Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].O.[Br:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Br:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:18]
Reactant: CC(C)C(Br)C(=O)Cl
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(Br)C(=O)Nc1ccccc1O

Procedure:
To a mixture of 2-aminophenol (27 25 g), sodium hydrogencarbonate (31.5 g), ethyl acetate (250 ml), and water (200 ml), a solution of 2-bromo-3-methylbutyryl chloride (49.8 g) in ethyl acetate (100 ml) was added dropwise with ice-cooling and with stirring. After stirring with ice-cooling for further 1 hour, the ethyl acetate layer was separated, washed with water, and dried (MgSO4), and the solvent was evaporated off. The residue was crystallized from hexane, to give 2-(2-bromo-3-methylbutyryl)aminophenol. Yield was 59.7 g (87.9%). Recrystallization from isopropyl ether gave colorless prisms, mp 110°-111° C.
Reaction SMILES: [C:1]1([Si:7]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:8]2[CH:39]=[CH:38][C:11]3[O:12][C:13]4[CH:18]=[CH:17][C:16]([Si:19]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:55]=[O:56])C.Cl>C1COCC1.C1CCCCC1>[C:32]1([Si:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[CH:17]=[C:18]([CH:55]=[O:56])[C:13]3[O:12][C:11]4[CH:38]=[CH:39][C:8]([Si:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[CH:9][C:10]=4[C:14]=3[CH:15]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc3oc4ccc([Si](c5ccccc5)(c5ccccc5)c5ccccc5)cc4c3c2)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=Cc1cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc2c1oc1ccc([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
1 g (1.46 mmol) 2,8-di-(triphenylsilyl)-dibenzofuran are dissolved in 100 ml dry THF at 45° C. and 10 ml of 1.4 M sec-Buthyllithium solution in cyclohexane is added. After stirring for 15 min. at 45° C., 2 ml of dry DMF is added; the reaction mixture is stirred for 1 h. 100 ml of 0.5 M HCl is added to quench the reaction. The product is extracted with ethylacetate and purified by column chromatography on silica gel with heptane:ethylacetate (3:1) as an eluent. 2,8-di-(triphenylsilyl)-dibenzofuran-4-carboxaldehyde (5.3) is obtained in 30.2% yield.
Reaction SMILES: B(F)(F)F.C[CH2:6][O:7]CC.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1([CH2:21][CH2:22][CH3:23])[O:20][CH2:19]1.C(=O)(O)[O-].[Na+]>CO>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]([O:20][CH3:19])([CH2:21][CH2:22][CH3:23])[CH2:6][OH:7]
Reactant: CCCC1(c2ccc(Cl)cc2Cl)CO1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCC(CO)(OC)c1ccc(Cl)cc1Cl
Temperature: 30 °C
Reaction time: 6 h

Procedure:
12.5 ml of boron trifluoride ethyl etherate are added dropwise slowly to a solution of 20.7 g (90 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxypentane in 100 ml of absolute methanol. The temperature is kept at 18°-20° C. by occasional cooling. The temperature is then kept at 18°-20° C. for a further 6 hours, and the mixture is then stirred for a further hour at 30° C. The solution is poured into ice-cold, dilute sodium bicarbonate solution, and the resulting mixture is extracted twice with diethyl ether. The combined ether extracts are washed twice with half-saturated sodium bicarbonate solution and then twice with sodium chloride solution and are dried over sodium sulfate, filtered and concentrated. This gives 26.2 g of a yellowish, slightly viscous liquid, which is distilled in a high vacuum using a Vigreux column. The 2-(2,4-dichlorophenyl)-2-methoxypentan-1-ol thus obtained is a colourless, viscous oil of boiling point 88°-90° C./10.7×10-3 mbar and n50D 1.5322. Yield 12.1 g (=51% of theory), 100 mHz-1H-NMR(CDCl3): δ=7.15-7.6 ppm (m, 3H, aromatic); 4.1 ppm (dd, 2H, --CH2OH); 3.25 ppm (s, 3H, --OCH3); 1.7-2.3 ppm (m, 3H, ##STR19## 1H disappears on adding D2O); 0.7-1.25 ppm (m, 5H, --CH2CH2CH3).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(C(C)C)n2)n[nH]1
Reactant: ClCCN1CCOCC1
Product: Cc1cc(Nc2cc3cc(OCCN4CCOCC4)ccc3c(C(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 329 was used, starting from 1-Isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and N-(2-chloroethyl)-morpholine to give [1-Isopropyl-6-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 396(MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9]>C(Cl)Cl>[CH2:2]1[NH:1][C:8](=[O:9])[N:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]12
Reactant: NC[C@@H]1CCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1NC[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.2 %

Procedure:
(S)-2-(Aminomethyl)pyrrolidine (250 mg) and carbonyldiimidazole (400 mg, 1.0 equiv.) were dissolved in DCM (50 mL). The resulting mixture was stirred at room temperature for 18 hours, then concentrated under vacuum. The residue was purified by flash column chromatography (SPE cartridge, SiO2), using DCM-methanol (95:5) as eluent to afford the title compound as colourless solid (150 mg, 50% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]([CH2:12][CH2:13][C:14](=O)[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[CH3:4][N:5]([CH2:12][CH2:13][C:14](=[N:2][OH:3])[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: CC(=O)CCN(C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(CCN(C)c1ccccc1)=NO
Reaction time: 72 h

Procedure:
Add hydroxylamine hydrochloride (4.9 g=70 mmol) in 20 ml water to a solution of 4-(N-methylanilino)-2-butanone (12.4 g=70 mmol) and sodium carbonate (8.6 g=80 mmol) in 60 ml 50% ethanol. Stir for three days, concentrate and extract with ethyl acetate. Dry, concentrate and recrystallize from ether-hexane to obtain product having a melting point 46°-49° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1ccc(O)c[nH]1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1ccc(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 5-hydroxypyridin-2(1H)-one (4.44 g, 40.0 mmol) in methanol (50 mL) was added potassium hydroxide (2.64 g, 40.0 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature, followed by the addition of benzyl bromide (5.2 mL, 44 mmol). The reaction mixture was kept stirring at ambient temperature for 2 hours and then heated at 45-50° C. for 1 hour. The solvent was removed in vacuo, and the residue was washed with water, dichloromethane and then recrystallized from methanol to afford the title compound (5.39 g, 67%): 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.42-7.26 (m, 6H), 7.09 (d, J=3.0 Hz, 1H), 6.30 (d, J=9.6 Hz, 1H), 4.89 (s, 2H); MS (ES+) m/z 202.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[OH-].[Na+]>[C:13]1([NH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Nc2ccnc3ccccc23)cc1
Temperature: 150 °C
Yield: 101.8 %

Procedure:
A mixture of 4-chloroquinoline (10 g) and aniline (11.4 g) was warmed to 150° C. for 30 min. A solution of sodium hydroxide 1 N (200 ml) was added. After extraction with ethyl acetate (1 L), the organic layer was separated and dried over sodium sulfate. The solvent was removed to afford an amorphous materiel, which was crystallized in cyclohexane. Phenyl-quinolin-4-yl-amine (13.7 g) was obtained after filtration.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.Cl.C(O)(C)C.C([O-])(O)=O.[Na+]>C(OC(C)C)(=O)C>[NH2:25][C@H:22]([CH2:23][CH3:24])[C:20]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:7]2[C:6]3[C:2]([CH3:1])([CH3:33])[CH2:3][O:4][C:5]=3[C:10]([CH3:11])=[CH:9][CH:8]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: CC(C)O
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
The 1,1-dimethylethyl {(1R)-1-[({6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate (Intermediate 30, 480 mg, 1.05 mmol) was dissolved in iso-propyl acetate (5 mL) and HCl 5-6N in isopropanol (1 ml, 5.25 mmol) was added. The solution was stirred at room temperature for 1 hour and then heated to −50-55° C. until complete conversion. The mixture was cooled to room temperature and treated with an aqueous saturated solution of NaHCO3. Two phases were separated and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol 95:5 as eluents affording the title compound (0.31 g) as yellowish foam.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:15]([NH:28][NH2:29])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C1COCC1>[Br:13][C:14]1[C:15]2[N:16]([C:5](=[O:11])[NH:29][N:28]=2)[CH:17]=[CH:18][C:19]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(-c2ccnc(NN)c2Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
To a solution of triphosgene (1.50 g, 5.20 mmol) in anhydrous THF (10 mL) at 60° C. was added 4-(3-bromo-2-hydrazinylpyridin-4-yl)benzonitrile (500 mg) in small portions over 5 min. The resulting yellow suspension was then refluxed for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the THF. Water (5 mL) was added carefully to the remaining solution to destroy the excess triphosgene, then the resulting aqueous suspension was stirred at room temperature for 30 min. The suspension was filtered, and the collected solid was washed with water (10 mL×2), then dried in a 45° C. vacuum oven for 16 h to afford 575 mg of the title compound as a yellow solid. HPLC/MS: retention time=2.44 min, [M+H]+=315.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=1[CH2:24]Cl>CN(C=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:15]2[C:14](=[CH:19][C:18]=1[O:20][CH3:21])[CH2:13][C:2]([C:1]([O:8][CH3:9])=[O:7])([C:3]([O:5][CH3:6])=[O:4])[CH2:24]2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)Cc2cc(OC)c(OC)cc2C1
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
To a solution of dimethyl malonate (1.7 ml, 14.9 mmol) in DMF (30 ml) at room temperature under nitrogen was added sodium hydride (1.3 g of a 60% dispersion in oil). The mixture was stirred for 20 minutes, and 1,2-bis(chloromethyl)-4,5-dimethoxybenzene (3.5 g, 14.9 mmol) was added. After 16 hours, the mixture was quenched with water and extracted three times with ether. The combined extracts were washed twice with water and dried (McSO4), filtered and evaporated. The residue was dissolved in methylene chloride and filtered through a pad of silica gel. Evaporation gave dimethyl 5,6-dimethoxyindane-2,2-dicarboxylate as a white solid (2.24 g, 55% yield).
Reaction SMILES: [OH-].[Na+].CC(C)=O.Cl.[OH:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ncccc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: OCc1ncccc1OCc1ccccc1
Yield: 104.9 %

Procedure:
Sodium hydroxide (31.5 grams, 0.78 mole) was dissolved in 100 ml water and 100 ml of acetone was added followed by 3-hydroxy-2(hydroxymethyl)pyridine hydrochloride (63.8 grams; 0.39 mole). 250 ml of acetone was added followed by benzyl bromide (74.1 grams; 51.5 ml; 0.43 mole). The mixture was refluxed for a period of 4.5 hours and the acetone evaporated in vacuo. The aqueous layer was extracted with CH2Cl2 (three times 150 ml) and the extracts dried (anhydrous Na2SO4) and concentrated to yield 88.1 grams of a brown liquid. The brown liquid (88.1 grams) was dissolved in ether and ether-HCl added to form the hydrochloride salt. The HCl salt was filtered and the filter cake dissolved in water. The aqueous solution was basified to afford a brown pasty precipate which on trituration with ether afforded 58.7 grams of material. Recrystallization from ethanol yielded 31.6 grams of a tan solid, m.p. 79°-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCCCC2)CC1

Procedure:
Prepared in analogy to Example 1 from piperazine-1-carboxylic acid tert-butyl ester and cyclohexanone.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[N:20][C:21]#[N:22])OC2C=CC=CC=2)[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3].[C:23]([NH2:28])([CH2:26][CH3:27])([CH3:25])[CH3:24]>C(O)(C)C>[N:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:20][C:21]#[N:22])=[N:28][C:23]([CH3:25])([CH3:24])[CH2:26][CH3:27])[CH:7]=[C:8]([I:10])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: CCC(C)(C)N
Reactant: N#CN=C(Nc1cc(I)cc(N=[N+]=[N-])c1)Oc1ccccc1
Solvent: CC(C)O
Product: CCC(C)(C)N=C(NC#N)Nc1cc(I)cc(N=[N+]=[N-])c1
Yield: 64.9 %

Procedure:
Step B-2. To a stirred suspension of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1, 1.09 g, 2.69 mmol) in isopropanol (20 mL) is added tert-amylamine (0.95 mL, 8.08 mmol). The reaction mixture is heated to reflux for 2.5 hour. The cooled reaction mixture is concentrated and the residue is diluted with ether (50 mL) and washed with 1 N aqueous sodium hydroxide (2×15 ml). The aqueous is extracted with ether (2×30 mL). The combined organics are dried (MgSO4), filtered and concentrated. The organic residue is purified by flash chromatography using 25% ethyl acetate in hexane as an eluent to afford 0.694 g of N-(3-azido-5-iodophenyl)-N'-cyano-N"-(1,1-dimethylpropyl)guanidine (B-2) as a foam. IR (mull) 3310, 3251, 3077, 2954, 2924, 2869, 2854, 2174, 2109, 1603, 1582, 1572, 1497, 1457, 1421, 1408, 1366, 1301, 1231, 844 cm-1 ; 1H NMR (CDCl3)δ8.29 (bs, 1 H), 7.33 (t, 1 H, J=2 Hz), 7.24 (t, 1 H, J=2 Hz), 6.83 (t, 1 H, J=2 Hz), 4.64 (bs I H), 1.70 (q, 2 H, J=7 Hz), 1.32 (s, 6 H), 0.84 (t, 3 H, J=7 Hz); 13C NMR (CDCl3) δ156.7, 142.7, 138.5, 129.0, 125.4, 116.9, 114.2, 94.8, 55.6, 32.9, 26.3, 8.1; Mass Spec (70eV, EI) m/z 397 (parent), 369, 328, 299, 258, 242, 232, 213, 172, 145, 130, 105, 71, 55, 43 (base); Exact mass calculated for C13H16IN7 : 397.0514. Found: 397.0532.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19](=[O:20])[NH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C(C)(C)CN
Product: CCOC(=O)C(C)(C)CNC(=O)NCc1ccccc1
Yield: 60.4 %

Procedure:
According to the procedure described in the synthesis method of Compound V-3, ethyl 3-amino-2,2-dimethylpropanoate (2.90 mg, 20 mmol) was reacted with benzyl isocyanate (1.24 ml, 10 mmol) to obtain the title compound (1.68 g, 30%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:31])([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:31])([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[N+:33]=[N-:34]
Reactant: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCOS(C)(=O)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCOC(=O)C(C)(CCCc1ccccc1)Cc1ccc(OCCN=[N+]=[N-])cc1
Yield: 84.1 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methyl-2-(3-phenylpropyl)propionate (1.16 g), which is the product of Reference example 7(g), and sodium azide (0.50 g) and the reaction mixture was treated to afford the desired compound (0.86 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]2)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)N[C@H]3CC[C@H](O)CC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with trans-4-aminocyclohexanol using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=511.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1.[Br:13]Br>ClCCl>[Br:13][C:3]1[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2ccccc2)n[nH]1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 5-methyl-3-phenyl-1H-pyrazole (8.0 g, 50.6 mmol) in dichloromethane (150 mL) was added bromine (8.08 g, 50.6 mmol) dropwise at 0° C., The reaction was stirred at that temperature for 30 min and continued at room temperature for 2 h. After the reaction was quenched with an aqueous solution of Na2SO3 (10% w/w, 10 mL), the organic solvent was removed and the aqueous mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow oil (9.5 g). LCMS m/z=236.9 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 7.30-7.57 (m, 5H), 13.12 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N+:3]([O-:18])=[C:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:13])[NH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])O.[K+].CN(C)C=O.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:5]([O:13][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:4]([CH2:14][CH:15]([CH3:17])[CH3:16])[N+:3]=1[O-:18]
Reactant: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
There were mixed 1.00 g of 5-amino-6-ethoxycarbonyl-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide, 1.18 g of potassium hydrogencarbonate (powder), 20 ml of dry dimethylformamide and 932 μl of benzyl bromide. The mixture was stirred for 16 hours at room temperature to effect a reaction. After completion of the reaction, the reaction mixture was poured into 50 ml of ethyl acetate. The resulting mixture was washed with 30 ml of water three times. The aqueous layer was extracted with 30 ml of ethyl acetate twice. The extract was combined with the above ethyl acetate layer. The combined solution was washed with 30 ml of water twice, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was recrystallized from ethanol to obtain 1.06 g of 2-amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide (Compound B-10) as pale yellow fine needle-like crystals having a melting point of 114.5°-115.5° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCN(CC)CC>C(O)C>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)C[C@H](N)C(=O)O
Temperature: 90 °C
Reaction time: 24 h

Procedure:
The Merrifield resin (2.1 g) was suspended in 30 ml of ethanol. A solution of 0.70 g (2.71 mM) of Boc-Leu and 0.9 equivalent of Et3N (2.43 mM, 0.34 ml) in 3 ml of ethanol was added to the resin suspension. The mixture was stirred slowly at 90° C. under anhydrous conditions for 24 hours using a magnetic stirrer. The esterified resin was washed successively with EtOH, H2O, MeOH and CH2Cl2 ; floated 3 times with CH2Cl2 to get rid of fine resin particles; and dried in vacuo over P2O5. Amino acid analysis gave a value of 0.25 mM of Leu/g of substituted resin.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH2:33][C:34]1([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][N:37]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:32])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH2:36][CH2:35]1
Reactant: NC1(C(=O)O)CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: NC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-piperidine-4-carboxylic acid following General Procedure B.