Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][C@H:10]([NH:13]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:11]O)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.Cl>ClCCl.O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][C@H:10]([NH2:13])[CH2:11][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC[C@H](N)CN1CCOCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
[(S)-3-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-hydroxybutyl]carbamic acid tert-butyl ester (128 mg, 0.301 mmol) obtained in Step 1 above was dissolved in dichloromethane (2.0 ml), and then methanesulfonyl chloride (35 μl, 0.452 mmol) and triethylamine (84 μl, 0.603 mmol) were added thereto at 0° C. After stirring for one hour, a saturated aqueous sodium bicarbonate solution (5 ml) and water (15 ml) were added to the mixture. The solution was extracted three times with dichloromethane (20 ml). The dichloromethane solutions were combined together and sequentially washed with a saturated aqueous sodium chloride solution, 0.1N hydrochloric acid, and a saturated aqueous sodium chloride solution. The washed dichloromethane solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was dissolved in tetrahydrofuran (2.0 ml), and then morpholine (105 μl, 1.21 mmol) was added thereto. The mixture was heated at 65° C. for 16 hours. Water (5 ml) and 1N hydrochloric acid (1 ml) were added to the reaction solution, and washed with ethyl acetate (5 ml). A saturated aqueous sodium bicarbonate solution (20 ml) was added to the washed aqueous solution. The mixture was extracted three times with ethyl acetate (25 ml) and then three times with dichloromethane (25 ml). The ethyl acetate/dichloromethane solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to yield ((S)-3-amino-4-morpholin-4-ylbutyl)carbamic acid tert-butyl ester (24 mg) as a colorless oily material.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH:12](=[N:11][NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: NNS(=O)(=O)c1ccccc1
Solvent: CO
Product: O=S(=O)(NN=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 86 g (0.5 mol) of benzenesulfonohydrazide and 700 ml of methanol, and 63.6 g (0.6 mol) of benzaldehyde was dropwise added thereto in one hour while stirring at room temperature and heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([CH2:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:33][C:34]1([CH3:38])[CH2:37][NH:36][CH2:35]1>>[NH2:33][C:34]1([CH3:38])[CH2:37][N:36]([C:21]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:20]=2)=[N:6][C:7]2[N:8]([CH2:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:35]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CC1(N)CNC1
Agent: CS(=O)(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(C)(N)C4)cc3nc21
Yield: 78.4 %

Procedure:
8-(3-Amino-3-methyl-1-azetidinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.52 g of 7,8-difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid and 2.22 g of 3-amino-3-methylazetidine dimethanesulphonate, for 72 hours at approximately 20° C. and then 1 and a half hours at a temperature in the region of 90° C. The insoluble matter in the reaction mixture is drained at approximately 20° C., washed with twice 20 cm3 of water, recrystallized in 70 cm3 of dimethylformamide and washed with 40 cm3 of ethanol at approximately 75° C. 1.45 g of 8-(3-Amino-3-methyl-1-azetidinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 334° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].O>CC(CC(C)C)=O>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][S:21][C:19](=[O:22])[CH3:20])[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(=O)SCC1CCOCC1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 95.4 %

Procedure:
To a solution of 224 g (0.83 mol) of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70° C. for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through Celite® (20 g), activated charcoal (20 g) and Na2SO4 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester as a yellow-orange oil (CAUTION: Stench!). Yield: 96%; ES-MS: m/z 175 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.40 (2H, m), 1.59-1.78 (3H, m), 2.33 (3H, d, J=4.16 Hz), 2.82 (2H, dd, J=6.24, 3.79 Hz), 3.27-3.39 (2H, m), 3.88-4.02 (2H, m)
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1.Cl[CH:10]([C:14](=[O:16])[CH3:15])[C:11](=[O:13])[CH3:12]>CO>[CH3:15][C:14](=[O:16])[CH:10]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[C:11](=[O:13])[CH3:12]
Reactant: Sc1nc[nH]n1
Reactant: CC(=O)C(Cl)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C(Sc1nc[nH]n1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium hydroxide (13 g) in methanol (200 ml), with cooling it on ice, was added 3-mercapto-1H-1,2,4-triazole (20 g), followed by 3-chloro-2,4-pentanedione (24 ml). Then, mixture was stirred at room temperature overnight. Insoluble materials in the reaction solution were filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered through a small amount of silica gel, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was recrystallized in ethyl acetate-hexane to yield the title compound (33.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20](=[O:26])[N:21]([CH3:25])[C:22]=1[CH2:23]Br)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH3:25][N:21]1[C:22]2=[CH:23][N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]1=[O:26]
Reactant: Nc1ccccc1O
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3ccccc3O)cc2n(C)c1=O
Yield: 96.3 %

Procedure:
In a 25 mL round bottom was placed o-aminophenol (163 mg, 1.5 mmol) and EtOH (10 mL). The mixture was warmed until homogenous and then compound 4a (250 mg, 741 μmol) was added (see Example 2 for synthesis of 4a). The mixture was stirred vigorously at reflux during which a precipitate formed. After 1 h the mixture was cooled in an ice bath, filtered, and the precipitate washed with cold EtOH to yield 5e (248 mg, 96.4%) as a white powder. 1H NMR (600 MHz,) δ 10.02 (s, 1H), 7.29-7.26 (m, 2H), 7.24-7.17 (m, 4H), 7.10 (dd, J=1.6, 7.8, 1H), 6.96 (s, 1H), 6.90 (dd, J=1.1, 8.2, 1H), 6.77 (td, J=1.2, 7.6, 1H), 3.34 (s, 3H), 3.21 (s, 3H). 13C NMR (151 MHz, DMSO d6) δ 159.11, 152.86, 150.91, 133.81, 130.35, 129.98, 129.67, 129.13, 128.58, 127.83, 127.18, 125.95, 118.99, 116.39, 106.16, 101.88, 31.50, 27.46. MS (ES+) (m/z): [M+1]+ calculated for C20H18N3O3, 348.13. found 348.11.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].C1COCC1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>O>[N+:36]([C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:26]=1[N:13]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14]1)([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 200-mL RBF was added (s)-3-n-boc-amino piperidine (10.9 g, 54.4 mmol), Sodium bicarbonate (11.4 g, 136 mmol), THF, and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.62 ml, 54.4 mmol). The yellow mixture was heated to 70° C. with a water-cooled reflux condenser. The orange mixture was allowed to stir for 14 h, and was then cooled to ambient temperature, and filtered through a glass frit, rinsing with EtOAc. Concentration in vacuo afforded an orange oil, which crystallized on standing to an orange solid. The material was treated with 250 mL hexanes and heated on the rotovap (no vacuum) to 60° C. Small amounts of EtOAc were added until all solid dissolved, total volume of EtOAc was approx 10 mL. The solution was allowed to cool overnight, resulting in the formation of orange crystals. The liquid was decanted and the crystals rinsed twice with 50 mL hexanes. The crystals were collected to give (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate as orange crystals. The filtrate was concentrated to an orange solid. This material was treated with 150 mL hexanes and was heated to 65° C. Almost all of the material had dissolved. The hot liquid was decanted into a flask and allowed to cool overnight, resulting in an orange solid. The liquid was discarded, and additional crystals of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate were collected. MS m/z=390 [M+H]+. Calc'd for C17H20F3N3: 389.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[NH2:29][CH2:30][CH2:31][C:32]#[N:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:33][CH2:32][CH2:31][C:30]#[N:29])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: N#CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NCCC#N)s3)C[C@H]2OC)nc1Cl
Yield: 79.9 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (75 mg, 0.18 mmol), 3-aminopropionitrile (14 mg, 0.20 mmol), WSC hydrochloride (111 mg, 0.58 mmol), HOBT (39 mg, 0.29 mmol), dichloromethane (1.5 mL) and DMA (1.5 mL), to obtain 69 mg of the title compound as a white solid (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18](I)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:19]=[C:18]([C:26]#[C:25][CH2:24][OH:27])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Reaction time: 18 h
Yield: 77 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-2-iodo-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 23) (1.632 g) in diethylamine (40 mL) is added copper iodide (0.210 g) and Pd(PPh3)2Cl2 (0.125 g) followed by addition of propargyl alcohol (0.29 mL). The reaction is stirred at art for 18 h. The diethylamine is removed in vacuo and the resulting brown solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield an orange solid which is recrystallized from ethanol to yield 1.06 g (77%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:8][N:7]([CH2:28][C:27]5[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=5)[CH2:6][CH:5]4[CH2:1]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: FC(F)(F)c1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[2-[[4-(trifluoromethyl)phenyl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(N2CCN(C)CC2)c1
Temperature: 80 °C

Procedure:
A mixture of Trifluoro-methanesulfonic acid 3-((R)-1-tert-butoxycarbonylamino-ethyl)-phenyl ester (0.340 g, 0.921 mmol), 1-methylpiperazine (0.37 g, 3.68 mmol), Pd2(dba)3 (0.042 g, 0.046 mmol), 2-(di-tert-butylphosphino)-biphenyl (0.054 g, 0.184 mmol), and potassium phosphate (0.273 g, 1.29 mmol) in 20 mL of 1,4 dioxane was heated at 80° C. in a sealed tube for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and the washed with water (20 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford the crude title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O.Cl.[NH2:20][OH:21]>CO>[CH3:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[N:20][OH:21]
Reactant: NO
Reactant: CC(C)(C)CCC1CCCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCC1CCCC1=NO
Temperature: 50 °C
Reaction time: 15 h

Procedure:
At 0° C., aq. sodium carbonate solution is added to a solution consisting of 20.0 g of (119 mmol) of 2-(3,3-dimethylbutyl)cyclopentanone and 16.5 g (238 mmol) of hydroxylamine hydrochloride in 200 ml of methanol until the pH is 8. The mixture is then stirred at 50° C. for 15 hours. After the reaction has ended, the mixture is cooled to room temperature and filtered off and the product is concentrated under reduced pressure. The residue is extracted with water/diethyl ether. The org. phase is dried with sodium sulphate and concentrated under reduced pressure. This gives 20.0 g (92% of theory) of an 2-(3,3-dimethylbutyl)-N-hydroxycyclopentanimine.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:31]3[O:30][CH2:29][CH2:28][N:27]([CH3:32])[C:26]=3[CH:25]=[C:24]([Cl:33])[CH:23]=2)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38](C(O)=O)=[C:37]([O:45][CH3:46])[CH:36]=1>>[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:31]4[O:30][CH2:29][CH2:28][N:27]([CH3:32])[C:26]=4[CH:25]=[C:24]([Cl:33])[CH:23]=3)=[O:21])[CH2:11]2)=[O:7])=[C:37]([O:45][CH3:46])[CH:36]=1
Reactant: CN1CCOc2c(C(=O)NCCCCN3CCC(CNC(=O)OC(C)(C)C)C3)cc(Cl)cc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2cc(Cl)cc3c2OCCN3C)C1

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide (0.7 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.37 g) to give N-(4-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)-pyrrolidin-1-yl)butyl)-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])#[N:11].C(NCC)C.C(O)(=O)C>C(O)(C)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[CH:4][CH:3]=1
Reactant: CCCCC(CC)COC(=O)CC#N
Reactant: Nc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: CCNCC
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)C(C#N)=Cc1ccc(N)cc1
Reaction time: 4 h
Yield: 66.1 %

Procedure:
36.3 g (0.3 mol) of p-aminobenzaldehyde are suspended in 450 ml of isopropanol. A mixture of 59.1 g (0.3 mol) of 2-ethylhexyl cyanoacetate and of catalyst (0.375 ml of diethylamine and 1.125 ml of acetic acid) is introduced therein. The mixture is refluxed for 5 hours. The same amount of catalyst is added again and refluxing is continued for a further 4 hours. The insoluble materials are removed by hot filtration and the mixture is concentrated to a volume of 300 ml and left to crystalize. After filtration and drying, 59.6 g (66% yield) of an orange-coloured powder are obtained, and are used without further purification for the following step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(C)(C)C>[Br:1][C:2]1[C:3]([CH:9]([O:15][C:3]([CH3:9])([CH3:4])[CH3:2])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C(O)c1c(C)sc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 176 %

Procedure:
To a suspension of ethyl 2-(4-bromo-2,5-dimethylthiophen-3-yl)-2-hydroxyacetate (28d) (830 mg, 2.83 mmol) in tert-butylacetate (29 mL) at −10° C. was added perchloric acid (1 mL). The mixture was stirred at −5° C. for 1 hour. The mixture was then basified with a saturated aqueous solution of sodium bicarbonate until pH 8. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (28e) as a colorless oil (870 g, 2.49 mmol, 88%).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].Cl[C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=[C:11]([CH3:20])[C:10]=1[CH:21]=O>C(O)C>[CH3:20][C:11]1[C:10]2[CH:21]=[C:2]([C:3]([OH:5])=[O:4])[S:1][C:9]=2[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=1
Reactant: O=C(O)CS
Reactant: Cc1nn(-c2ccccn2)c(Cl)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2ccccn2)c2sc(C(=O)O)cc12
Reaction time: 2 h

Procedure:
In a 1.0-liter egg plant-type flask, mercaptoacetic acid (10.3 g, 0.15 mol) and potassium hydroxide (35.6 g, 0.54 mol) were added to an ethanol (600 mL) solution of 5-chloro-3-methyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde (30.0 g, 0.14 mol), and stirred for 2 hours with heating under reflux. Ethanol was removed from the reaction solution under reduced pressure, then the residue was diluted with water and made acidic with aqueous 5 N hydrochloric acid solution added thereto, and the formed precipitate was taken out through filtration, washed with methanol and ethyl acetate in that order, and dried under reduced pressure to obtain the title compound as a pale brown solid.
Reaction SMILES: ClC(OCC)=O.[C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([OH:9])=O.C(N(CC)CC)C.Cl.[CH2:53]([O:60][C:61](=[O:64])[CH2:62][NH2:63])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[O:64]=[C:61]([O:60][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:62][NH:63][C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:9]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.4 %

Procedure:
To a -10° C. methylene chloride (2 mL) solution of ethyl chloroformate (57 mg, 0.53 mmol) was added a methylene chloride (2 mL) solution of compound 29 (220 mg, 0.44 mmol) and triethylamine (530 mg, 0.13 mmol). The resultant solution was stirred between -5° C. and 5° C. for 1 h. Glycine benzyl ester hydrochloride (0.11 g, 0.64) was added, followed by triethylamine (0.53 g, 0.13 mmol). The resulting suspension was stirred at room temperature for 21 h and filtered through a sintered glass funnel. The solid was washed with methylene chloride. The filtrate and the washing portion were combined and washed with 1N HCl, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:EtOAc/9:1) to afford 140 mg (47%) of the title product.