Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:32]([OH:34])=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:43]>ClCCl>[C:1]([NH:18][C@H:19]([C:32]([F:43])=[O:34])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)F)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
N-FMOC-O-t-Butyl-L-tyrosine (5 g, 10.88 mmol) (Bachem) was dissolved in dichloromethane (50 mL). Pyridine (0.88 mL, 10.88 mmol) (Aldrich) and cyanuric fluoride (1.47 g, 10.88 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 5 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-FMOC-O-t-butyl-L-tyrosyl fluoride as a white powder. (Yield 4.43 g, 88%).
Reaction SMILES: Cl[CH:2]([O:5][CH3:6])[CH2:3][Cl:4].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[CH2:9]([O:8][P:7]([CH:2]([O:5][CH3:6])[CH2:3][Cl:4])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: COC(Cl)CCl
Product: CCOP(=O)(OCC)C(CCl)OC
Yield: 57.8 %

Procedure:
0.9 mole of methyl 1,2-dichloroethyl ether was added dropwise to 1 mole of triethyl phosphite at 120° C., under a N2 atmosphere. After a reaction time of 8 hours, the mixture was fractionated. 120 g of 1-methoxy-2-chloroethane-phosphonic acid diethyl ester were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]([NH2:22])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:22][C:31]([C:28]3[N:29]=[CH:30][C:25]([Br:24])=[CH:26][N:27]=3)=[O:32])[CH:18]=[C:19]([Br:21])[CH:20]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)cc(Br)c2)COC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cc(NC(=O)c3ncc(Br)cn3)c2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[(R)-5-(3-Amino-5-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (33 mg, 0.082 mmol), 5-bromo-pyrimidine-2-carboxylic acid (18 mg, 0.090 mmol) and HOBT (16 mg, 0.106 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (10.54 mg, 0.082 mmol) and EDC (17 mg, 0.090 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated column chromatography (cyclohexane/ethyl acetate) to yield the title compound as a tan foam. MS: 569 [(M+H)+].
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:13](Br)([CH2:15][CH3:16])[CH3:14].[OH:18][C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:31])([CH3:30])[O:26]2)=[CH:21][CH:20]=1>COCCOCCOC>[CH:13]([O:18][C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:30])([CH3:31])[O:26]2)=[CH:21][CH:20]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COCCOCCOC
Product: CCC(C)Oc1ccc2c(c1O)OC(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In 80 ml of dimethyl sulfoxide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 10 ml of diethylene glycol dimethylether, 4.1 g (30 millimoles) of potassium carbonate, 0.5 g of potassium iodide and 3.3 (2.6 ml, 24 millimoles) of sec. butyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours, poured onto 200 ml of crushed ice and extracted with 100 ml of carbon tetrachloride. To the aqueous phase 20 ml of 10% sodium hydroxide solution are added, the mixture is cooled to 0° C., acidified with concentrated hydrochloric acid and stirred at 0° C. for 2 hours. The product is filtered, washed twice with 20 ml of water, dried and crystallized from 20% ethanol. Thus 4.4. g of the desired compound are obtained, yield 83%, mp.: 108°-110° C.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1)[CH3:2].Br[C:17]([Br:20])([CH3:19])C.[C:21](=O)([O-])[O-].[Cs+].[Cs+].C(OC(C)C)(=O)C>CN(C=O)C>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:21][CH2:19][CH2:17][Br:20])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(O)ccc2c(CC)noc12
Reactant: CC(C)(Br)Br
Agent: [Cs+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCCc1c(OCCCBr)ccc2c(CC)noc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 54.8 %

Procedure:
A solution of 3-ethyl-6-hydroxy-7-propylbenz[4,5]isoxazole (2.00 grams; 9.74 mmol) in dry DMF was treated with dibromopropane (7.17 mL; 38.97 mmol) and cesium carbonate (3.49 grams; 10.71 mmol). The solution was stirred at room temperature for 10 hours, then partioned between isopropyl acetate and pH 4.0 buffer. The organic layer was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound (1.74 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[N:8](COC(=O)[C@@H](C3C=CC=CC=3)O)[C:7]=2[CH:36]=1.[OH-].[Na+].C(OC)=O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])=[N:8][C:7]=2[CH:36]=1
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(COC(=O)[C@H](O)c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 77 %

Procedure:
0.23 g (0.45 mmol) of the more hydrophilic diastereomer of 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[(R)-mandeloyloxymethyl]-1H-benzimidazole was dissolved in 15 ml methanol. A solution of 36 mg (0.9 mmol) sodium hydroxide in 0.45 ml water was added, and after 10 minutes the mixture was evaporated on a rotavapor. The residue was partitioned between 15 ml water and 15 ml dichloromethane. The organic solution was extracted with 15 ml water and to the combined aqueous solutions was added 85 μl (1.4 mmol) methyl formate. After 15 minutes the mixture was extracted with 3×10 ml dichloromethane. The organic solution was dried over Na2SO4 and then evaporated. There was obtained 0.12 g (77%) of the title compound as a colorless syrup. The optical purity (e.e.) which was analyzed by chiral column chromatography was 94%. [α]D20 =-155° (c=0.5%, chloroform).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[CH:35]=[CH:36][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1-c1ccc(C(=O)NCC2CC2)cn1
Yield: 60.1 %

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5 mg, 0.073 mmol) and 4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) (30 mg, 0.072 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 4 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-cyclopropylmethyl-6-[2-methyl-5-(3-pyridin-2-yl-phenylcarbamoyl)-phenyl]-nicotinamide as a white solid (20 mg). LCMS: retention time 3.18 min, MH− 463. NMR: δH [2H6]-DMSO 10.43, (1H, s), 9.14, (1H, s), 8.86, (1H, t), 8.69, (1H, s), 8.53, (1H, s), 8.34, (1H, d), 8.11, (1H, s), 8.01, (1H, d), 7.95-7.89, (3H, m), 7.81-7.78, (2H, m), 7.53-7.46, (2H, m), 7.38, (1H, t), 3.21, (2H, t), 2.44, (3H, s), 1.07, (1H, m), 0.47, (2H, m), 0.27, (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22](O)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1C
Yield: 75.4 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.6 mg (0.131 mMol) 3,4-dimethylbenzoic acid, 12.0 mg (76%) of the title compound were recovered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]#[N:30])[CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42]C(=O)NC1(C2C=CC(C3C(=O)C4C(=CC(OC)=C(Br)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([O:42][CH3:38])=[C:24]([C:29]#[N:30])[CH:25]=4)[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C#N
Yield: 77 %

Procedure:
Following the procedure used to prepare {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(6-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (115 mg, 0.20 mmol) was reacted to give the title compound (81 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 7.45-7.14 (m, 9H), 7.00 (s, 1H), 5.05 (s, 1H), 4.05 (s, 3H), 2.60-2.39 (m, 4H), 2.16-2.00 (m, 1H), 1.92-1.77 (m, 1H), 1.56-1.14 (m, 9H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:15][C:16](=[O:37])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25]3[C:30]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:18]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[I-].[Na+].O>CN(C=O)C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]([O:4][CH2:3][CH2:2][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[CH:6]=2)=[O:37])=[CH:18][C:19]=1[NH:24][C:25]1[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(C(=O)Nc2cc(OCCCl)cc(C(F)(F)F)c2)cc1Nc1ncccc1-c1ccncn1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)Nc2cc(OCCN3CCN(C)CC3)cc(C(F)(F)F)c2)cc1Nc1ncccc1-c1ccncn1
Temperature: 100 °C

Procedure:
A mixture of N-(3-(2-chloroethoxy)-5-(trifluoromethyl)phenyl)-4-methyl-3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)benzamide (200 mg, 0.38 mmol), 1-methylpiperazine (76 mg, 0.76 mmol) and sodium iodide (catalytic amount) in DMF (5 ml) was heated at 100° C. for 20 hr. After cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (3×50 ml) and dried over Na2SO4. The solvent was removed in vacuo and the product was purified by flash column chromatography eluting with MeOH(NH3)/DCM (1 to 5%) to afford the title compound as a light yellow solid. MS m/z=592 [M+1]+. Calc'd for C31H32F3N7O2: 591.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(NC(=O)c2cc(Cl)ccn2)CC1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN1CCC(NC(=O)c2cc(Oc3ccc(N)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.557 g, 5.06 mmol) in DMA (8.5 mL) was treated with potassium tert-butoxide (0.639 g, 5.69 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-(1-methylpiperidin-4-yl)picolinamide (1.07 g, 4.22 mmol) in DMA (8.5 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM/NH4OH) to afford 4-((6-aminopyridin-3-yl)oxy)-N-(1-methylpiperidin-4-yl)picolinamide (0.654 g, 47%). 1H NMR (400 MHz, DMSO-d6): δ 8.49-8.48 (m, 2H), 7.81 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 3.69 (d, J=9.9 Hz, 1H), 2.69 (d, J=11.1 Hz, 2H), 2.13 (s, 3H), 1.93 (t, J=11.2 Hz, 2H), 1.68-1.62 (m, 4H); MS (ESI) m/z: 328.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([CH:23]=O)=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl-:25].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>CO>[ClH:25].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([CH2:23][NH:29][CH3:28])=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: [BH3-]C#N
Reactant: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Agent: C[NH3+]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC)cc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
1-[(4-Methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (240 mg) was dissolved in methanol (5 mL), methylammonium chloride (856 mg) and sodium cyanoborohydride (131 mg) were added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue; and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→ethyl acetate). The obtained oil was dissolved in ethyl acetate (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as colorless crystals (yield 148 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:14]([CH3:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.[OH-].[Na+].O>ClCCl.II>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:25][C:14]2([CH3:15])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=C(C)C)c1ccc(Cl)cc1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1(c2ccc(Cl)cc2)OC1(C)C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
A solution of ethyl 2-(4-chlorophenyl)-3-methylbut-2-enoate (11.4 g, 0.048 mol), prepared in Example 1c, m-chloroperbenzoic acid (15.7 g, 0.050 mol) and iodine (0.1 g) in dichloromethane (400 ml) was stirred for 48 hours at 50°-55° c. During this period, the course of the reaction was monitored by analytical thin layer chromatography and three further portions (2.0 g) of m-chloroperbenzoic acid and two further portions (0.1 g) of iodine were added to the mixture. The precipitate which formed during this time was dissolved by the addition of 2N sodium hydroxide solution (40 ml) and iced water (200 ml). The organic phase was then separated and washed with dilute sodium hydroxide solution (100 ml) and then with water (3×200 ml). The solution was dried (sodium sulphate), evaporated in vacuo, and the crude product purified by flash silica column chromatography, eluting with 1,2-dichloroethane, to give the title compound (8.6 g, 71%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O.C(Cl)[Cl:20]>[Ni].CCO>[Cl:20][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Reactant: ClCCl
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Reaction time: 8 h

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Raney Nickel (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% EtOAc/Hexanes to give 3-chlorobenzo[f][1,7]naphthyridine-5,8-diamine as a white solid. 1H NMR (methanol-d4): δ 8.75 (d, 1H), 8.08 (dd, 1H), 7.70 (d, 1H), 6.84-6.81 (m, 2H). LRMS [M+H]=245.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:21][CH:22]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C(OCCCCCl)c2ccc(F)cc2)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(OC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCNCC1
Reaction time: 72 h
Yield: 30 %

Procedure:
Piperazine (4.31 g, 50 mmol) was dissolved in 40 mL of anhydrous DMF and stirred with K2CO3 powder (2.76 g, 20 mmol) and KI (100 mg, 0.6 mmol) for 0.5 h. To this turbid solution, 1-[bis(4-fluorophenyl)methoxy]-4-chlorobutane (2, 1.55 g, 5 mmol) in 10 mL of DMF was added slowly. The reaction mixture was stirred for 72 h at 60°-70°. The turbid reaction mixture was poured into 200 mL of ethyl acetate, washed with sat. NaCl solution (60 mL×5), dried over MgSO4 and evaporated to dryness. The crude oil was applied to a silica gel column for purification. Elution with CHCl3:MeOH (93:7) afforded the desired mono-alkylated product 3 (540 mg, 1.5 mmol, 30%) as a slightly yellow oil. 1H NMR (CDCl3): δ 1.55-1.69 (4H, m), 2.31 (2H, t, J=7.5), 2.39 (4H, br s), 2.88 (4H, t, J=4.8), 3.43 (2H, t, J=6.0), 5.28 (1H, s), 6.98-7.02 (4H, m), 7.25-7.29 (4H, m). mp (bis oxalate salt): 215°-218° C. Anal. C25H30N2O9F2) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:45]([O:52][C:53](=[O:71])[C@H:54]([CH2:67][CH:68]([CH3:70])[CH3:69])[NH:55][C:56](=[O:66])[C@H:57]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH2:58])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([O:52][C:53](=[O:71])[C@H:54]([CH2:67][CH:68]([CH3:69])[CH3:70])[NH:55][C:56](=[O:66])[C@H:57]([CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:58][C:27](=[O:28])[C@H:25]([CH3:26])[NH:24][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
14.0 Parts N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and 3.5 parts N-methylmorpholine are dissolved in 200 parts dimethylformamide and cooled to -15° C. Then, 5.2 parts isobutyl chloroformate is added dropwise over a 30 minute period while maintaining the temperature at -15° C. Then, a solution of 9.8 parts L-phenylalanyl-L-leucine benzyl ester in 50 parts dimethylformamide is slowly added at -15° C., and the mixture stirred at this temperature for 30 minutes. The cooling apparatus is removed and the mixture stirred at ambient temperatures for an additional two hours. The product is isolated by diluting the reaction mixture with 10 volumes water and extracting with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate and stripped to dryness under reduced pressure. Purification of the residue by low pressure column chromatography affords N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanyl-L-phenylalanyl-L-leucine benzyl ester.