Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (2:1) (5.0 g, 29 mmol) and imidazole (4.4 g, 64 mmol) in N,N-dimethylformamide (90 ml) was added trimethylsilyl chloride (4.0 ml, 32 mmol) at 0-5° C. Stirring for 1 h at room temperature was followed by partitioning between tert-butyl methyl ether (300 ml) and water (150 ml). The layers were separated. The organic layer was washed with two 150-ml portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.7 g, 94%) as colorless oil. MS m/e: 245 ([M+H]+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=2)=[CH:5][N:6]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)=[N:6][CH:5]=2)=[CH:8][C:9]=1[F:15])#[N:12]
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1F
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)c(F)c3)o2)c1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)-2-fluorobenzonitrile 39 (0.225 g, 1.01 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.188 g, 1.01 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Reaction mixture was evaporated and crude product was purified using MPLC (Biotage) silica column (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-cyano-3-fluorophenyl)oxazol-2-yl)amino)phenyl)methane sulfonamide 40 (0.319 g, 84% yield) as a solid. MS (ES) m/z 373 (M+H+).
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.Cl.[O:20]1[C:24]([CH2:25][S:26][CH2:27][CH2:28]N)=[CH:23][CH:22]=[CH:21]1.[O-]CC.[Na+]>C(O)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:24]1[CH2:25][S:26][CH2:27][CH2:28][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: NCCSCc1ccco1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(NCCSCc2ccco2)ncc1Cc1cccnc1

Procedure:
(b)(i) 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (12.36 g) was added to a stirred mixture of 2-(5-furylmethylthio)ethylamine hydrochloride (10.65 g) and sodium ethoxide (prepared from 1.26 g sodium) in dry ethanol (300 ml) and the mixture was boiled under reflux for 44 hours and evaporated to dryness. The residue was triturated with water (discarded) and recrystallised from aqueous 2-propanol to give 2-[2-(2-furylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 136°-139°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]3[N:18]([CH3:19])[N:17]=[CH:16][N:15]=3)=[N:7][NH:8][C:9]2=[O:12])=[C:4](/[N:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[NH:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:13]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][N:15]=3)[C:6]3=[N:7][NH:8][C:9](=[O:12])[C:10]([CH:11]=1)=[C:5]23
Reactant: Cn1ncnc1Cc1n[nH]c(=O)c2cc(F)cc(/N=C/c3ccc(F)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a suspension of (E)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)phthalazin-1(2H)-one (8) (2.0 g, 5.3 mmol) in THF (80 mL) was added cesium carbonate (3.4 g, 10.6 mmol). The reaction mixture was stirred at 55° C. for 4 hours and cooled down to room temperature. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to dryness to afford the title compound as a white solid (1.6 g, yield 80%). LC-MS (ESI) m/z: 381 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, J1=2.4, J2=11.2 Hz, 1H), 7.06-7.09 (dd, J1=2.4, J2=8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CCCCCCCCCC>>[C:5]1([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[CH2:18][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:17][N:15]2[CH3:16])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: C[N+]([O-])=C(Cn1cncn1)c1ccc(Cl)cc1
Reactant: C=CCCCCCCCCCCCCCCCC
Product: CCCCCCC1CC(Cn2cncn2)(c2ccccc2)N(C)O1

Procedure:
Derivative 3 (R=H, n=5) is prepared by a procedure similar to that described in Example 1 by reacting 1-phenyl-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1: R=H) with 1-octene (2: n=5). The resulting cis- and trans-diastereomeric mixture of compound 3 (R=H, n=5) is flash-chromatographed on neutral silica gel using as eluent a 98:2 by volume mixture of chloroform-methanol. Isomer A has a melting point of 93°-99° C. (ethyl acetate).
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(OC(C)(C)C)=O>>[CH3:2][C:7]1[C:13]([N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Yield: 22.5 %

Procedure:
Using 2,3-dichloro-5-trifluoromethylpyridine (25 g) and 1-Boc-piperazine (23.84 g) and by the reaction and treatment in the same manner as in Preparation Example 79, the title compound (6.38 g) was obtained.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH2:17].CC(O)=O.[BH3-]C#N.[Na+]>ClCCCl>[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:17][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 1-benzylpiperidin-3-one hydrochloride (1.00 g, 4.10 mmol), tert-butyl hydrazinecarboxylate (0.596 g, 4.51 mmol), and AcOH (0.470 mL, 8.21 mmol) in DCE (20 mL) was stirred at ambient temperature for about 1 h then NaCNBH3 (0.258 g, 4.10 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (50 mL). The organic layer was separated, concd under reduced pressure and purified by RP-HPLC (Table 1, Method h) to afford tert-butyl 2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate (1.25 g, 100%) as a clear oil: LC/MS (Table 1, Method b) Rt=1.66 min; MS m/z: 306 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3](OCC)=[O:4].[BH4-].[Na+]>C(O)C>[F:14][C:2]([F:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 19.5 g (97 mmol) of ethyl difluoro-2-pyridylacetate 4 in 200 mL of absolute ethanol at 0° C. was added 4.42 g (1 16 mmol) of sodium borohydride in small portions. After 30 min, the reaction was quenched by the addition of 50 mL of sat. NH4Cl. The reaction mixture was concentrated at reduced pressure and the residue partitioned between 500 mL of ethyl acetate and sat. NaHCO3. The organic layer was washed with water, brine, and dried over Na2SO4 and concentrated at reduced pressure to give a brown oil that was purified on SiO, (10×17 cm) using 1:1 EtOAc-hexane. After re-chromatographing the mixed fractions, all clean fractions were combined and concentrated at reduced pressure, giving 5 as a beige crystalline solid: 1H NMR (CDCl3) δ3.6 (t, 1H), 4.17-4.3 (m, 2H), 7.4-7.45 (m, 1H), 7.73 (d, 1H), 7.84-7.91 (m, 1H), 8.61 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][S:10][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].O.S(=O)(=O)(O)[OH:18]>C(O)C>[N+:11]([C:5]1[C:6]2[S:10][N:9]=[CH:8][C:7]=2[C:2]([OH:18])=[CH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c2cnsc12
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(O)c2cnsc12
Yield: 86 %

Procedure:
43 g of 4-chloro-7-nitro-1,2-benzisothiazole and 16 g of sodium hydroxide powder in 400 ml of ethanol are stirred for 1 hour at 70° C. When the mixture has cooled, 500 ml of water are added, the batch is neutralized with dilute sulfuric acid whilst cooling with ice, and the product which has precipitated is filtered off. The filter cake is then washed with a little ice-cold methanol, and dried. 34 g (86% of theory) of 7-nitro-4-hydroxy-1,2-benzisothiazole are obtained, melting at 284° C. (with decomposition) after one recrystallization from n-butanol.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH3:21])=[CH:10][CH:11]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.Cl.CCOC(C)=O>[ClH:1].[CH2:18]([C:16]1[C:15](=[O:20])[NH:14][C:13]([CH3:21])=[C:12]([C:9]2[S:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:11][CH:10]=2)[CH:17]=1)[CH3:19]
Reactant: CCc1cc(-c2ccc(CNC(=O)CCl)s2)c(C)[nH]c1=O
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cc(-c2ccc(CNC(=O)CN3CCCC3)s2)c(C)[nH]c1=O
Yield: 33 %

Procedure:
To a solution of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (0.5 g, 2 mmol) and triethylamine (0.6 mL) in THF (5 mL) and dichloromethane (20 mL) is added chloroacetyl chloride (0.24 mL, 3 mmol) at 0° C. After 2 hr at rt, the mixture is quenched with aqueous NaHCO3 solution, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-5% MeOH to afford 0.3 g of 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide. A mixture of so formed 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide (0.15 g, 0.46 mmol), and excess of pyrrolidine and potassium carbonate in acetonitrile (10 mL) is heated for 6 hr at 75° C., and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-10% MeOH to afford the free base, which is dissolved in HCl-EtOAc and concentrated. Lyophilization in acetonitrile and water affords 60 mg (33%) of N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophen-2-ylmethyl]-2-(pyrrolidin-1-yl)acetamide hydrochloride as a solid. LC/MS: RT 1.93 min; m/e 360 (M+H); 1H NMR (DMSO-d6, δ, ppm): 10.5 (1H, brs), 9.4 (1H, t), 7.2 (1H, s), 6.98 (1H, d), 6.95 (1H, d), 4.5 (2H, d), 4.1 (2H, d), 3.55 (2H, brs), 3.02 (2H, brs), 2.4 (2H, q), 2.25 (3H, s), 1.8-2.05 (4H, m), 1.22 (3H, t).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@@:7]([CH3:17])([C:14]([NH:34][CH2:33][CH2:31][OH:32])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)NCCO)O2
Yield: 81.6 %

Procedure:
Following the amide coupling procedure described in protocol A, 1.846 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (7.37 mmol), 1.315 g CDI (8.11 mmol) and 991 mg ethanolamine (16.22 mmol) produced 1.765 g of (R)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a waxy white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 50 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of N-(4-acetylphenyl)acetamide (1 g, 5.65 mmol, 1.00 equiv) in acetic acid (10 mL). This was followed by the addition of a solution of bromine (910 mg, 5.69 mmol, 1.01 equiv) in acetic acid (2 mL) dropwise with stirring at 50° C. The resulting solution was stirred for 1.5 h at 50° C. The reaction was then quenched by the addition of 100 mL of water/ice. The solids were collected by filtration and dried under vacuum. This resulted in 0.5 g (33%) of N-(4-(2-bromoacetyl)phenyl)acetamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[N:10]3[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=2)=[CH:4][CH:3]=1.[N+](=[CH2:31])=[N-]>C(OCC)C.C(OCC)(=O)C.C(OCC)C>[CH3:31][O:17][C:16]([C@@H:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:19](=[O:20])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:9]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=3)[N:10]12)=[O:18]
Reactant: C=[N+]=[N-]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2C(C(=O)O)CCC3)n1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(SC)n3)n21
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid, 30, in diethyl ether/ethyl acetate (2.5:1, 7o mL) is added freshly generated diazomethane in diethyl ether (5 mL). The reaction is stirred for 5 minutes then quenched by the addition of HOAc (0.5 mL). The resulting solution is washed with NaHCO3, brine, dried, and concentrated in vacuo to afford 1 g (98% yield) of the desired product as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.S(Cl)([Cl:15])(=O)=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=[N:7][CH:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Fc1ccc2cnccc2c1
Product: Fc1ccc2cncc(Cl)c2c1
Temperature: 25 °C

Procedure:
A solution of 1.5 g 6-fluoro-isoquinoline (23) in 4.5 ml sulfuryl chloride was heated to 60° C. in a microwave reactor (CEM Discovery) for 8 h. After cooling to room temperature the mixture was poured on ice and extracted three times with CHCl3. After drying over Na2SO4 the solvent was distilled off and the crude product was purified by flash chromatography to yield 930 mg of compound 24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]([C:16]([O:18]CC)=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:14](=[O:15])[C:13]([C:16]([OH:18])=[O:17])=[N:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nc2cccnc2n(-c2ccc(OC)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-n2c(=O)c(C(=O)O)nc3cccnc32)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2.9 g (9 mmol) of ethyl 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate was dissolved in 1,4-dioxane (30 mL). A solution in which 1.8 g (13 mmol) of potassium carbonate was dissolved in water (60 mL) was prepared, and was added to the reaction solution at room temperature, and then the mixture was stirred for one hour at 50° C. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. Water (50 mL) was added, and then the reaction solution was cooled to 0° C., and adjusted to pH 1 using 6 N hydrochloric acid. Subsequently, a solid was separated by filtration and dried, to obtain 2.6 g (yield: 98%) of 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=[O:18])[C:15]([Cl:17])=[O:16])=[CH:3]1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A stirred solution of 1-methyl-6-nitro-1H-indole in diethyl ether (Et2O) (5 mL) was cooled to 0° C., and treated with oxalyl chloride (0.15 mL, 1.7 mm). After stirring at room temperature overnight, solids were collected, washed with ether and dried to afford (255 mg, 96%) (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FCCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoroacetic acid (3 ml, 17.5 mmol) was added to a solution of 4-(2-fluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.5 mmol) in methylene chloride (12 ml). The reaction mixture was stirred at ambient temperature for 40 minutes, before the solvent was evaporated under high vacuum. The residue was azeotroped with toluene to give 1-(2-fluoroethyl)-piperazine diTFA salt (377 mg, 96%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:24]=[C:22]1[O:21][CH2:20][C:19]([N:3]2[CH2:4][CH2:5][C:6]3([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]3)[C:2]2=[O:1])=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C(N2CCC3(CCNCC3)C2=O)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (5.70 g, 16.9 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (26.1 mL, 339 mmol) and the resulting solution was stirred at rt for 1 h. After concentration the residue was basified on ion exchange column followed by washing with 1N ammonia in methanol solution to give 2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 237.06.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:18])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[C:5]([Cl:3])(=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCC(=O)Cl
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 13.13 ml (180 mmol) of thionyl chloride, and a water condenser, is placed 20.03 g (100 mmol) of dodecanoic acid. Addition of the thionyl chloride is completed with heating to about 45° C. over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, dodecanoyl chloride. This acyl chloride, 7.65 g (35 mmol), is put into a dry separatory funnel and combined with 50 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH2:63]>CN(C=O)C.C(OCC)(=O)C>[CH3:58][O:59][C:60](=[O:64])[CH2:61][CH2:62][NH:63][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([CH2:25][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)[N:13]=2)=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.3 %

Procedure:
4-({(4-Chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoic acid (47 g, 93 mmol) was dissolved in DMF (500 mL) and 1-hydoxybenzotriazole (18.9 g, 140 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.7 g, 140 mmol) were added and the mixture was stirred at room temperature for 1.5 hours. Di PEA (i 9.1 mL, 111 mmol) and 3-aminopropionic acid methyl ester hydrochloride (15.5 g, 111 mmol) were added to the mixture and the resulting mixture was stirred at room temperature for 16 hours. Ethyl acetate (500 mL) was added and the mixture was washed with water (500 mL). The aqueous phase was extracted with ethyl acetate (500 mL). The combined organic phases were washed with water (2×500 mL) and saturated aqueous ammonium chloride (2×300 mL), dried (Na2SO4) and concentrated in vacuo to afford 60 g (quant.) of crude 3-[4-({(4-chlorophenyl)-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester as a solid. Recrystallisation from ethanol afforded 31.2 g (55%) pure product.
Reaction SMILES: [NH2:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1.CC(C)=O>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[N:4][CH:3]=1
Reactant: CC(C)n1nc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2Br)ccc1=O
Solvent: CC(C)=O
Solvent: Clc1ccccc1Cl
Product: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2Br)ccc1=O
Yield: 102.7 %

Procedure:
A mixture of 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxylic acid (601 mg) in 1,2-dichlorobenzene (3 ml) was refluxed for 2 hours. After cooling, the mixture was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended with acetone and collected by filtration to give 6-[5-amino-3-(2-bromophenyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (554 mg).