Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:25]=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[OH:23])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CO.C1COCC1.[Ni]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]([OH:23])[CH:16]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(NC(=O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Compound 39 (470 mg, 1 mmol) was dissolved in MeOH (15 mL) and THF (15 mL). Raney Nickel (50% slurry in water) (2 mL) was added to the reaction mixture followed by anhydrous hydrazine (1 mL). The reaction mixture was stirred at room temperature for 30 minutes until the bubbling was stopped. The solid was filtered off through Celite under reduced pressure and washed with MeOH. The solvent was removed under reduced pressure. Liquid-liquid extraction was performed using CHCl3 (15 mL) and H2O (8 mL×2). The organic layer was dried over MgSO4, filtered and concentrated to give the compound 40 (263.8 mg, 59.9% crude yield) LC-MS (ESI): m/e=441.1 [M+1]+
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:19]([C:21]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:11])[F:13])=[O:22])[N:20]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=429.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:4]=2[N:3]=1.[P:29]([O:40][Si](C)(C)C)([O:35][Si](C)(C)C)[O:30][Si](C)(C)C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([C:27]([P:29](=[O:30])([OH:40])[OH:35])=[O:28])=[CH:26][C:4]=2[N:3]=1
Reactant: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2cnc3c(N)nc4cc(C(=O)P(=O)(O)O)ccc4c3c2)c(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (Example 9—Step 1) (1.0 equiv.) in toluene (0.27 M) was added tris(trimethylsilyl) phosphite (1.0 equiv.). The reaction was stirred at 80° C. for 60 minutes, then solvents were removed, and the resulting residue was taken up in DMSO (0.27 M), and IBX (1.5 equiv.) was added. The reaction was stirred at room temperature for 2.5 hour, and was filtered and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbonylphosphonic acid (14) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.84 (s, 1H), 9.35 (s, 1H), 9.09 (s, 1 H), 8.89 (s, 1 H), 8.76 (d, 1H, J=8.4 Hz), 8.60 (s, 1H), 8.19 (d, 1H, J=8.8 Hz), 7.04 (d, J=8.8 Hz, 1H), 6.70 (d, 1H, J=2.8 Hz), 6.62 (dd, 1H, J=2.8, 8.4 Hz), 3.64 (s, 3H), 3.15-3.09 (m, 2H), 2.97-2.91 (m, 2H), 2.23 (s, 3H). LRMS [M+H]=452.1
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[CH2:19]([N:26]1[C:30]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:36](OC)=[O:37])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>O1CCCC1.C(OCC)(=O)C.C(O)C.O>[CH2:19]([N:26]1[C:30]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:36]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2)=[O:37])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: COC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
130 Milligrams of lithium aluminum hydride was suspended in 70 ml of tetrahydrofuran, then 2.2 g of 6-amino-3,4-dihydro-2(1H)-quinolinone was added gradually thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was further stirred for 2 hours under refluxing condition, then 1 g of methyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate was added, the reaction was continued by refluxing for 3 hours. After the reaction was finished, then water and 10% aqueous solution of potassium hydroxide were added, the reaction mixture was diluted with ethyl acetate and filtered with Celite, and the filtrate was washed with chloroform, the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added ethanol and heated, the insoluble matters were collected by filtration and recrystallized from dimethylformamide, there was obtained 0.11 g of 1-benzyl-6-chloro-2-(3,4-dihydro-2(1H)-quinolinon-6-ylaminocarbonyl)benzimidazole as in the form of yellow powdery product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[O:12]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=O)C1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To a suspension of LiOH monohydrate (1.06 g, 25.2 mmol) in THF (20 mL) at 0° C. to 5° C. was added 3.78 g (22.2 mmol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine, followed by a 5 mL THF rinse. To this solution was added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF. Following a 5 mL THF rinse, 0.5 mL of water was added, and the reaction mixture was allowed to warm to 20° C. with stirring. After 6 hours, the reaction was cooled to 10° C. and quenched with water (55 mL). The THF was removed under reduced pressure, MTBE (50 mL) was added, and the biphasic solution was adjusted to pH 9.0 with 4 N HCl. The layers were separated and the aqueous layer was washed with an additional 50 mL of MTBE. The aqueous layer was stirred with 130 mL of toluene and adjusted to pH 3 with 4 N HCl, and the phases were separated. The aqueous, product-containing layer was stirred with 50 mL of toluene and adjusted to pH=3.0 with 4 N HCl. The aqueous layer was separated and extracted once more with 50 mL of toluene. The combined organic extracts were concentrated in vacuo. The residue obtained was redissolved in toluene, filtered and rinsed with toluene (approx. 50 mL total). The combined filtrates were concentrated in vacuo to an oil. Toluene (25 mL) and heptane (25 mL) were aded and warmed to 50° C. The clear solution was allowed to cool until cloudy and then was seeded with N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-Valine. The resulting slurry was stirred for at least 12 hours and the product was collected by filtration and washed with heptane (5 mL). The resulting solid was dried in a vacuum oven at 50° C. to yield the desired product as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C#Cc1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccc(OC)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized from (4-methoxy-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in a 88% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.32 (m, 2H), 7.21 (m, 1H), 7.11-6.85 (m, 6H), 6.70 (m, 1H), 6.50 (m, 1H), 6.13 (s, 0.5H), 6.03 (s, 0.5H), 4.40 (m, 2H) 4.10 (q, 2H, J=7.2 Hz), 3.86 (s, 1.5H), 3.83 (s, 1H), 3.76 (t, 2H, J=5.2 Hz), 3.70 (t, 2H, J=6.0 Hz), 3.20 (t, 2H, J=6.8 Hz), 2.70 (t, 2H, J=6.8 Hz, J=6.8 Hz), 1.90 (m, 2H), 1.49 (s, 9H), 1.23 (t, 1.5H, J=7.2 Hz), 1.18 (t, 1.5H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C30H32N3O4 498.2 (M-Boc+H); found 498.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:11]([CH2:17][CH2:18][OH:19])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C@H:11]([CH2:17][CH2:18][O:19][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[O:10][C:9]1([CH3:20])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H]1[C@H](CCO)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
200 mg of the compound obtained in Example 10 was dissolved in 2 ml of dry methylene chloride, and 115 μl of triethylamine and 152 mg of tosyl chloride were added thereto. The mixture was stirred at room temperature overnight. Then, 115 μl of triethylamine was further added, and the mixture was reacted at room temperature and then evaporated to dryness under reduced pressure. A solution mixture of benzene/ethyl acetate (30/1) was added to the residue. After filtering insolubles off, the filtrate was purified by silica gel column chromatography to obtain 281 mg of (4S,5S)-3-tert-butyloxycarbonyl-2,2-dimethyl-5-(2-p-toluenesulfonyloxyethyl)-4-isobutyloxazolidine as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10]COC)[C:7]([CH2:14][CH:15]=[CH2:16])=[C:6]([O:17]COC)[CH:5]=1.Cl>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[C:6]([OH:17])[C:7]([CH2:14][CH:15]=[CH2:16])=[C:8]([OH:10])[CH:9]=1
Reactant: C=CCc1c(OCOC)cc(C(=O)OC)cc1OCOC
Agent: Cl
Solvent: CO
Product: C=CCc1c(O)cc(C(=O)OC)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 4-allyl-3,5-bis-methoxymethoxy-benzoic acid methyl ester (10a) (513 mg, 1.73 mmol) in MeOH (4 mL) was added 4N HCl (4 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with H2O (80 mL) and extracted with EtOAc (2×80 mL). The organic layers were dried over MgSO4 and concentrated to give yellow oil which was purified by flash column chromatography eluting with 15-25% EtOAc in hexanes to give a pale yellow solid (285 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 2 H) 5.95-6.06 (m, J=5.31, 5.31 Hz, 1 H) 5.76-5.82 (m, 2 H) 5.15-5.20 (m, 1 H) 5.12-5.15 (m, 1 H) 3.90 (s, 3 H) 3.50-3.55 (m, 2 H); LCMS for C11H12O4S m/z 209.10 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)=[N:3]1.[Br:24]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Br:24][C:5]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1nc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Br)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 21 h
Yield: 77.5 %

Procedure:
4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-o-dinitrobenzene (17.7 g, 54.9 mmol) was dissolved in a mixture of glacial acetic acid (90 cm3) and acetic anhydride (10 cm3) and the solution was warmed to 80° C. N-Bromosuccinimide (14.7 g, 82.4 mmol) was added, and the mixture was stirred at 80° C. for 21 hours, and then cooled to room temperature. The precipitate was collected, washed with water, and then taken up in ethyl acetate (500 cm3). The solution was washed with saturated sodium bicarbonate solution (2×300 cm3), dried (MgSO4), filtered and evaporated under reduced pressure to give 4-(4-bromo-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-o-dinitrobenzene (17.5 g) as a colourless solid m.p. 152°-153° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[F:25])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:14]2[CH:13]=[CH:12][C:11]([F:25])=[C:10]([CH:15]=2)[CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1F)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(F)c(CP(=O)(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a solution of [5-(4-ethylbenzyl)-2-fluorobenzyl]phosphonic acid diethylester (0.70 g) in dichloromethane (12.0 mL) was added bromotrimethylsilane (1.2 mL) at 0° C., and the reaction mixture was stirred for 18 hr at room temperature. Methanol (7.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate-n-hexane to give the title compound (0.53 g) as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:37]CC1C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:37][C@H:13]([C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NCC1c2ccccc2-c2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
6-tert-butoxycarbonylamino-2-(S)-(9H-fluoren-9-yl)methylamino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)hexanamide (Compound III-13) 19.9 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 11.1 g, (yield 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([C:23]5[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[N:27][CH:28]=5)[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1CCOC1
Product: CN1C[C@H]2CCN(c3ccc(N4CCN(c5ccc(C#N)nc5)CC4)cc3)[C@H]2C1
Temperature: 120 °C

Procedure:
The product of Example 75A (78.0 mg, 0.27 mmole), 5-bromo-2-cyanopyridine (74.8 mg, 0.41 mmole), palladium acetate (2.5 mg, 0.011 mmole), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19.0 mg, 0.037 mmole), cesium carbonate (142.1 mg, 0.44 mmole) and 3 ml of tetrahydrofuran were mixed under N2 in a Emrys process vial. The vial was sealed and heated in the microwave for 2 hours at 120° C. using the Emrys Creator. The mixture was diluted with water and extracted with dichloromethane (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.36 (d, J=2.71 Hz, 1H) 7.53 (d, J=8.82 Hz, 1H) 7.13 (dd, J=8.82, 3.05 Hz, 1H) 6.86-6.98 (m, 2H) 6.50-6.65 (m, 2H) 4.06 (t, J=8.65 Hz, 1H) 3.44-3.59 (m, 5H) 3.11-3.24 (m, 5H) 2.88-3.02 (m, 1H) 2.56-2.72 (m, 4H) 2.33 (s, 3H) 2.06-2.24 (m, 1H) 1.83-2.01 (m, 1H). MS: (M+H)+=389.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[N:12]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:18]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(-n2ccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-n2ccnc2)c1
Temperature: 110 °C
Yield: 19.1 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitropyridine (4.1 g, 17 mmol), 3-(imidazol-1-yl)phenylamine (2.5 g, 16 mmol) and potassium carbonate (1.3 g, 9.4 mmol) in N,N-dimethylformamide (15 ml) was heated at 110° C. for 2 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate (100 ml) and methanol (100 ml) then pre-adsorbed on to silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/0.880 NH3 (97:2.7:0.3) gave N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(imidazol-1-yl)phenyl]amine as a red solid (1.1 g, 19%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[CH:11][C:10]=1[NH:23][C:24](=[O:41])[C:25]1[CH:30]=[CH:29][C:28]([C:31](=[NH:40])[NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[O:41])=[CH:30][CH:29]=1)(=[NH:32])[NH2:40]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)Nc2cc(C(=O)NCCC(=O)O)ccc2OCc2ccccc2)cc1
Solvent: O=CO
Product: N=C(N)c1ccc(C(=O)Nc2cc(C(=O)NCCC(=O)O)ccc2OCc2ccccc2)cc1
Yield: 95.7 %

Procedure:
173 mg of N-[4-(benzyloxy)-3-[p-[N-(t-butoxycarbonyl)amidino]benzamido]benzoyl]-β-alanine in 4 ml of formic acid are stirred at 20° C. for 4 hours. The reaction mixture is evaporated in a vacuum, the residue is suspended in water and adjusted to pH 8-9 with ammonia. After stirring for a short time the mixture is suction filtered, the filter residue is washed with water and dried at 50° C. in a vacuum. There are obtained 136 mg of N-[3-(p-amidinobenzamido)-4-(benzyloxy)benzoyl]-β-alanine, m.p. >250° C., MS: 461 (41, M+H), as a hydrate (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7][CH2:6]2.C([Li])(CC)C.B(OC)(OC)[O:19]C.OO.[Cl-].[NH4+]>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[OH:19]
Reactant: COc1ccc2c(c1)CCCC2
Reactant: COB(OC)OC
Agent: OO
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1O)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a well-stirred solution of 6-methoxy-1,2,3,4-tetrahydronapthalene (14.05 g, 86.67 mmol) in sec-butyllithium (100 mL, 110 mmol) at 0° C., under nitrogen, was added freshly distilled N,N,N′,N′-tetramethylethylenediamiene (13.61 mL) dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. Then, the reaction mixture was cooled again to 0° C. and trimethyl borate (12.55 mL, 110 mmol) was added dropwise and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was cooled back to 0° C. and 7 mL of glacial acetic acid was added dropwise, the reaction mixture was let to cool to 0° C. and then 35% wt. hydrogen peroxide in water (15 mL) was added dropwise. The reaction mixture was then allowed to stir at room temperature for 12 h. Saturated ammonium chloride (100 mL) was added. The organic phase was separated and collected, and the aqueous phase was extracted with ether. The combined organic phases were washed with brine (if necessary) and dried over anhydrous sodium sulfate, filtered, concentrated in vacuo. Purification by flash column chromatography (silica gel, 2:98 EtOAc:Hexanes) yielded 3.5 g (23%) of 33 along with 9.7 g (63.1%) of 7-hydroxy-6-methoxy-(1,2,3,4-tetrahydro)naphthalene (obtained in 5:95 EtOAc:Hexanes). Rf value for 33 is 0.48 (15:85 EtOAc:Hexanes), for 7-hydroxy-6-methoxy-1-tetrahydronapthalene 0.37.