Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:37])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(CC)CC)C>>[C:12]([CH:14]([CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:37])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 40A, 0.76 g (6.00 mmol) of oxalyl chloride, 1.01 g (12.9 mmol) of dimethyl sulphoxide, 1.95 g (3.93 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenyl-pentanamide and 4.36 g (43.1 mmol) of triethylamine are reacted to give 2-acetyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1([CH3:21])[CH:14]=[CH:13][C:12]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:21])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Yield: 94.3 %

Procedure:
A solution of 6.25 g (49.00 mmoles) of 4-chloroaniline in 10 ml of methylene chloride was added to a solution of 9.85 g (49.95 mmoles) of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide the title compound (87% yield) with a melting point of 174-176° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([F:13])=[N:9][NH:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([F:13])=[N:9][N:10]2[S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirring suspension of sodium hydride (60% in mineral oil) (0.677 g) in THF (25 ml) at 0° C. was added a solution of 6-bromo-3-fluoro-4-nitro-1H-indazole (4 g) in THF (25 ml) dropwise. The reaction mixture was allowed to stir for 30 min then allowed to warm to RT before benzenesulfonyl chloride (2.17 ml) was added. After approximately two hours the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the aq was then extracted again with ethyl acetate. The combined organics were then washed with brine, dried over magnesium sulphate, filtered and concentrated. The solid was triturated with methanol (50 ml) and filtered to yield the title compound, 5.96 g as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:27]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.42 g of benzylpiperazine are dissolved in 35 ml of methylene chloride and there are added thereto 2.1 g of triethylamine and then, dropwise and while cooling with ice, 3.4 g of 3-methoxybenzoyl chloride in 30 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature and then washed with H2O. After being dried over sodium sulphate, the solution is concentrated to dryness by evaporation in vacuo. The oily 1-benzyl-4-(3-methoxybenzoyl)-piperazine is dissolved in 150 ml of fine spirit and debenzylated over 0.5 g of Pd-C. When the hydrogenation is complete, the catalyst is filtered off from the mixture and the filtrate is concentrated to dryness by evaporation in vacuo. The oily N-(3-methoxybenzoyl)-piperazine so obtained is placed in a sulphonating flask with 3.8 g of p-chlorophenethyl bromide and heated to 100°. At 60° a slight exothermic reaction takes place. After 3 hours at 100° , the mixture is cooled and dissolved in 400 ml of methylene chloride, and then 2N NaOH is added thereto; the whole is extracted by shaking and the methylene chloride phase is washed twice with H2O. The organic phase is dried over Na2SO4 and concentrated to dryness by evaporation in vacuo. The oily 1-[2-(4-chlorophenyl)-ethyl]-4-(3-methoxybenzoyl)piperazine is dissolved in isopropanol, and hydrochloric acid is added thereto. After the addition of ether, the hydrochloride, which has a melting point of 230°-232°, crystallises.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[N:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]4[CH:23]([CH2:24][CH2:25][CH:26]([O:39]C(=O)C)[CH2:27]4)[N:22]=3)=[CH:17][CH:16]=2)=[O:14])[NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[N:12][C:13](=[O:14])[C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]4[CH:23]([CH2:24][CH2:25][CH:26]([OH:39])[CH2:27]4)[N:22]=3)=[CH:19][CH:20]=2)[NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)N=C(N)N2CCN(C(C)=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1cc2c(cc1OC)C1CC(O)CCC1N=C2c1ccc(C(=O)N=C(N)N2CCN(C(C)=O)CC2)cc1
Yield: 52.4 %

Procedure:
484 mg of acetic acid (2RS,4aRS,10bRS)-6-(4-{[1-(4-acetyl-piperazin-1-yl)-1-amino-methylene]-carbamoyl}phenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound 10) and 137 mg of cesium carbonate are stirred in 10 ml of methanol for 16 h at room temperature. The solvent is removed and the solid residue purified by chromatography on silica gel to yield 235 mg of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O>[N+:1]([C:8]1[CH:9]=[CH:10][C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])=[CH:6][CH:7]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(C#N)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)C(C#N)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.17 h

Procedure:
Into mixed acids (5 ml of 90% nitric acid and 60 ml of concentrated sulfuric acid), held at -2° to -3° with a dry-ice/acetone bath, was dripped 15.92 g of 2-phenyl-3-methylbutyronitrile, causing a very exothermic reaction during the 7-minutes addition period. After an additional 70 minutes at -5° to 0°, the dark reddish orange reaction mixture was poured into excess ice. The thick oil which formed was extracted into butyl chloride, and the butyl chloride extract washed twice each with water and saturated sodium bicarbonate solution. Drying (MgSO4) and evaporation of the butyl chloride solution provided an orange-yellow oil. Vacuum distillation gave 17.1 g of yellow oil, bp 118°-130°/(0.2-0.3 Torr). Crystallization from butyl chloride/hexane provided white 2-(4-nitrophenyl)-3-methylbutyronitrile of m.p. 69°-71°.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[CH:18][N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:16][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:17])[N:7]3[CH:18]=[CH:19][S:20][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.086 mmol), 6-bromo-9H-purine (0.031 g, 0.16 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H15FN7OS (M+H)+: m/z=408.1. Found: 408.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:32])[C@H:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[NH2:26].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH:25]([NH:26][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[C:24]([O:23][CH3:22])=[O:32]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[CH:35]=[C:34]([O:36][Si](C(C)(C)C)(C)C)[CH:33]=[CH:32][C:31]=1B(O)O>COCCOC.O.CCOC(C)=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>[Cl:29][C:30]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3Cl)ccc12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (0.97 g, 2.91 mmol), tetrakis(triphenylphosphine) palladium (0) (0.13 g, 0.116 mmol), 2 M Na2CO3 (13.6 mL) and 2-chloro-4-[((1,1-dimethylethyl)dimethylsilyl)oxy]phenylboronic acid (1 g, 3.49 mmol) in ethylene glycol dimethyl ether (15.5 mL) was heated at 80° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, and transferred to a separatory funnel. The organic phase was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an oil. The crude material was purified by flash chromatography over SiO2 with a Hex:EtOAc (0 to 20% EtOAc) gradient to afford 0.74 g (82%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1 H), 8.75 (d, J =9 Hz, 1 H), 8.22 (d, J=8 Hz, 1 H), 8.13 (d, J=7 Hz, 1 H), 8.01 (s, 1 H), 7.68 (m, 1H), 7.61 (t, J=8 Hz, 1 H), 7.34 (d, J=9 Hz, 1 H), 6.96 (m, 1 H), 6.86 (m, 1 H), 3.93 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Reaction time: 0.25 h

Procedure:
A solution of the product from Example 61F (0.1000 g, 0.227 mmoles) in DMF (0.57 mL) was treated with NaH (0.0109 g, 0.27 mmoles, 60% dispersion). After 15 min, ethyl 4-bromobutyrate (0.039 mL, 0.27 mmoles) was added and the reaction was stirred overnight. The crude products were diluted with diethyl ether, washed with sat. NH4Cl, extracted with H2O (2×), washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane to 7:1 hexane:ethyl acetate) to provide the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:27][CH2:28][NH2:29].Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[CH:35]([O:34][C:32]([NH:29][CH2:28][CH2:27][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:33])([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCN
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(CCNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-{2-(2-amino-ethyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester (26 mg, 0.064 mmol) in CH2Cl2 (2 mL) at 0° C. was treated with TEA (0.2 mL) and isopropyl chloroformate (0.13 mL, 1.0 M in ether). The resulting mixture was allowed to warm gradually to ambient temperature. After 2 h, the mixture was concentrated to a residue, which was purified by silica gel chromatography (hexanes/EtOAc 7/3) to afford the isopropyl carbamate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.19 (d, 6H, J=5.9 Hz), 2.42 (s, 3H), 2.54 (t, 2H, J=7.8 Hz), 2.79 (t, 2H, J=6.8 Hz), 2.89 (t, 2H, J=7.8 Hz), 3.05 (br s, 2H), 3.38 (br s, 2H), 3.60 (s, 3H), 4.26 (t, 2H, J=6.8 Hz), 4.68 (br s, 1H), 4.89 (q, 1H, J=6.4 Hz), 6.70 (br s, 1H), 6.71 (d, 1H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 7.47 (m, 3H), 8.10 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([O:23][CH3:24])[CH:9]=1)=[O:6].[NH3:26]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[CH:9][C:10]=1[O:23][CH3:24]
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(OC)c1
Solvent: CO
Product: COc1cc(NC(=O)CC(N)=O)ccc1OCc1cccc(F)c1
Yield: 71 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield=71%. Colorless solid. MS: m/e=333.0 (M++H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:4]([OH:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.O.[C:32]1(C)[CH:37]=CC(S(O)(=O)=O)=C[CH:33]=1>CC(C)=O>[CH3:33][C:32]1([CH3:37])[O:14][C@H:4](/[CH:5]=[CH:6]/[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:3]([N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:2][O:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(/C=C/[C@@H](O)C(CO)N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 94 %

Procedure:
A mixture of 1,3-diol, 2-hydrazino (7B) (59 mg, 0.14 mmol) and p-toluene sulfonic acid monohydrate (2.7 mg, 0.014 mmol) in 5.0 mL anhydrous acetone was stirred at rt for 42 h. The reaction mixture was quenched with 5% NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:55])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[C:39]([O:41]CC3C=CC=CC=3)=[O:40])=[O:33])[N:27]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:55])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[C:39]([OH:41])=[O:40])=[O:33])[N:27]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3ccccc3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 4.0 g 4-[(S)-2-({5-[2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-3-tert-butoxycarbonyl-propionyl]-piperazine-1-carboxylic acid ethyl ester in 50 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 3.0 g colorless foam.
Reaction SMILES: C1C=CN=CC=1.F.[Si]([O:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:26]=1[CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:23]([C:32]([NH:34][C:35]1[CH:40]=[C:39]([O:41][CH:42]([CH3:44])[CH3:43])[C:38]([C:45]#[N:46])=[CH:37][N:36]=1)=[O:33])[CH2:22][CH2:21][CH2:20]2)(C(C)(C)C)(C)C>C1COCC1>[C:45]([C:38]1[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:40][C:35]([NH:34][C:32]([N:23]2[C:24]3[C:19](=[CH:18][C:17]([CH2:16][OH:15])=[C:26]([CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:25]=3)[CH2:20][CH2:21][CH2:22]2)=[O:33])=[N:36][CH:37]=1)#[N:46]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Reaction time: 0.33 h

Procedure:
HF-Pyridine (300 μL, 3.33 mmol) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 165, 861 mg, 1.549 mmol) in THF (8 ml) at room temperature. The reaction mixture was stirred for 5 h and 20 min, quenched with saturated aqueous NaHCO3 and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried using Na2SO4, filtered and concentrated to yield the title compound as a white solid. (UPLC-MS 3) tR 1.11 min; ESI-MS 442.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 13.92 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 5.46 (s, 1H), 4.90-4.79 (m, 1H), 4.72 (d, 2H), 4.08-4.00 (m, 2H), 3.54 (s, 6H), 2.86 (t, 2H), 2.07-1.95 (m, 2H), 1.57 (br s, 1H), 1.44 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]=[CH2:22]>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:22][CH:21]=[CH2:20])=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCc1c(O)cc(O)c(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
In 15 ml of anhydrous tetrahydrofuran was dissolved 3.0 g of 2',4',6'-trihydroxyacetophenone, and 7.4 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 2.5 g of 3-bromo-1-propene was added to the mixture and reaction was carried out at room temperature for 3 hours. After the reaction, the reaction mixture was extracted with 500 ml of diethyl ether, and the solvent was removed from the extract by distillation. The obtained residue was recrystallized from benzene to obtain 1.5 g (yield=41.5%) of 2',4',6'-trihydroxy-3'-(2-propenyl)acetophenone in the form of a colorless prism.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9](=[O:27])[C:10](=[CH:23]OCC)[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1[F:22])=[O:12])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9](=[O:27])[C:10](=[CH:23][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1[F:22])=[O:12])[CH3:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(C)(C)N
Solvent: CCO
Product: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
A solution of 1.77 g (24.2 mmoles) tert-butylamine in 2 mL ethanol was added to a mixture of 7.05 g (22 mmoles) of 3-(2,3,4,5-tetrafluorophenyl)-3-oxo-2-(ethoxymethylene)-propanoic acid ethyl ester and 9 mL ethanol cooled in a bath containing ice and salt. More ethanol (2.3 mL) was added and the mixture was stirred at room temperature for 2 hours. After cooling at 0° C., the resulting precipitate was filtered and washed with ethanol to give 3.72 g of titled compound. MP 112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.Br[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:12][C:13]#[N:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)cc(C)c1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Cl)cc(C)c1OCC#N

Procedure:
4-Chloro-2,6-dimethylphenol (5.0 g, 32 mmol), bromoacetonitrile (2.2 mL, 32 mmol) and potassium carbonate (6.6 g, 48 mmol) are combined with acetone (50 mL) and heated at reflux for 18 h. The reaction is filtered, concentrated and the residue partitioned between dichloromethane and water. The organic phase is washed with 1N HCl and water and is then dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 10% ethyl acetate in hexanes) to provide the title compound. MS (EI) 195 (M)+, Cl pattern.