Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:35])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].Cl>O1CCOCC1>[ClH:34].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:35])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(Cl)ccc3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(Cl)ccc3[nH]2)o1
Reaction time: 16 h
Yield: 137 %

Procedure:
210 mg of 6-tert-butyloxy-9-[5-(5-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (example 130) are dissolved in 1.4 ml of dioxane and combined with 1.415 ml of 4N HCl in dioxane. The reaction mixture is stirred for 16 hours at room temparature. The formed insoluble material is then collected by filtration, washed with 2×1 ml of dioxane and 2×1 ml of diisopropylether. The residue is then purified on a silica gel column (12 g) eluted with a mixture of dichloromethane and methanol (95/5, v/v). The fraction containing the expected product are concentrated under reduced pressure to yield 135 mg of 9-[5-(5-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride as an orange powder. Yield=77%. Analytical LC/MS (method B): m/z=508 (negative ion mode, [M−H]−, 1 Cl present), m/z=510 (positive ion mode, [M+H]+)
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].C(N(C(C)C)CC)(C)C.[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:3]1[N:2]=[N:1][C:5]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[N:4]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1nn[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.9 %

Procedure:
To a solution of 2-[4-(2H-tetrazol-5-yl)-butyl]-isoindole-1,3-dione (4.07 g, 15.0 mmol) and diisopropylethylamine (7.8 mL, 45.0 mmol) in DCM (60 mL) was added trityl chloride (5.86 g, 21.0 mmol). The solution was stirred at ambient temperature for 14 h, and concentrated. The resulting residue was partitioned between EtOAc/DCM (3:1) and H2O. Organic layer was separated, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with DCM/hexane (40, 80, and 100%) followed by EtOAc/DCM (1 and 2%) to give the title compound (5.08 g, 66% yield) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([N+]([O-])=O)=[N:10][O:9][N+:8]=2[O-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].C(N(CC)CC)C>CO>[C:1]1([C:7]2[C:11]([S:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])=[N:10][O:9][N+:8]=2[O-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1no[n+]([O-])c1-c1ccccc1
Reactant: COC(=O)CS
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CSc1no[n+]([O-])c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4.6 g of 3-phenyl-4-nitrofuroxan, 2.4 g of methyl thioglycolate and 2.2 g of triethylamine in 50 ml of methanol is stirred under a nitrogen atmosphere. In the course of this, the mixture warms to about 40° C. After 1 hour, it is poured into ice-water, whereupon a solid separates after stirring briefly, which is filtered off with suction and recrystallised from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH3:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:10])[C:3]=1[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)cccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(Cl)c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To 100 ml DMF, was dissolved 3-chloro-o-cresol in an amount of 13.6 g (0.095 mole), and the resulting solution was then stirred for 2 hours at 80° C. following to the addition of potassium carbonate in an amount of 14.5 g (0.105 mole) and methyl iodide in an amount of 17.6 g (0.124 mole) into the solution at an ambient temperature. After cooling the mixture, insoluble materials therein were separated by filtration, and the mixture was then poured into water and extracted with ethyl ether. The organic layer obtained was washed with saturated saline solution and dried with anhydrous magnesium sulfate, and the solvent remained in the layer was distillated out to obtain 2-chloro-6-methoxytoluene in an amount of 14.6 g. The yield was 95.4%.
Reaction SMILES: [Li].[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:7][CH2:6][CH2:5][O:4]1.O1CCC[CH2:15]1.C[Li]>C(OCC)C>[CH3:2][C:3]1([CH2:8][CH2:9][CH2:10][C:11](=[O:13])[CH3:15])[O:4][CH2:5][CH2:6][O:7]1
Reactant: C1CCOC1
Reactant: CC1(CCCC(=O)O)OCCO1
Agent: [Li]
Agent: [Li]C
Solvent: CCOCC
Product: CC(=O)CCCC1(C)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
348 Mg. of the lithium salt of the ketal acid, 4-(2-methyl-1,3-dioxolan-2-yl)butanoic acid was dissolved in 5 ml. anhydrous tetrahydrofuran. The solution was cooled to 0° C and 1.25 ml. of a 1.6 molar solution of methyllithium in diethylether was added dropwise over a period of one hour while stirring under a nitrogen atmosphere. The solution was allowed to rise approximately to 20° C and kept at this temperature over a period of two hours. The reaction mixture was added to crushed ice and the organic solvents were removed in vacuo. The residue was extracted with ether, the extract was washed with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated in vacuo to give crude 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:4].[C:17]1([CH2:23][CH2:24]O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[CH:9]=[C:10]([O:15][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[CH:14]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(O)cc2oc1=O
Reactant: OCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(OCCc3ccccc3)cc2oc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.6g, 3 mmol) and 2-phenyl ethanol (0.36 mL, 3 mmol) are dissolved in anhydrous tetrahydrofuran (60 mL). Triphenylphosphine (1.2 g, 4.5 mmol) is added, and diethyl azodicarboxylate (0.72 mL, 4.5 mmol) is added dropwise and slowly at 0° C. The resulting solution is stirred for 24 hours at room temperature. After the solvent was removed under reduced pressure, the residue is diluted with methanol and a white solid is separated out. The solid is recrystallized with methanol to give 0.45 g of the captioned compound, yield: 46.3%. m.p. 100-101° C. 1H NMR(CDCl3): δ=3.12(t, J=6.8 Hz, 2H), 3.92(s, 3H), 4.14(t, J=7.1 Hz, 2H), 6.79(d, J=2.4 Hz, 1H), 6.88(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.21-7.35(m, 5H), 7.47(d, J=8.7 Hz, 1H), 8.50(s, 1H); Element Anyalysis, C19H16O5 (324): Calculated C, 70.37; H, 4.94. Found C, 70.25; H, 4.93; IR(KBr) :3045.1, 2952.5, 1751.1, 1693.2, 1610.3, 1554.4, 1506.2, 1436.7, 1375, 1307.5, 1222.7, 1114.7, 1018.2, 835, 749.5, 738.6, 700, 594 cm−1; EI-MS(m/z): 324(24, M+), 105(100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:21]=O>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc2c(c1)CNCC2c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CN(C)CC2c1cccc(Cl)c1

Procedure:
The free base isolated from 8.0 g. of rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is taken up in 150 ml. of methanol, 6 ml. of a 35% formaldehyde solution are added and the mixture is shaken until the precipitate formed again completely dissolves. The mixture is thereupon hydrogenated over 6 g. of Raney nickel, filtered and, after acidification with ethanolic hydrogen chloride, crystallized. Recrystallization from methanol-ether gives rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, m.p. 250°-251°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>O1CCCC1>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-4-nitroaniline (5.00 g, 32.9 mmol) and pyridine (7.97 ml, 98.6 mmol) in tetrahydrofuran (100 ml) was added acetyl chloride (3.51 ml, 49.4 mmol) with ice-cooling, the mixture was stirred for 3 hours with ice-cooling, the reaction mixture was poured into ice-water and the desired product (2.60 g, 40.7%) as a solid was collected by filtration.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN[C@@H]1CCCC[C@H]1NC>[Al].[Cu]I.C1(C)C=CC=CC=1>[C:23]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(-c2ccccc2)c2ccccc12
Temperature: 110 °C

Procedure:
A 5 mL screwtop vial containing methyl 1H-indole-3-carboxylate (100 mg, 0.571 mmol) and potassium phosphate (254 mg, 1.199 mmol) was degassed and purged with nitrogen after the addition of each of the following in sequential order: PhMe (1142 μl), bromobenzene (59.7 μl, 0.571 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (54.4 μl, 0.342 mmol), and copper(I) iodide (32.6 mg, 0.171 mmol). The vial was sealed, wrapped in aluminum foil, and heated to 110° C. for 24 h. Concentration on silica gel and ISCO purification (20% EtOAc/hexanes) gave the title compound as a white solid.
Reaction SMILES: CI.[Mg].[CH2:4](OCC)C.[ClH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:15]3[CH2:27][N:28]([CH2:30][CH2:31][CH2:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH2:29][C:14]=3[C:13]=2[CH:12]=1>O.O1CCCC1>[ClH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:15]3[CH2:27][N:28]([CH2:30][CH2:31][CH2:32][C:33]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)([OH:41])[CH3:4])[CH2:29][C:14]=3[C:13]=2[CH:12]=1
Reactant: O=C(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Reactant: CCOCC
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A methyl Grignard reagent prepared from 852 mg. (6 m moles) of methyl iodide and 144 mg. (6 m mole) of magnesium in 40 ml. of diethyl ether is divided into equal portions. To one-half is added portionwise 500 mg. (1.1 m moles) of 7-fluoro-4-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrochloride in 20 ml. of tetrahydrofuran, and the mixture allowed to stir for 1 hour. To the mixture is then added the other half of the Grignard solution, and stirring maintained for 30 min. The mix is poured into ice and water and extracted with ether. The combined ether extracts are dried over magnesium sulfate, concentrated to dryness, and the residue chromatographed on 20 g. of silica gel using 3:1 diethyl ether-ethanol as the eluate, each collecting fractions being 3 ml. Fractions 10-27 are combined and converted to the hydrochloride salt, 180 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29]([C:28]2[CH:32]=[CH:33][C:25]([C:23]([NH:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[O:24])=[N:26][CH:27]=2)=[O:30])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccn2)nc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)NCc2ccccn2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to pyridin-2-ylmethanamine via Procedure G. Crude methyl 6-(pyridin-2-ylmethylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-dicarboxamide. MS (Q1) 444.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].[CH2:20]([NH:22][C:23](=[O:43])[NH:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[C:27]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:26]=1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:28]3[CH:29]=[N:30][C:25]([NH:24][C:23](=[O:43])[NH:22][CH2:20][CH3:21])=[CH:26][C:27]=3[C:34]3[S:35][CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[N:38]=3)=[CH:11][N:10]=2)[C:5](=[O:19])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]1)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2ncc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3CC)cn1
Temperature: 85 °C
Yield: 20.6 %

Procedure:
In a round bottomed flask, ethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 15, 400 mg, 1.3 mmol), 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 700 mg, 1.72 mmol) and cesium carbonate (3.78 g, 2.46 mmol) were combined and suspended in 10 mL of dioxane:water (8:2). The suspension was purged with argon for 15 min. then tetrakis (triphenylphosphine) palladium (140 mg, 0.2 mmol) was added under argon atmosphere and the reaction mixture was heated to 80-90° C. for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to a residue, to which acetonitrile was added. The precipitated solid was filtered and dried to afford 150 mg (25%) of ethyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][S:18][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:8]2[C:9](=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=2[OH:28])[S:18][N:19]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccccc3F)c2c1O
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-7-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 422.0 (M−1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCc2cccc(C(F)(F)F)c2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 1-[3-(trifluoromethyl)phenyl]methanamine (45.58 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 75 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.06 (s, 9H), 3.56 (s, 2H), 4.61 (s, 2H), 7.16 (t, J=75.3 Hz, 1H), 7.18-7.25 (m, 1H), 7.36-7.51 (m, 2H), 7.57-7.65 (m, 3H), 7.71-7.77 (m, 2H), 7.83 (d, J=15.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.82-8.88 (m, 1H); APCI-MS (m/z) 580.29 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH2:24][CH3:25])=[C:15]([NH:17]C(=O)C(C)(C)C)[CH:16]=3)[N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[C:35]([C:40]([F:43])([F:42])[F:41])=[N:36][CH:37]=[CH:38][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)C>[CH2:24]([C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[C:35]([C:40]([F:43])([F:42])[F:41])=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:7][N:6]3[CH:8]=2)=[CH:16][C:15]=1[NH2:17])[CH3:25]
Reactant: CC1(C)OB(c2cccnc2C(F)(F)F)OC1(C)C
Reactant: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC(C)O
Product: CCc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1N
Temperature: 60 °C
Yield: 75.3 %

Procedure:
A 250 mL flask is charged with N-(5-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-ethylphenyl)pivalamide (2.45 g, 0.00686 mol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (2.34 g, 0.00857 mol), K2CO3 (2.37 g, 0.0171 mol), palladium(II)acetate (0.154 g, 0.686 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.563 g, 0.00137 mol), isopropanol:water (150 mL, 3:1). The mixture is stirred and heated at 60° C. for 6 hr. The mixture is concentrated to dryness, crude product taken up in EtOAc (100 mL), washed with water (50 mL), organic collected and concentrated onto celite and purified by silica gel chromatography (0-75% EtOAc in CH2Cl2). Intermediate is taken up in EtOH (100 mL) and conc. HCl (90 mL) is added. The reaction mixture is heated to reflux for 18 hrs. Reaction is concentrated, taken up in EtOAc (100 mL), washed with 100 mL Sat. NaHCO3. Compound is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (1.98 g, 75% over two steps). LCMS m/z=384.4, 385.4 [M+H]+, tR=2.59 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([NH:25][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NC1CCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NC2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cycloheptylamine (57 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (20 mg) and a syn-form compound (31 mg).
Reaction SMILES: [C:1]([N:4]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])(=[O:3])[CH3:2].[NH2:26][C@H:27]([C:30]([O:32]CC)=[O:31])[CH2:28][OH:29].[OH-].[K+]>C(O)C>[C:1]([N:4]([CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:26][C@H:27]([C:30]([OH:32])=[O:31])[CH2:28][OH:29])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCCC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)CO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N(CCCCCC(=O)N[C@@H](CO)C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-6-benzhydrylaminocaproic acid and ethyl L-serinate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-(N-acetyl-6-benzhydrylaminohexanoyl)-L-serine.