Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([I:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:39])[C@@H:28]([NH:38][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([I:37])[CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(I)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(I)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(4-chloro-3-iodo-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C, to afford title compound. HPLC: RT=10.87 min. MS (ESI+): mass calcd. for C23H17ClI2N4O5S2, 782.80; m/z found, 783/785 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.31 (s, 1H), 8.37 (dd, J=7.0, 0.9, 1H), 8.23 (dd, J=8.8, 0.9, 1H), 8.09 (d, J=1.5, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.55 (d, J=2.0, 1H), 7.35-7.33 (m, 2H), 7.00-6.94 (m, 2H), 6.46 (d, J=7.1, 1H), 4.97-4.91 (m, 1H), 3.82 (s, 3H), 3.21-3.10 (m, 2H).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.C[O:15][C:16](=[O:19])[CH2:17][NH2:18].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([NH:18][CH2:17][C:16]([OH:19])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CN
Reactant: CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of decanoyl chloride (5) (2.7 mL, 13 mmol, 1.0 eq) in methylene chloride (20 mL) in an ice/acetone bath was added a mixture of glycine methyl ester hydrochloride (91) (2.0 g, 16 mmol, 1.2 eq) and DIPEA (5.1 mL, 29 mmol, 2.2 eq) in methylene chloride (20 mL) dropwise. The reaction was stirred a further 60 min after complete addition, then washed with 3N hydrochloric acid (50 mL) twice, followed by saturated sodium bicarbonate (50 mL). The organics were dried over magnesium sulfate and the solvents removed under reduced pressure. n-Decylglycine, a compound of formula (96) (3.0 g, 12 mmol, 95%) was obtained, and used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:31]2[CH2:32][CH2:33][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[N:3]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, brownish powder; MS: [M+H]+=430.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[N:16]([C:20]3[C:29]([N+:30]([O-])=O)=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:33])[CH:21]=3)[CH:17]=[CH:18][N:19]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:30][C:29]1[C:20]([N:16]2[CH:17]=[CH:18][N:19]=[C:15]2[C@H:12]2[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10][CH2:11]2)=[CH:21][C:22]([CH3:33])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(-n2ccnc2[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1C
Reaction time: 8 h

Procedure:
To a solution of 1.05 g of the yellow solid having methyl 4-[2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-imidazol-1-yl]-2-methyl-5-nitrobenzoate obtained as a low-polarity compound in 15 mL of methanol was added 0.40 g of 10% palladium on carbon (50% wet), followed by stirring overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 0.62 g of methyl 5-amino-4-[2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-imidazol-1-yl]-2-methylbenzoate as a yellow oily substance.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=[O:26])[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[Si]([N:38]=C=O)(C)C.CO>C(OCC)(=O)C>[C:25]([N:22]1[CH2:23][CH2:24][C@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:20]([O:32][CH3:33])[CH2:21]1)(=[O:26])[NH2:38]
Reactant: C[Si](C)(C)N=C=O
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (30 ml, 120 mmol) was added to a solution of tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (103a) in ethyl acetate (10 mL). The mixture was stirred for 45 minutes and the solvent was evaporated under reduced pressure. The residue was diluted with dichloromethane, washed with a 1 N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Trimethylsilyl isocyanate (0.86 g, 7.5 mmol) was added to the resulting residue, and the mixture was stirred at room temperature for 15 hours. Methanol (1 mL) was added, followed by stirring for 30 minutes. The precipitated solid was filtered off and washed with dichloromethane to obtain 1.44 g of the title compound as a colorless solid (81%).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=C1)(C)C.[NH:30]1C=CC(B(O)O)=N1>>[NH:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[N:30]1
Reactant: OB(O)c1cc[nH]n1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Product: CCOC(=O)c1cn2cc(-c3cc[nH]n3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with pyrazole-3-boronic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([O:16][CH3:17])[CH2:12][CH2:11]2)[C:3]=1[NH2:18].C1C[O:22][CH2:21]C1>>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:18][C:21](=[O:22])[N:9]2[C@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][CH3:17])[CH2:14][CH2:15]2)=[C:2]([Cl:1])[N:7]=1
Reactant: CO[C@H]1CC[C@H](Nc2nc(N)nc(Cl)c2N)CC1
Reactant: C1CCOC1
Product: CO[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(N)nc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-chloro-N4-(trans-4-methoxycyclohexyl)pyrimidine-2,4,5-triamine (5.5 g, 20.36 mmol) in 300 mL of anhydrous THF (use oven dried glassware) was added 1,1-carbonyldiimidazole (newly opened bottle, 19.8 g, 122.2 mmol, 6 equiv.) as a solid, in portions. The reaction mixture was stirred at room temperature for 2 h (completion of the reaction checked by HPLC and MS). The solvent was removed in vacuo. Water (250 mL) was added to the residue and the mixture stirred at room temperature for 10 min. The solid formed was filtered under vacuum, washed with cold water and thoroughly dried to give the desired product as a brown solid (67% yield), which was used in the next step without further purification. MS (EI) m/z 298 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2Cl)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O.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>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2Cl)c1
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(NC(=O)c2cccnc2-c2cccc(F)c2)c1
Temperature: 90 °C
Yield: 99.2 %

Procedure:
To a mixture of N-(3-tert-butylphenyl)-2-chloronicotinamide (570.2 mg, 2 mmol), 3-fluorophenylboronic acid (401.2 mg, 2.8 mmol), 3 mL of toluene, and 1 mL of 2 N potassium carbonate in water was added tetrakis(triphenylphosphine)palladium(0) (234.5 mg, 0.2 mmol). The mixture was then heated at 90° C. for 3 hour under nitrogen, before it was cooled down to room temperature. The reaction mixture was then diluted with 30 mL of water and 150 mL of EtOAc. The organic layer was separated, washed with brine, and dried (Na2SO4). The organic solvent was removed under reduced pressure and the residue was purified by silica gel column (40% EtOAc in hexane) to give N-(3-tert-butylphenyl)-2-(3-fluorophenyl)nicotinamide (691.4 mg, 99%). MS: (ES) m/z 394.5 (M+H+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Br:24])[NH2:20].[CH:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CO>[CH2:27]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Br:24])=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CCCCCCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCNc1ccc(Br)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 53 %

Procedure:
Sodium triacetoxyborohydride (4 g) was added to a solution of 3-trifluoromethyl-4-bromoaniline (1.5 g) and decanal (4 mL) in methanol (90 mL). After stirring for 1 h the solution was partitioned between water and petroleum ether. The organic extract was concentrated under reduced pressure and the residue was purified via flash column chromatography using petroleum ether as eluent to give N-Decyl-4-broma-3-trifluoromethylaniline (4) (1.2 g, 53%). 1H NMR (CDCl3) δ 7.44 (d, 1H, ArH); 6.92 (d, 1H, ArH); 6.61 (dd, 1H, ArH); 3.11 (t, 2H, NCH2); 0.80 (t, 3H, CH2CH3). TLC (silica gel): Rf=0.35 (petroleum ether).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=C(C)C=CC=2)=CSC=1[C:36](OC)=[O:37].[CH:40](OCC)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:36][O:37][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[C:19]([CH3:40])[CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1scc(-c2cccc(C)c2)c1N
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4cccc(C)c4)csc3c2=O)cc1
Yield: 32.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(m -tolyl)thiophene-2-carboxylate (80 mg, 0.32 mmol), triethyl orthoformate (0.7 ml), p-anisidine (74.1 mg, 0.6 mmol), and acetic acid (0.1 ml) were used to give 36.5 mg (0.11 mmol, 32.7% yield) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18](S(C)(=O)=O)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)n1c(-c2ccc(OCCCN3CCCCC3)cc2)cc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2[nH]c(-c3ccc(OCCCN4CCCCC4)cc3)cc2c1
Temperature: 40 °C
Reaction time: 48 h
Yield: 11.1 %

Procedure:
A solution of the product from Step F, Example 1 (41.4 mg, 0.10 mmol) in methanol (2.0 mL) was treated with potassium hydroxide (1.0 mL, 40% aq). The reaction was stirred at 40° C. for 48 hours and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol:dichloromethane) to provide pure title compound (3.7 mg). MS (ESI) m/z 335 (MH+); 1H-NMR (CDCl3) δ 8.19 (bs, 1H), 7.48 (d, 2H), 7.27 (m, 2H), 7.07 (t, 1H), 7.00 (t, 1H), 6.86 (d, 2H), 6.61 (s, 1H), 3.96 (t, 2H), 2.5 (m, 6H), 1.4 (m, 8H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)C1(Cc2ccc3ccccc3c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccc3ccccc3c2)CCNCC1
Reaction time: 8 h

Procedure:
The above ester was dissolved in ethyl acetate and the solution was treated with gaseous hydrogen chloride at 0° C. for 2 h. After standing overnight the solvent was evaporated in vacuo and the residue was treated with ammonium hydroxide and extracted with diethyl ether. The organic phase was dried (K2CO3) and the solvent was evaporated affording ethyl 4-(2-naphtylmethyl)-4-piperidinecarboxylate (3.2 g).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([O:19]C(C)(C)C)=O)[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:39](=[O:48])([O:44][CH:45]([CH3:47])[CH3:46])[O:40][CH:41](Cl)[CH3:42].[NH:49]1[CH:53]=[C:52](C(O)=O)[N:51]=[N:50]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(N(C)C)=O>[CH:45]([O:44][C:39]([O:40][CH:41]([O:13][C:11](=[O:12])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:53]1[NH:49][N:50]=[N:51][CH:52]=1)=[O:19])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)[CH3:42])=[O:48])([CH3:47])[CH3:46]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O
Reactant: CC(C)OC(=O)OC(C)Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OC(C)OC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
(2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (50 mg, 120 μmol, 1.0 eq.), DMA (1 mL), DIPEA (0.13 mL) and 1-chloroethyl isopropyl carbonate (83 mg, 0.5 mmol, 4.0 eq.) were combined. The reaction vessel was capped and microwaved at 80° C. for 2 hours. The mixture was dried under vacuum, dissolved in MeCN (2 mL), and combined with 4 M of HCl in dioxane (500 μL). The resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and discarded, and the filtrate containing the intermediate was concentrated down and submitted to the next step. 1,2,3-Triazole-4-carboxylic acid (14 mg, 120 μmol, 0.5 eq.) and HATU (48 mg, 120 μmol, 1.0 eq) were dissolved in DMF (1 mL) and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (44 μL) and the intermediate from last step. The mixture was stirred for 5 minutes. The reaction was quenched with water and the product dried under vacuum. The product was then purified by preparative HPLC to yield the title compound (6 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H32N4O7, 525.23. found 525.4.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10](OC)=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.S1C2C=C[N:20]=CC=2C=C1CN>>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][NH2:20])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2ncsc2c1
Reactant: NCc1cc2cnccc2s1
Agent: Cl
Product: NCc1ccc2ncsc2c1

Procedure:
Intermediate T was prepared from methyl benzo[d]thiazole-6-carboxylate (T-2) following similar procedures for synthesizing intermediate D from D-2, as described above. MS (m/z): 165 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:36][C:37](=[O:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:9]2[CH:13]=[CH:14][S:15][C:8]=2[C:7]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:23])[CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2[nH]c1=O
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2sccc2n(CC(=O)c2ccccc2)c1=O
Temperature: 0 °C

Procedure:
A solution of 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (5) (750 mg, 1.79 mmol), Cs2CO3 (1.76 g, 5.40 mmol), 2-chloroacetophenone (0.333 g, 2.15 mmol) in dry NMP was heated overnight at 90° C. The solution was poured into ice water and the solids formed were filtered, washed by cold water, and dried. The crude product was purified by recrystallization with acetone. MP 240° C. 1H-NMR (DMSO-d6) δ 1.26 (t, J=7.2 Hz, 3H), 3.39 (m, 4H), 3.83 (m, 4H), 4.23 (q, J=7.2 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 5.75 (s, 2H), 7.16 (m, 1H), 7.34 (d, J=5.6 Hz, 1H), 7.50 (dd, J=1.2, 3.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 2H), 7.74 (m, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.01 (d, J=7.0 Hz, 1H), 8.10 (m, 2H); EIMS m/z 536(M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][S:19][C:13]=2[N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:11]1=[O:29].[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=[O:41])=[CH:32][CH:31]=1>C1COCC1>[OH:41][CH:40]([C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1)[C:18]1[S:19][C:13]2[N:12]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:11](=[O:29])[N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[C:17]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: O=Cc1ccnc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(O)c2ccnc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide (5.52 g) in anhydrous THF (80 ml) was added dropwise over 1 h to a stirred solution of the product of step c) (8.02 g) and 4-quinolinecarboxaldehyde (8.12 g) in anhydrous THF (80 ml) at −78° C. under nitrogen. The mixture was stirred for a further 1 hour at −78° C. then quenched with glacial acetic acid (10 ml), allowed to warm to room temperature, diluted with saturated sodium bicarbonate solution (100 ml) and extracted into ethyl acetate (2×100 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with 3:2 ethyl acetate/i-hexane, to give the sub-title compound as a white solid (7.35 g). MS(ESI) 468 {M+H]+. δ 1HCDCl3 0.85 (3H,d), 0.88 (3H,d), 1.43 (3H,t), 2.10-2.16 (1H,m), 3.38 (3H,s), 3.49 (1H,dd), 3.61 (1H, s,br), 3.71 (1H,dd), 4.48 (2H,quartet), 6.78 (1H,s), 7.52 (1H,t), 7.72 (1H,t), 7.83 (1H,d), 7.90 (1H,d), 8.17 (1H,d), 9.02 (1H,d)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.18 g, 4.98 mmol) in dichloromethane (40 ml) was added DIPEA (2.70 ml, 15.45 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.613 g, 4.98 mmol). The reaction mixture was stirred for 1 h 20 min at room temperature. The reaction mixture was then washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum to give the crude title compound (2.5 g) which was used directly in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:30])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([CH3:28])[CH2:23]4)=[C:17]([F:29])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([CH3:28])[CH2:23]2)=[C:17]([F:29])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:30])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(C)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CN(c2c(F)cc3cc4c(=O)c(C(=O)O)cn(C)c4nc3c2F)CCN1
Yield: 64.3 %

Procedure:
A suspension of 1.5 g of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 20 cm3 of ethanol and 20 cm3 of N aqueous potassium hydroxide solution is heated at a temperature close to 75° C. for 1 hour and a half. 12 g of a 10% aqueous solution of acetic acid is added to the solution obtained, at this latter temperature. The insoluble matter obtained is drained at about 75° C. and washed 3 times with 30 cm3 of water at about 20° C. After recrystallizing once from 100 cm3 of dimethylformamdide, 0.9 g of (RS)-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 380°-382° C.