17]=[C:18]([CH:19]([OH:20])[CH3:21])[N:12]([CH3:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)C(=O)O
Reactant: CNc1cccc(OCc2ccccc2)c1N
Agent: Cl
Agent: N
Product: CC(O)c1nc2c(OCc3ccccc3)cccc2n1C
Yield: 19.4 %

Procedure:
A mixture of 3-benzyloxy-2-amino-N-methylaniline (400 mg), lactic acid (473.8 mg) and 4N hydrochloric acid (1.6 ml) was refluxed for 1.5 hours. After cooling, the mixture was adjusted to pH 8 with 28% ammonia solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1, v/v) to give 4-benzyloxy-2-(1-hydroxyethyl)-1-methyl-1H-benzimidazole (96.2 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[C:22]=1[Cl:32].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([Cl:31])[C:22]=2[Cl:32])[C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c(Cl)c1Cl
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A suspension of 26.7 g (0.096 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde (prepared in Example 96 (i) and (ii)) and 28.01 g (0.203 mol) of dry potassium carbonate in 350 mL of dimethylformamide was stirred under argon for 20 minutes. Then 30 g (0.10 mol) of methyl 4-bromomethyl-2,3-dichlorobenzoate was added and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was poured into water and extracted several times with ether. Filtration of the solid formed at the ether-water interface gave 19.35 g of product. The ether layer was washed 4 times with water, once with brine, and then concentrated under vacuum to give a solid. Recrystallization of the combined solids from methanol gave 32.55 g (68%) of product; mp 135°-173° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:34]1([NH:39][C:29]2[CH:28]=[N:27][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=3)=[N:31][CH:30]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(NC2CCCC2)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and cyclopentylamine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][C:10]2[CH2:9][CH2:8][C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=3[C:5]=2[N:4]=1)[NH2:2].[C:17](/[N:19]=[C:20](\OC1C=CC=CC=1)/[NH:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)#[N:18]>C(O)(C)C>[N:4]1[C:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=[N:12][C:3]=1[N:1]1[C:17]([NH2:18])=[N:19][C:20]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)=[N:2]1
Reactant: NNc1ncc2c(n1)-c1ccccc1CC2
Reactant: CN1CCN(c2ccc(N/C(=N/C#N)Oc3ccccc3)cc2)CC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3nc(N)n(-c4ncc5c(n4)-c4ccccc4CC5)n3)cc2)CC1
Temperature: -20 °C

Procedure:
2-Hydrazinyl-5,6-dihydrobenzo[h]quinazoline (40 mg, 0.19 mmol) and (Z)-phenyl N′-cyano-N-(4-(4-methylpiperazin-1-yl)phenyl)carbamimidate (67 mg, 0.20 mMol) were suspended in isopropanol and subjected to microwave irradiation (150° C., 20 min). A precipitate formed in the microwave vial. After further cooling at −20° C., the solid was filtered off, washed with cold isopropanol and dried under vacuum to give 1-(5,6-dihydrobenzo[h]quinazolin-2-yl)-N3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #92, 32 mg; 1H NMR (DMSO-d6, 300 MHz) 8.76 (s, 1H), 8.65 (s, 1H), 8.16 (d, 1H), 7.65 (s, 2H), 7.46-7.53 (m, 4H), 7.37 (m, 1H), 6.84 (d, 2H), 2.90-3.05 (m, 8H), 2.48 (m, 4H), 2.22 (s, 3H) ppm; MS (ES) 454.17 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Nc1cccc(CO)c1)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1

Procedure:
A solution of 2′,4′-dichloro-N-(3-(hydroxymethyl)phenyl)biphenyl-4-sulfonamide (340 mg, 0.83 mmol) in DCM (10 mL) was stirred under argon at room temperature. Dess-Martin reagent (390 mg, 0.92 mmol) was added in one portion and the mixture was stirred for an hour. The suspension was filtered through Celite, rinsing well with DCM. The filtrate was washed with 1 M Na2S2O3 (10 mL) and water (10 mL) and the DCM was dried over MgSO4. The solvent was evaporated and the residue absorbed onto SiO2 and purified by column chromatography (4×16 cm SiO2, 25% acetone/hexane) and the title compound obtained as a yellow waxy solid (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: Cn1cc(CCl)cn1
Reactant: N#Cc1cc(COc2cc[nH]c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-1,2-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 514 [M+H]+; 3.97 min (ret time).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([C:16]#[CH:17])=[CH:10][CH:11]=3)[C:6]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1)#[CH:2].I[C:39]1[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=1>C1(C)C=CC=CC=1.CCN(CC)CC.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.[Cu]I>[CH3:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:6]1([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:7]2[CH:8]=[C:9]([C:16]#[C:17][C:39]3[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=3)[CH:10]=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][C:3]([C:1]#[C:2][C:39]1[S:43][C:42]([CH:44]=[O:45])=[CH:41][CH:40]=1)=[CH:15][CH:14]=2
Reactant: C#Cc1ccc2c(c1)C(CCOCCOCCOC)(CCOCCOCCOC)c1cc(C#C)ccc1-2
Reactant: O=Cc1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCOCCOCCC1(CCOCCOCCOC)c2cc(C#Cc3ccc(C=O)s3)ccc2-c2ccc(C#Cc3ccc(C=O)s3)cc21
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Air was removed from a solution of 2,7-diethynyl-9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene (0.120 g, 0.237 mmol) in 8.2 mL of toluene and 1.8 mL of Et3N by blowing argon for 20 min. Then Pd(PPh3)2Cl2 (10 mg, 6 mol %) and CuI (2.7 mg, 6 mol %), and 5-iodothiophene-2-carboxaldehyde (0.135 g, 0.568 mmol) were added, and deaeration was continued for 15 min. Thereafter the mixture was stirred at 40° C. for 17 h. After completion of the reaction, reaction mixture was filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (CH2Cl2/AcOEt 60:40 then AcOEt) to yield 0.140 g (81%) of 5,5′-[9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene-2,7-diyldi-2,1-ethynediyl]bis-2-thiophenecarboxaldehyde, mp 84° C.; 1H NMR (CDCl3) δ 2.43 (t, 4H, J=7.5 Hz), 2.79 (t, 4H, J=7.2 Hz), 3.21 (m, 4H), 3.33 (s, 6H), 3.39 (m, 4H), 3.54-3.46 (m, 8H), 7.37 (d, 2H, J=3.9 Hz), 7.57 (dd, 2H, J=1.5 Hz, J=7.1 Hz), 7.62 (d, 2H, J=1.2 Hz), 7.71 (d, 2H, J=7.1 Hz), 7.72 (d, 2H, J=3.9 Hz), 9.90 (s, 2H); 13C NMR (CDCl3) δ 39.6, 51.6, 59.0, 66.8, 70.1, 70.4, 70.5, 71.8, 83.0, 98.5, 120.5, 121.2, 126.6, 131.3, 132.6, 132.8, 136.2, 140.7, 143.9, 149.7, 182.5. HRMS (ESI) calcd for C41H42O8NaS2 [(M+Na)+] m/z 749.2219. found 749.2226. Anal. Calcd for C41H42O8S2 (726.90): C, 67.75; H, 5.82; S, 8.82. Found: C, 67.86; H, 5.82; S, 8.63.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([O:15][CH2:16][CH2:17][OH:18])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[C:27]([C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])([Cl:37])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[C:38]([C:27]([N:11]1[C:12](=[O:13])[CH:14]([O:15][CH2:16][CH2:17][OH:18])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:10])([Cl:37])[C:28]([NH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:29])(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)C(=O)C(Cl)(Br)C(=O)Nc1ccccc1
Reactant: O=C1NC(=O)N(Cc2ccccc2)C1OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(Cl)(C(=O)Nc1ccccc1)N1C(=O)C(OCCO)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 80.4 %

Procedure:
51.5 g of 1-benzyl-5-(2-hydroxyethoxy)hydantoin and 20 g of triethylamine were dissolved in 500 ml of methylene chloride, and a solution of 34.8 g of α-bromo-α-pivaloyl-2-chloroacetanilide in 200 ml of methylene chloride was dropwise added thereto in about 1 hour. After completion of the dropwise addition, the solution was stirred for 2 hours. Then, the reaction solution was washed twice with 300 ml of dilute hydrochloric acid, and twice with 300 ml of water. After drying the reaction solution with sodium sulfate, it was concentrated and purified by silica gel chromatography to obtain 42.2 g of oily α-pivaloyl-α-(1-benzyl-5-(2-hydroxyethoxy)hydantoin-3-yl)-2-chloroacetanilide. (Yield: 84%)
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:12]1([C:9]2[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OC1(c2ccc(C3OCCO3)cc2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C2=CCCCC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
1-(4-[1,3]Dioxolan-2-yl-phenyl)cyclohexanol (45 g) and p-toluenesulfonic acid (3.4 g) in 300 mL of toluene were refluxed for 3 hours under Dean-Stark conditions. After cooling, ethyl acetate and a saturated sodium hydrogen carbonate solution were added. The organic layer was washed twice with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The residual oil was dissolved in glacial acetic acid (250 mL) and 1 M hydrochloric acid (25 mL) was added and the mixture was stirred at 50° C. for 2 hours. After cooling, the mixture was concentrated in vacuo. The residual oil was partitioned between ethyl acetate and water. The organic phase was washed three times with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The residual oil was distilled in vacuo and the fraction boiling at 120-130° C. (0.2 mmHg) was collected to afford 4.7 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][C:12]=1[C:13](O)=[O:14].CCN(CC)CC.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl.O>[NH2:10][C:11]1[N:19]=[CH:18][C:17]([Br:20])=[CH:16][C:12]=1[C:13]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: NCc1ccc(F)cc1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(Br)cc1C(=O)NCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
To a degassed solution of (4-fluorophenyl)methanamine (500 mg, 4.0 mmol), 2-amino-5-bromonicotinic acid (867 mg, 4.0 mmol) and Et3N (1.21 g, 12.0 mmol) in dry DCM (10 mL) was added T3P (2.54 g, 8.0 mmol) at 0° C. under N2 protection. The mixture was stirred at 0° C. for 20 minutes. The mixture was diluted with water, and then it was extracted with EtOAc, dried over Na2SO4, filtrated and concentrated to give the crude product of 2-amino-5-bromo-N-(4-fluorobenzyl)nicotinamide (1.05 g, yield: 81%). 1H-NMR (CDCl3, 400 MHz) δ 8.18 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.31 (t, J=8.0 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.38 (d, J=4.0 Hz, 2H), 6.17 (d, J=5.2 Hz, 1H), 5.12 (d, J=6.4 Hz, 2H). MS (M+H)+: 324/326.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([CH:18]=O)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:23]([NH:25][CH:26]3[CH2:28][CH2:27]3)=[O:24])[CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:17]=[C:16]([CH2:18][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:23]([NH:25][CH:26]3[CH2:28][CH2:27]3)=[O:24])[CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C=O)c2c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(CN3CCCC3)c2c1
Reaction time: 0.17 h
Yield: 26 %

Procedure:
3-(2-Benzyl-4-formyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.13 g) was dissolved in dichloromethane (10 mL). Pyrrolidine (0.064 g) was then added and the mixture stirred for 10 minutes before adding sodium triacetoxyborohydride (0.25 g). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue purified (SiO2, eluting with 5% methanol in dichloromethane) to give the title compound as a solid (0.038 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)C>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=Cc1cccnc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1cccnc1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (1.0 g, 25 mmol) was added to a suspension of estrone (1.35 g, 5.0 mmol) and pyridine-3-carbaldehyde (595 mg, 5.0 mmol) in ethanol (40 mL) at room temperature. The resulting dark orange solution was stirred at room temperature for 4 hours. Then glacial acetic (ca. 10 mL) acid was added with stirring. The colour changed to light yellow and a light yellow solid precipitated. The solid was filtered off and washed with water (50 mL), ethanol (20 mL), diethyl ether (50 mL) and hexane (50 mL) and dried under high vacuum. Yield: 1.6313 g (90%) yellow powder. 1H-NMR (DMSO-d6, 400 MHz), δ: 0.90 (s, 3H, —CH3), 1.26-1.66 (m, 5H), 1.82-1.90 (m, 1H), 1.95-2.02 (m, 1H), 2.14-2.22 (m, 1H), 2.30-2.38 (m, 1H), 2.57-2.66 (m, 1H), 2.70-2.81 (m, 2H), 2.83-2.92 (m, 1H), 6.45 (d, J=2.3 Hz, 1H), 6.51 (dd, J=8.2, 2.3 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 7.34 (s, 1H), 7.47 (dd, J=8.2, 5.1 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.56 (dd, J=4.7, 1.2 Hz, 1H), 8.82 (d, J=1.6 Hz, 1H), 9,03 (s, 1H, —OH). LRMS (FAB+): 360.2 (100, [M+H]+). LRMS (FAB−): 276.1 (100), 358.2 (90, [M−H]−). HRMS (FAB+): 360.196434 C24H26NO2 requires 360.196354
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.O.Cl[Sn]Cl>C(O)(=O)C.Cl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Br)nc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of 2-bromo-7-nitro-5H-pyrrolo[2,3-b]pyrazine (21.76 g, 89.54 mmol) in acetic acid (108.8 mL) and concentrated hydrogen chloride (108.8 mL) was added dichlorotin dihydrate (101.0 g, 447.7 mmol). The reaction mixture was left to stir for 1 hour at ambient temperature. Reaction mixture was quenched by addition of 2M NaOH solution and the aqueous extracted with EtOAc (×3). Organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was washed with saturated NaHCO3 solution and the solid collected, washed with water and dried to give 2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-amine (10.4 g, 54.6%). 1H NMR (400.0 MHz, DMSO) δ 11.50 (br s, 1H), 8.22 (s, 1H), 7.16 (s, 1H) and 4.35 (br s, 2H) ppm; MS (ES+) 214.79
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][O:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:26])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2c(N)nc3ccccc3c21
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CC(C)(C)OC(=O)NCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Yield: 66.7 %

Procedure:
Using the general method of Example 5 Part C, tert-butyl[2-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (7 g, 19 mmol)) was reacted with N-hydroxyphthalimide (3.65 g, 22.3 mmol) to provide 6.37 g of tert-butyl (2-{4-amino-2-[(1,3-dioxo-1,3-dihydroisoindol-2-yl)oxymethyl]-1H-imidazo[4,5-c]quinolin-1-yl}ethyl)carbamate as a yellow solid.
Reaction SMILES: CC([O:5][CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:5][CH2:6][C:7]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([CH:16]([CH3:18])[CH3:17])[O:9][N:8]=1
Reactant: COC(=O)c1c(COC(C)(C)C)noc1C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(CO)noc1C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.9 %

Procedure:
To a solution of methyl 3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (500 mg, 1.96 mmol) in dichloromethane (97 mL) was added trifluoroacetic acid (97 mL, 1.25 mol). The solution was stirred at ambient temperature for approximately 45 minutes and then concentrated. The residue was taken up with ethyl acetate and poured into saturated sodium bicarbonate. Solid sodium bicarbonate followed by solid sodium carbonate were added until the pH was basic. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 25% ethyl acetate in hexanes) to afford the methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (304 mg, 78%). 1H-NMR (400 MHz, DMSO-d6) δ 5.29 (t, J=6 Hz, 1H), 4.62 (d, J=6 Hz, 2H), 3.77 (s, 3H), 3.68 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(N(CC)CC)C.Cl[CH2:38][C:39]([NH2:41])=[O:40]>O.C(O)C>[C:1]([C@@H:4]([NH:13][C@H:14]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:38][C:39](=[O:40])[NH2:41])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: NC(=O)CCl
Reactant: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)CNCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 4.0 ml of water there was dissolved N-[N2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline (406 mg, 0.0001 mole), after which triethylamine (364 mg, 0.0036 mole) was added, followed by slow, dropwise addition of a solution of 2-chloroacetamide (140.3 mg, 0.0015 mole) in 6.0 ml of ethanol. The reaction mixture was stirred at room temperature for 15 minutes, followed by refluxing with stirring for 15 hours. Thin layer chromatography indicated a nearly complete reaction, and the refluxing was continued for 2 more hours. The reaction mixture is allowed to cool and then concentrated under vacuum, flushed with benzene 3 times, then further concentrated under vacuum. The crude product was purified on a 2.5×240 cm LH-20 chromatographic column using a methanol system. Product-rich fractions were evaporated to dryness and freeze-dried to give N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -carbamoylmethyl-L-lysyl]-L-proline.