Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5].Cl.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23].[OH-].[Na+]>C(OCC)C>[CH2:20]([NH:24][C:4]([C:6]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11]1)=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C)CC1
Reactant: CCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCNC(=O)C1(c2ccccc2)CCN(C)CC1

Procedure:
Pethidine hydrochloride (2.56 g, 9 mmol) and butylamine (5 ml) were heated in an autoclave at 180° C. for 3 days. The reaction mixture was shaken between 10 ml of 1N NaOH and diethyl ether and the ether extracts dried (MgSO4). The solvent was evaporated and the residue chromatographed on aluminium oxide with ethyl acetate as eluent. The crystalline product (1.0 g) was recrystallized from n-hexane yielding 0.59 g with m.p. 73°-76.5° C.
Reaction SMILES: C(OC([N:8]1[C:31](=[O:32])[C:11]2[CH:12]=[N:13][C:14]3[C:15]([NH:20][C:21](=[O:30])[C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[N:9]1[CH3:33])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[ClH:28].[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[C:21]([NH:20][C:15]1[C:14]2[N:13]=[CH:12][C:11]3[C:31](=[O:32])[NH:8][N:9]([CH3:33])[C:10]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: Cn1c2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc32)c(=O)n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1[nH]c(=O)c2cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc3c21
Reaction time: 1 h
Yield: 137.3 %

Procedure:
To a solution of 2-tert-butoxycarbonyl-6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-one (30 mg) in methanol (1 ml) was added 4M solution of hydrogen chloride in ethyl acetate (1 ml) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The mixture was concentrated in vacuo, and the residue was crystallized from ethanol-ethyl acetate to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-1-methyl-1H-pyrazolo[4,3-c]quinolin-3-one hydrochloride (17.9 mg).
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[C:26]([O:25][C:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:5][CH2:6]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(=O)O)ccc1-n1cccc12

Procedure:
A solution of 1′-tert-butyl 7-methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate (3.5 g, 8.8 mmol) in LiOH (18 mL of 2.0 M, 35.1 mmol) and dioxane (18 mL) was stirred at 55° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and was washed with water. The aqueous layer was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield 1′-(tert-butoxycarbonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid which was used without further purification. ESI-MS m/z calc. 384.4. found 385.3 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: CN([CH2:4][CH:5]=[N:6][C:7](=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.O.[NH2:18][NH2:19]>C(O)(=O)C>[CH3:4][C:5]1[N:6]=[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:19][N:18]=1
Reactant: NN
Reactant: CN(C)CC=NC(=O)C=Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c(/C=C/c2ccccc2)n1
Temperature: 90 °C
Yield: 96 %

Procedure:
N-[(Dimethylamino)ethylidene]-cinnamamide (2.0 g, 9.0 mmol) was added to a solution of hydrazine hydrate (0.59 mL, 10 mmol) and acetic acid (25 mL). The mixture was heated to 90° C. for 3 h, cooled, and concentrated in vacuo. The resulting material was basified (pH 8) with solid K2CO3, and partitioned between ethyl acetate and water. The organics were dried over Na2SO4 and concentrated in vacuo. The resultant material was purified by flash column chromatography on silica eluting with 1:2 hexane-ethyl acetate to afford 3-methyl-5-[(E)-2-phenylethenyl]-1H-1,2,4-triazole (1.6 g, 96% yield) as a white powder. M.p. 131–134° C. 1H NMR (CDCl3,300 MHz) δ 7.68 (d, J=16 Hz, 0.3H), 7.59 (d, J=16 Hz, 0.7H), 7.49 (m, 2H), 7.32 (m, 3H), 7.05 (d, J=16 Hz, 1H), 6.49 (d, J=16 Hz, 0.4H), 6.21 (br s, 0.3H), 5.88 (br s, 0.3H), 2.53 (s, 3H). MS (EI ionization) 184 (M+−H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:22])[C:18]=3[CH2:20][CH3:21])[CH:13]=[CH:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[N:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH:34]=O)[N:25]=1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)(Cl)[Cl:53]>>[ClH:53].[ClH:53].[N:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH2:34][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:22])[C:18]=4[CH2:20][CH3:21])[CH:13]=[CH:12][C:11]3=[O:23])[CH2:6][CH2:7]2)[N:25]=1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(N)CC3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(nn4)OCCO5)CC3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
1-[2-(4-amino-1-piperidinyl)ethyl]-8-ethyl-7-fluoro-1,5-naphthyridin-2(1H)-one (0.117 g, 0.368 mmol) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (0.061 g, 0.368 mmol) were dissolved in CHCl3 (2 ml) and MeOH (0.2 ml) at rt under argon. NaBH(OAc)3 (0.234 g, 1.10 mmol) was added and the reaction was allowed to stir at rt for 16 h. After which it was purified by chromatography on silica gel using a 0-30% MeOH in DCM gradient to give the free base of the title compound as a clear oil (0.045 g, 26%).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[N:14]2[CH:20]=[N:19][CH:18]=[C:15]2[S:16][CH:17]=1.[CH2:21]([O:24][C:25]([N:27]1[C@H:31]([CH:32]=[O:33])[CH2:30][C@@H:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28]1)=[O:26])[CH:22]=[CH2:23].O>C1COCC1>[CH2:21]([O:24][C:25]([N:27]1[C@H:31]([CH:32]([OH:33])[C:17]2[S:16][C:15]3=[CH:18][N:19]=[CH:20][N:14]3[C:13]=2[CH3:12])[CH2:30][C@@H:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH2:28]1)=[O:26])[CH:22]=[CH2:23]
Reactant: Cc1csc2cncn12
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1sc2cncn2c1C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A 1.69 M n-butyllithium/n-hexane solution (7.4 ml) is added dropwise to a solution of 1.56 g of 3-methylimidazo[5,1-b]thiazole in 25 ml of dry THF over a period of 10 min while maintaining the temperature at −70° C. or below, and the mixture is stirred at that temperature for 2 hr. A solution of 3.54 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 15 ml of THF is gradually added dropwise to the mixed solution, the temperature is raised from −70° C. to 0° C. over a period of 3 hr, the mixture is stirred at 0° C. for 2 hr and at room temperature for 2 hr. Water is added to the reaction solution, and the mixture is extracted three times with ethyl acetate. The organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product which is then successively purified by column chromatography on silica gel (ethyl acetate) and on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 2.74 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(3-methylimidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) as a colorless amorphous material.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:9](=[O:20])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)(=O)C>[C:1]1([CH:7]2[CH2:8][C:9](=[O:20])[N:10]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:11](=[O:13])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)CC(=O)N1c1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)CC(=O)N1C1CCNCC1
Reaction time: 8 h

Procedure:
The mixture of 14.6 g of 4-phenyl-1-(4-pyridyl)-piperidin-2,6-dione, 12.3 g of 10% palladium on carbon and 200 ml of glacial acetic acid is hydrogenated at 1.7 atm. and 100° for 8 hours. After cooling, the mixture is filtered, evaporated, the residue dissolved in the minimum amount of water and the solution basified with sodium carbonate. It is extracted with ethyl acetate, the extract evaporated and the residue crystallized by trituration with 75 ml of diethyl ether-hexane (3:1) and recrystallized from 50 ml of isopropanol to yield the 4-phenyl-1-(4-piperidinyl)-piperidin-2,6-dione nelting at 182°-189°; its p-methoxyphenyl analog melts at 127°-129°.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)N=1.[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].[C:27](=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[CH3:14][O:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:11]=[C:10]([C:12]#[N:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:27]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(Cl)nc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(C#N)c3ccccc3c2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
2-Chloroquinoline-4-carbonitrile (0.20 g), 4-methoxycarbonylphenylboronic acid (0.21 g), tetrakis(triphenylphosphine)palladium (0.061 g) and sodium carbonate (0.22 g) were suspended in a mixed solvent of dimethoxyethane (2 mL) and water (0.5 mL), and the resulting mixture was stirred at 150° C. for 30 minutes using microwave reactor (Biotage). To the reaction mixture was added ethyl acetate, and the reaction mixture was filtered through a Celite pad. The filtrate was poured into water, and the organic layer was washed with water and brine. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 4-(4-cyanonaphthalene-2-yl)benzoic acid methyl ester (0.12 g). To a solution of this compound (0.12 g) in a mixed solvent of tetrahydrofuran (2 mL), ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.14 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (0.35 mL). The precipitated solid was collected by filtration, washed with methanol, and dried under reduced pressure to give the title compound (0.024 g).
Reaction SMILES: C1(C([O:14][C:15](=[O:41])[C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)C2C=CC=CC=2)C=CC=CC=1.[H][H]>C(O)(C)(C)C.C(O)C.[Pd]>[CH3:39][C:37]([CH3:40])([O:36][C:34]([NH:33][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=1)[C:15]([OH:41])=[O:14])=[O:35])[CH3:38]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 92.9 %

Procedure:
(S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g. 2.8 mmol) and 10% Pd/C (300 mg) in t-butanol (20 mL) was blanketed with hydrogen (1 atm). To prevent the solvent from freezing, a warm water bath (40° C.) was used to heat the reaction mixture. Upon the consumption of 2 equivalents of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates combined and concentrated. The residue was purified by recrystallization from hexanes to give (S)-2-[[(1,1-dimethylethoxy) carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)3-oxopropyl]phenyl]propanoic acid (1.0 g. 2.6 mmol) in 94% yield, mp. 88.5°-90° C., [α]D +21.2° (0.90% in ethanol).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[NH2:24][C:23]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:2][CH3:1]
Reactant: [H][H]
Reactant: CNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1cc(Oc2cccc(NC(=O)OC(C)(C)C)c2)ccc1N
Yield: 100.9 %

Procedure:
Using tert-butyl {3-[3-(methylamino)-4-nitrophenoxy]phenyl}carbamate (10.9 g, 30.4 mmol), 10% palladium-carbon (1.8 g), tetrahydrofuran (150 mL), ethanol (100 mL) and hydrogen (3 atm) as starting materials, and in the same manner as in Example C1(iii), the title compound (10.1 g) was obtained as a black tar-like substance.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.[CH3:18][NH:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:29])[CH2:24][CH2:23]1>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[N:19]([CH3:18])[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=2)=[O:29])[CH2:24][CH2:23]1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(N(C)CCC2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (20.58 mg, 0.145 mmol) and triethylamine (81 μl, 0.579 mmol) in MeOH (483 μl) was warmed to 45° C. for 30 mins. 3,5-Dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (50 mg, 0.145 mmol) was added drop wise and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated under reduced pressure and the crude oily product was dissolved in water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and solvent concentrated under reduced pressure. The crude product was suspended in MeOH and sonicated. The resulting white solid was filtered and dried to afford the title compound;
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:33][C:34]1[NH:35][C:36]2[NH:37][CH2:38][CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[NH:40][C:41]=2[C:42](=[O:44])[N:43]=1>C(Cl)Cl.N1C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:13]([N:40]1[CH:39]([CH:45]([OH:49])[CH:46]([OH:48])[CH3:47])[CH2:38][NH:37][C:36]2[NH:35][C:34]([NH2:33])=[N:43][C:42](=[O:44])[C:41]1=2)=[O:15])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1c2c([nH]c(N)nc2=O)NCC1C(O)C(C)O
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a stirred solution of N-Boc-L-Valine (4.56 g, 21 mmol) in DCM (15 ml) at 0° C. was added a solution of DCC (2.17 g, 10.5 mmol) in DCM (10 ml). The resulting solution was stirred for 1 h after which a white precipitate formed. The white solid was filtered and filtrate added to a stirred solution of 2-amino-6-(1,2-dihydroxy-propyl)-5,6,7,8-tetrahydro-1H-pteridin-4-one dihydrochloride (3.0 g, 9.55 mmol) dissolved in pyridine (80 mL). The mixture was stirred at room temperature under an atmosphere of nitrogen for 1.5 h. The reaction mixture was quenched by addition of methanol (20 ml). The solvent was evaporated in vacuo and the residue purified by preparative RP-HPLC to give the sub-title product as a tan solid (3.2 g, 76%). MS: ESI (positive): 441 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:18](OC(C)(C)C)(=[O:26])[C:19](OC(C)(C)C)=[O:20].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:19](=[O:20])[C:18]([OH:26])=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CCNc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 84 h
Yield: 47.8 %

Procedure:
To a solution of the title compound of Example C (5.41 g, 22.6 mmol) in dry THF (100 ml) was added di-tert-butyl oxalate (4.57 g, 22.6 mmol), followed by potassium tert-butoxide (5.07 g, 45.2 mmol) and the resulting dark yellow solution was stirred for 84 h at room temperature. The reaction mixture was then acidified with 1N HCl to pH=3, followed by the addition of H2O (35 ml) and the mixture was then extracted with CH2Cl2. The combined organic layers were dried with MgSO4, filtered and dried to give a solid which was chromatographed on silica gel eluting with 1/1/98 MeOH/HOAc/CH2Cl2 to give the title Compound (3.166 g, 48%). Anal calcd for C15H16NO4F: C, 61.43; H, 5.50; N, 4.78. Found: C, 61.16; H, 5.50; N, 4.77.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:25][C:24]4[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:23]=4[CH:22]=3)(=[O:20])=[O:19])[CH2:14][C:13]2=[O:31])[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:23]2[CH:22]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][N:12]([CH2:11][C:8]4[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=4)[C:13](=[O:31])[CH2:14]3)(=[O:20])=[O:19])[S:25][C:24]=2[CH:26]=1
Reactant: CCOC(=O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1csc(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)n1
Reaction time: 2 h

Procedure:
A solution of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid ethyl ester (75 mg, 0.15 mmol) is dissolved in THF/MeOH −3:1 (2 mL) and a solution of 1N NaOH is added (0.5 mL). The reaction is stirred for 2 h and then diluted with EtOAc and washed with 2N HCl. The organic phase is dried (MgSO4) and concentrated to yield 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-thiazol-4-yl-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (d, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 8.04 (d, 1H), 7.57 (dd, 1H), 4.74 (s, 2H), 3.87 (s, 2H), 3.49 (s, 4H); MS (Ion Spray) 471 (M)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=N/S(C2SC=CC=2)(=O)=O)/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].ClC1C(=O)C2C(=CC=CC=2)/C(=N/S(C2SC=CC=2)(=O)=O)/C=1.CCOC(C)=O.[N+:55]([C:58]1[CH:63]=[CH:62][C:61]([S:64]([NH2:67])(=[O:66])=[O:65])=[CH:60][CH:59]=1)([O-:57])=[O:56]>ClCCCl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:67][S:64]([C:61]2[CH:60]=[CH:59][C:58]([N+:55]([O-:57])=[O:56])=[CH:63][CH:62]=2)(=[O:65])=[O:66])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1cc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2c1O

Procedure:
5.2.25 Ethyl 2-(1-hydroxy-4-(4-nitrophenylsulfonamido)naphthalen-2-ylthio)acetate (9e) was prepared according to the procedure for 8a except using 4-nitrobenzenesulfonamide, 1,2-dichloroethane as solvent and applying 100° C. to the reaction. The reaction was worked up according to the procedure for 12a and the title compound was isolated from the product mixture by flash chromatography (EtOAc/Hex) affording 48 mg (10.4%) as a brown solid, m.p.: 143-145° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 71 %

Procedure:
As described for example 342 g, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (170 mg, 71%) which was obtained as a white solid. MS: m/e=414.2 [M+H]+.
Reaction SMILES: Cl.[C:2](N1CC2C=C(C3C=CC=CC=3)C=CC=2N(CC2N=CNC=2)C[C@H]1CC1C=CC=CC=1)(=O)C.[NH2:35][C:36]1[CH:66]=[CH:65][C:39]2[CH2:40][N:41]([C:58]([O:60][C:61]([CH3:64])([CH3:63])C)=[O:59])[CH:42]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:43][N:44]([CH2:45][C:46]3[N:47]=[CH:48][NH:49][CH:50]=3)[C:38]=2[CH:37]=1.C1(C)C=CC=CC=1.[Cl:74]C(OC(C)C)=O>CCOC(C)=O.CCCCCC>[ClH:74].[C:36]([C:66]1[CH:2]=[CH:37][C:38]2[N:44]([CH2:45][C:46]3[N:47]=[CH:48][NH:49][CH:50]=3)[CH2:43][C@@H:42]([CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[N:41]([C:58]([O:60][CH:61]([CH3:63])[CH3:64])=[O:59])[CH2:40][C:39]=2[CH:65]=1)#[N:35]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2N(Cc2c[nH]cn2)CC1Cc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Yield: 42 %

Procedure:
Example 358 was prepared as a light yellow solid in 42% yield from Compound C of Example 248 by the following sequence: Compound E of Example 248, using a toluene solution of isopropyl chloroformate with chromatography using 40% hexane in EtOAc and with the free base carried on; Example 354. MS: [M+H]+ =430.