Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:15]([OH:17])=O)([CH3:3])[CH3:2].[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[N:29]=[CH:28][C:27]([NH:30][C:15]([C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[O:8][C:4]=3[CH:1]([CH3:2])[CH3:3])=[O:17])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CC(C)c1oc(-c2ccccc2)nc1C(=O)O
Product: CC(C)c1oc(-c2ccccc2)nc1C(=O)Nc1ccc(N2CCOCC2)nc1

Procedure:
With a procedure similar to example 16 above, 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5]2)[CH:16]=[CH:15][N:14]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: CCOC(=O)c1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)n(Cc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (50 mg, 0.28 mmol) and 2-chloro-4-(chloromethyl)pyridine (50 mg, 0.31 mmol) in DMF (2 mL), K2CO3 (116 mg, 0.84 mmol) was added. The mixture was stirred at RT overnight, and was then diluted with H2O (20 mL), extracted with EtOAc (3×20 mL), 4:1 CHCl3:iPrOH (3×20 mL), dried with MgSO4 and concentrated under reduced pressure. The crude product was purified on a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100% EtOAc) to afford ethyl 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (29 mg, 40%) as a white solid. MS (ES+) C12H13ClN4O2 requires: 280 found: 281[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]1[CH2:23][CH:22]([NH2:24])[CH2:21][CH2:20][O:19]1>>[CH3:17][CH:18]1[CH2:23][CH:22]([NH:24][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:21][CH2:20][O:19]1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CC1CC(N)CCO1
Product: CC1CC(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)CCO1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2-methyl-2H-pyran-4-amine (CAN 89584-06-5) as starting materials, MS (EI): m/e=331.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])(C)(C)C.CC1(C)O[C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=[O:40])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:30]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]#[N:36])[CH2:29][C:28](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(Cl)cc4)cc3NC(=O)C2)c1
Yield: 47 %

Procedure:
Prepared from [2-amino-4-(4-chloro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G13) (187 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (184 mg, 0.6 mmol) according to the general procedure K. The obtained material (234 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (93 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7](O)(=O)[CH2:8][CH3:9]>>[CH2:8]([C:9]1[O:4][CH2:3][CH:2]([CH2:5][OH:6])[N:1]=1)[CH3:7]
Reactant: CCC(=O)O
Reactant: NC(CO)CO
Product: CCC1=NC(CO)CO1

Procedure:
The procedure of Example 1 is repeated in all essential details with the exception that the initial reactants are 2-amino-1,3-propanediol and propionic acid in a 1:1 molar ratio. The reactants are combined following the method of Purcell to form 2-ethyl-4-hydroxymethyl-2-oxazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:29][CH2:28][CH2:27][C@:20]5([O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]5)[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:29][CH2:28][CH2:27][C@:20]5([O:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]5)[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@]5(C4)CN(C)C(=O)O5)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@]2(CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)OC1=O
Reaction time: 0.5 h

Procedure:
To a solution of (5S,7S)-7-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one, 63d, (0.035 g, 0.060 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25% w/v, 9.255 mmol). The mixture was stirred for 30 min then concentrated in vacuo and purified by reverse phase HPLC (Water/HCl:MeOH). Pure fractions were combined and concentrated in vacuo to afford product 971 as the HCl salt.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[C:9]([CH:15]=O)[CH:8]=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:17][O:18][NH2:19].Cl>CCO.N1C=CC=CC=1>[CH3:17][O:18][N:19]=[CH:15][C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]3[C:14]=2[C:10]=1[CH:11]=[CH:12]3
Reactant: O=Cc1ccc2c3c1ccn3C(=O)CNC2
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=Cc1ccc2c3c1ccn3C(=O)CNC2
Yield: 23 %

Procedure:
A solution of 1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-carbaldehyde (Example 45, 0.050 g, 0.234 mmol) and MeONH2. HCl (0.020 g, 0.242 mmol) in EtOH (5 mL) and pyridine (5 mL) was refluxed for 20 h. The reaction mixture was then evaporated to dryness and the residue was taken up in H2O and extracted with EtOAc several times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-1% MeOH in CHCl3 to give 0.036 g (63%) of the (E) and 0.013 g (23%) of the (Z) isomers. (Z) isomer: 1H NMR (DMSO-d6) δ 3.54-3.58 (m, 2H), 3.96 (s, 3H), 4.43 (bs, 2H), 7.27 (t, 1H, J=9.0 Hz), 7.89-7.92 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 8.35-8.39 (m, 1H). HRMS calcd for C13H13N3O2 (M+) 243.1008, found 243.1020. Anal. (C13H13N3O2.0.1 H2O.0.1 EtOAc) C, H, N. (E) isomer: 1H NMR (DMSO-d6) δ 3.55 (bs, 2H), 3.87 (s, 3H), 4.37 (bs, 2H), 7.27 (t, 1H, J=7.5 Hz), 7.75 (s, 1H), 7.91 (d, 1H, J=7.5 Hz), 8.24 (d, 1H, J=7.5 Hz), 8.34-8.38 (m, 2H). HRMS calcd. for C13H13N3O2 (M+) 243.1008, found 243.1016. Anal. (C13H13N3O2.0.25 H2O) C, H, N.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCCN.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=O)[OH:15].N[C@H](C(O)=O)CCC(=O)O>>[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14](=[O:15])[NH2:1]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
N Lys: K Asp: D Glu: E
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[CH3:25][OH:26].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:25][OH:26])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(C)ccc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1ccc2nc(C)cc(CO)c2c1
Yield: 46 %

Procedure:
To a solution of 10.0 g (63.6 mmol) of 2,6-dimethylquinoline and 29.1 g (127.5 mmol) of ammonium peroxodisulfate in a mixed solvent of methanol (140 mL)-water (110 mL) was added 4.0 mL of concentrated sulfuric acid and heated under reflux for 24 hours. After the reaction mixture was left to cool, methanol was evaporated under a reduced pressure. The remaining solution was adjusted to pH 10 by adding sodium carbonate, and then extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by column chromatography (silica gel 200 g, developing solvent: chloroform:ethyl acetate:triethyamine=1:1:0.01) to obtain 5.50 g (yield 46%) of (2,6-dimethylquinolin-4-yl)methanol. Its physical properties are shown below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[N+:25](=[CH2:27])=[N-:26].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].C(OCCOCCO)C>O1CCCC1.C(OCC)C.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](=[O:16])[CH:27]=[N+:25]=[N-:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOCCOCCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)C=[N+]=[N-]
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.0 g in a mixture of 26 mL dry tetrahydrofuran and 26 mL dry diethyl ether) at -10° C. was added 1.91 mL of triethylamine followed by the dropwise addition of 1.78 mL isobutyl chloroformate. The reaction was stirred at -10° C. for 30 minutes then warmed to 0° C. Over the next hour, 26 mL of a solution of diazomethane in diethyl ether was added (prepared from: 8.0 g Diazald® in 70 mL diethyl ether; 4 g potassium hydroxide; 20 mL 2-(2-ethoxyethoxy)ethanol; 6 mL water and 12 mL diethyl ether using a mini Diazald Kit) and the mixture allowed to stir at room temperature for an additional 2 hours. At this time the reaction was quenched by the addition of 3 mL acetic acid at 0° C. This was then diluted with 100 mL water and 100 mL diethyl ether, the layers separated and the aqueous portion extracted with (2×75 mL) diethyl ether. The combined organics were washed with water (75 mL), saturated sodium bicarbonate (2×75 mL) and brine (75 mL) then dried over magnesium sulfate. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate, 8:2) gave the title compound, 2.99 g.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][CH3:11])=[C:5]([N+:12]([O-])=O)[C:4]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23].C(OCC)(=O)C>C1COCC1.CCCCCC.[Zn]>[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([O:10][CH3:11])=[C:5]([NH2:12])[C:4]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reaction time: 0.08 h
Yield: 94 %

Procedure:
Concentrated HCl (20 mL) was added to a solution of (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (I-3a: 8.0 g, 17 mmol) in THF (160 mL) and the resulting mixture was stirred for 5 minutes. This was followed by portion wise addition of zinc powder (6.8 g, 103 mmol) over a period of 30 minutes and stirring was continued for a further 30 min at room temperature. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was concentrated and the concentrate was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product was triturated with ether and filtered. The residue was dried to afford 6.3 g of the product (85% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[CH3:23][C:21]1[NH:12][N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[S:2][CH3:1])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CSc1ccccc1NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2SC)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of 15 g (0.07 mole) of 4-[2-(methylthio)phenyl]-3-thiosemicarbazide and 11.96 g (0.07 mole) of ethyl 2-chloroacetoacetate (97%) in 100 mL of absolute ethanol was stirred under nitrogen atmosphere for 1 hr at room temperature. The reaction was slightly exothermic and the mixture took on a yellow color as most of the solid dissolved. The mixture was treated with 50 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1.5 hr. The mixture had darkened to a deep, clear, orange color, with only a trace of insoluble material which was removed by filtering through a sintered glass filter. The solvent was removed in vacuo giving a yellow-orange solid (18.6 g). The solid was recrystallized from acetone, 17.4 g (85% yield), mp 135°-158° C. Thin layer chromatography indicated two impurities (10% methanol/benzene on silica gel). This crude product was recrystallized from benzeneligroin to give 12.1 g (59% yield), mp 126° -128° C. (some solid remained and melted at 158°-160° C.). Thin layer chromatography indicated that one of the two impurities had been removed. The solid was dissolved in methylene chloride and chromatographed on a 250 g column of Florisil® (60-100 mesh). The column was eluted with methylene chloride. The solid obtained was recrystallized from benzene-ligroin giving 4.6 g (22.5%) of product, mp 140.5°-142° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:22])[CH:14]=2)=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1.[NH2:23][C@@H:24]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([Br:34])[CH:28]=1)[CH2:25][OH:26].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][C:3]=1[C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:23][C@@H:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([Br:34])[CH:28]=2)[CH2:25][OH:26])=[C:15]([F:22])[CH:14]=1
Reactant: N[C@H](CO)c1cc(F)cc(Br)c1
Reactant: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)O)c(F)c2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)N[C@H](CO)c3cc(F)cc(Br)c3)c(F)c2)n1
Yield: 54.8 %

Procedure:
To a mixture of 4-(3-amino-6-(ethoxycarbonyl)pyrazin-2-yl)-2-fluorobenzoic acid (0.214 g, 0.7 mmol), (S)-2-amino-2-(3-bromo-5-fluorophenyl)ethanol (272 mg, 1.009 mmol),HOAt (187 mg, 1.376 mmol) and EDC (264 mg, 1.376 mmol) in DMF (2.5 mL) was added DIEA (0.961 mL, 5.50 mmol). The resultant mixture was stirred over night at RT. The mixture was diluted with EtOAc, washed with water three times and brine, dried, concentrated to afford the crude product as a light yellow viscous liquid. ISCO purification (12 g silica, 10 to 90% EtOAc in heptane, 30 min) provided the desired product (200 mg, 84% yield) as a light yellow liquid. LC-MS (m/z): 522.9 (MH+), 0.787 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:16]=2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.ClCCl>C(#N)C>[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([CH2:17][C:18](=[O:24])[N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: O=C(Cc1coc(-c2ccc(OCCCCl)cc2)n1)N1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC1CCCN1CCCOc1ccc(-c2nc(CC(=O)N3CCCC3)co2)cc1
Yield: 50 %

Procedure:
To a solution of 2-[4-(3-chloropropoxy)phenyl]-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole ax64 (0.51 g, 1.46 mmol, 1 eq) in acetonitrile (10 ml) is added sodium iodide (0.022 g, 0.15 mmol, 0.1 eq) and 2-methylpyrrolidine (0.25 ml, 2.92 mmol, 2 eq). The mixture is stirred at reflux overnight. The mixture is poured into dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified by chromatography over silica gel (eluent: dichloromethane/methanol/ammonia 95:4.5:0.5) to give 0.29 g of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazole 52 as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2ncccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2ncccc12

Procedure:
16.25 g (86 mmol) of 8-hydroxy-5-quinolinecarboxylic acid were dissolved in 70 ml of methanol, 3 ml of concentrated sulfuric acid were added and the mixture was heated under reflux for 25 hours. The solvent was then removed and the residue was taken up in ice-water, adjusted to a pH of 8 using sodium carbonate solution and filtered hot. The residue was extracted with methyl-tert-butyl ether for 7 hours on a jacketed Soxhlet extractor, and the solvent was subsequently removed from the extract. This gave 6.8 g of a brown powder;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][F:19].[Na+].[I-].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[F:19][CH2:18][CH2:17][N:13]1[C:12](=[O:15])[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14]1
Reactant: COc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(-c2ccc(=O)n(CCF)n2)cc1
Temperature: 70 °C
Yield: 97.1 %

Procedure:
A mixture of 6-(4-methoxyphenyl)-2H-pyridazin-3-one (170 mg, 0.83 mmol), 1-bromo-2-fluoroethane (122.5 mg, 1.5 eq.), NaI (20 mg) and cesium carbonate (553 mg, 2.0 eq.) in 5 mL of CH3CN was heated to 70° C. overnight. The reaction mixture was filtered and concentrated. The product was purified by ISCO combiflash with 50% hexane and EtOAc to give 2-(2-fluoroethyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one (200 mg, 97%); MS m/z 349 (M+H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:12][C:13](OCC)=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C1(C)C=CC=CC=1>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:12][CH:13]=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC1CCCCc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=CCC1CCCCc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Ethyl (6,7,8,9-tetrahydro-5H-5-benzocycloheptenyl)acetate (0.550 g) was dissolved in anhydrous toluene (10 ml), and the solution was slowly added with diisobutylaluminum hydride (0.93 M n-hexane solution, 2.8 ml) at −78° C. under an argon flow. The reaction mixture was stirred −78° C. for 1 hour, and then slowly added with methanol (3 ml) and 2 N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:300) to obtain the title compound (0.432 g, yield: 97%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH3:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C:27]1=[O:35])=O)(C)(C)C>C(O)=O.C(Cl)Cl>[NH2:25][C@H:26]1[C@H:29]([CH3:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C:27]1=[O:35]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=CO
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reaction time: 5 h

Procedure:
(3S-trans)-3-[(t-Butoxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinesulfonic acid tetra-n-butylammonium salt (6.3 g) is dissolved in 30 ml of 97% formic acid and stirred for 5 hours during which time a precipitate forms. The slurry is diluted with 30 ml of methylene chloride and filtered. The solids are further washed with methylene chloride and dried to yield 1.53 g of analytically pure product [α]D21 =-41.0[c=1, water].
Reaction SMILES: C([O:3][C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:10]=1)[CH3:7])=[O:5])C.[OH-].[K+]>C(O)C>[C:4]([CH:6]([O:8][C:9]1[N:13]=[CH:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:10]=1)[CH3:7])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2ccc(C)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-n2cnc(OC(C)C(=O)O)n2)cc1

Procedure:
A 2.5 g portion of the compound of Example 11 was refluxed for 4 hours with 1 g of potassium hydroxide in 50 ml of ethanol, and the product was collected as described in Example 22 to obtain 2.0 g of the desired product, m.p. 163°-165°.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].Cl[C:10]([O:12]C(Cl)(Cl)Cl)=[O:11]>>[CH2:5]1[C:6](=[O:7])[N:2]([O:1][C:10]([O:12][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:11])[C:3](=[O:8])[CH2:4]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
11.5 g (0.1 mol) of N-hydroxysuccinimide was admixed with 6 ml (0.05 mol) of trichloromethyl chloroformate (TCF), and the resultant admixture was melted by heating. The heating was continued for 10 minutes and then the resultant melt was allowed to cool and to deposit a colorless crystalline material. This crystalline material was filtered off from the liquid phase and recrystallized from acetonitrile, affording 6.5 g of the titled compound in the form of colorless crystals. Yield 50%.