Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(O)=[O:4].[O:6]1[C:17]2[C:9](=[CH:10][C:11](=[CH:15][CH:16]=2)[CH:12]=[CH:13][CH3:14])[O:8][CH2:7]1.S(=O)(=O)(O)O>O.CC(C)=O>[CH2:7]1[O:6][C:17]2[CH:16]=[CH:15][C:11]([CH2:12][C:13](=[O:4])[CH3:14])=[CH:10][C:9]=2[O:8]1
Reactant: O=CO
Reactant: CC=Cc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Hydrogen peroxide (70 ml, 30%) was added with caution to a solution of formic acid (350 ml, 88%) in a three-necked flask (1 L) cooled with running water. Isosafrole (72 ml) was added drop-wise, by a dropping funnel, to the reaction mixture at a rate to keep the temperature of the reaction mixture below 35° C. After the complete addition of isosafrole, a non-homogeneous solution was obtained. At this point, acetone (200 ml) was added to the reaction mixture at a rate to keep the temperature below 35° C. The reaction was allowed to stand at room temperature overnight. The solvent was removed by a rotary evaporator equipped with a dry-ice acetone cold trap, a high vacuum pump and a water bath with temperature not exceeding 30° C. Ethyl ether (500 ml) was added to the residue. The solution was transferred into a separatory funnel. The organic phase was washed with sodium bicarbonate (0.1 N, 2×500 ml) and water (3×300 ml). The organic phase was transferred into a round bottom flask. The solvent was removed by rotary evaporation. Concentrated sulfuric acid (75 ml) was diluted drop-wise in water (425 ml). Methanol (160 ml) was added to the oily residue, and mixed to obtain a homogeneous solution. The sulfuric acid solution was added to the methanolic reaction mixture. The flask was equipped with a water-cooled reflux condenser and a heating mantel. The reaction mixture was heated to reflux for 4 hours. The heat was removed and crushed ice (150 g) was added to the reaction mixture. The reaction mixture was transferred into a separatory funnel and extracted with ethyl ether (1×350 ml, 1×150 ml and 1×100 ml). The combined organic layers were washed with water (3×150 ml). Sodium hydroxide (40 ml, 0.1 N) was diluted in water (360 ml). The organic phase was washed with diluted sodium hydroxide (2×200 ml, 10 mM) and saturated sodium chloride solution (100 ml). The organic layer was dried with anhydrous sodium sulfate (20 g) overnight. The drying agent was filtered and the cake was washed with ethyl ether (2×10 ml). The solvent was removed by rotary evaporation. The product was distilled at reduced pressure (2-0.5 mmHg). The second fraction distilling at 90-100° C. (˜1 mmHg) contained product. The product was identified by El/MS with the m/z of 182. Infrared spectrum (cm−1) indicated 1714 (C═O) and 2898 (C—H) stretches corresponding to the product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11](I)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([Cl:15])=[N:10][C:11]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([F:28])[CH:34]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)nc1Cl
Reactant: OB(O)c1ccnc(F)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccnc(F)c2)nc1Cl

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-6-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-fluoro-4-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=37%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu]I>[CH3:13][CH:14]1[CH2:18][N:17]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:16]=[N:15]1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CC1CN(c2cc(N)cc(C(F)(F)F)c2)C=N1
Temperature: 120 °C

Procedure:
A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g, 24 mmol), potassium carbonate (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120° C. (oil bath temperature) for 15 h. The mixture was cooled down to 45-50° C. and 14% aq. NH4OH (20 mL) was added. The mixture was maintained at this temperature for 1 h. After cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was dried over sodium sulfate and concentrated on a rotavap. The crude product was recrystallized from EtOAc/hexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC>[O:19]=[C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.42 h

Procedure:
A solution of n-butyl lithium (100 mL, 1.6M, 160 mmol) in hexanes was added over 2 min. to a stirred solution of 2-bromopyridine (15.0 nL, 24.9 g, 157 mmol) in 500 mL of ether cooled in a dry ice/isopropanol bath, causing a temporary rise in temperature to −47° C. After 25 min., the solution was transferred rapidly to a stirred 0° C. solution of diethyl oxalate (75 mL, 81 g, 550 mmol) in 1000 mL of ether. After 2 h at 0° C., the mixture was washed with saturated aq. sodium bicarbonate (900 mL), water (900 mL), and saturated aq. brine (450 mL). The organic layer was dried (magnesium sulfate), filtered, and evaporated. Distillation gave the title compound as 11.68 g of yellow liquid, B.p. 96-108° C. (0.3 mm Hg pressure). For the title compound:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:19][CH2:20][CH2:21][N:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([N:33]3[CH2:54][CH2:53][C:36]4([NH:40]/[C:39](=[N:41]/[C:42]([C:44]5[C:49]([NH2:50])=[N:48][C:47]([NH2:51])=[C:46]([Cl:52])[N:45]=5)=[O:43])/[NH:38][CH2:37]4)[CH2:35][CH2:34]3)=[O:32])[C:25]=2[CH:24]=[CH:23]1>CO>[OH:19][CH2:20][CH2:21][N:22]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:31]([N:33]3[CH2:34][CH2:35][C:36]4([NH:40]/[C:39](=[N:41]/[C:42]([C:44]5[C:49]([NH2:50])=[N:48][C:47]([NH2:51])=[C:46]([Cl:52])[N:45]=5)=[O:43])/[NH:38][CH2:37]4)[CH2:53][CH2:54]3)=[O:32])[C:25]=2[CH:24]=[CH:23]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc5c4ccn5CCOC4CCCCO4)CC3)N2)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc5c4ccn5CCO)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
p-Toluenesulfonic acid monohydrate (1.6 mg, 0.0084 mmol) is added to a stirred solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-4-carbonyl}-1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide (Ex. 84) (50 mg, 0.084 mmol) in MeOH (3 ml) and the resulting solution is stirred at room temperature for 3 hrs, then heated at 50° C. for 16 hours. The solvent is removed in vacuo and the residue is dissolved in MeOH (3 ml) and loaded onto a 1 g PEAX cartridge which is eluted with MeOH (20 ml). The filtrate is concentrated in vacuo to afford the title compound; [M+H]+ 512/514
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:13][C:12]([C:26]2[CH:27]=[C:28]([C:32]3([NH:36]S(C(C)(C)C)=O)[CH2:35][O:34][CH2:33]3)[CH:29]=[CH:30][CH:31]=2)=[N:11]1)[CH3:9]>CO>[CH2:8]([N:10]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)=[CH:13][C:12]([C:26]2[CH:27]=[C:28]([C:32]3([NH2:36])[CH2:35][O:34][CH2:33]3)[CH:29]=[CH:30][CH:31]=2)=[N:11]1)[CH3:9]
Reactant: CCn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCn1nc(-c2cccc(C3(N)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
A solution of hydrochloric acid in dioxane (4 M, 1.55 mL, 6.2 mmol, 4.0 equiv) was added to a solution of N-[3-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (785 mg, 1.55 mmol, 1 equiv) in methanol (3.5 mL) at 22° C. The reaction mixture was stirred for 15 minutes, then was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)oxetan-3-amine, which was used in the next step without further purification. Calc'd (M+1)+: 404.2. Found: 404.1.
Reaction SMILES: O[C:2]1[N:3]2[C:7]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[N:6][CH:5]=[N:4]2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:3]2[C:7]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[N:6][CH:5]=[N:4]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)n2ncnc2n1
Product: CC(C)(C)c1cc(Cl)n2ncnc2n1

Procedure:
The mixture of 20 g of 4-hydroxy-6-t-butyl-1,3,3a,7-tetraazaindene and 80 ml of phosphorus oxychloride was refluxed over an oil bath at 140° to 150° C. for 3 to 4 hours. Excess phosphorus oxychloride was distilled away under reduced pressure and then the reaction mixture was poured into ice water. The product was extracted with methylene chloride, and dried over anhydrous sodium sulfate. Upon distilling off the methylene chloride, pale yellow crystal in yield of 16 g was obtained.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccn2nccc2n1
Product: Clc1ccn2nccc2n1

Procedure:
A mixture of the product (1.35 g, 10.0 mmol) from Step A above and 7.5 mL of phosphorus oxychloride was warmed at reflux for 4 h. The mixture was cooled, and the volatiles were removed under reduced pressure. The dark residue was partitioned between ice water and dichloromethane, and the aqueous layer was extracted with additional dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide a light brown solid, which was purified by flash chromatography (silica gel; 0.5% methanol in dichloromethane eluant) to afford the title compound as a white solid. MS 153.8 and 155.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]2[CH:8]=[N:7][C:6]([CH3:13])=[CH:5][C:4]=2[C:3]=1[NH2:14].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[F:1][C:2]1[C:3]([NH:14][C:23]([NH:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:28])[F:27])=[CH:26][CH:25]=2)=[O:24])=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH:8]=[N:7][C:6]([CH3:13])=[CH:5]2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(N)c(F)cc(F)c2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)c(F)cc(F)c2cn1

Procedure:
Prepared from 6,8-difluoro-3-methylisoquinolin-5-amine (Description 73) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 396 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Br)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:13]([O:15]CCCC)=[CH2:14].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: C=COCCCC
Reactant: Fc1cc(Br)c2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(F)cc2cccnc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 70.7 %

Procedure:
To a solution of 6-fluoro-8-bromo-quinoline (1.53 g, 6.8 mmol) in acetonitrile (35 mL) was added palladium(II) acetate (0.31 g, 1.36 mmol, 0.2 eq.), butyl vinyl ether (2.04 g, 20 mmol, 3.0 eq.), and 1,3-bis(diphenylphosphino)propane (0.70 g, 1.7 mmol, 0.25 eq) was added triethylamine (1.1 g, 11 mmol, 1.6 eq). The resulting mixture was heated to 90° C. for 17 hr and then evaporated under reduced pressure. The residue was dissolved in aqueous hydrochloric acid (2M, 15 mL) and stirred, at room temperature, for 1.5 hr. This mixture was then diluted with water (35 mL) and the pH adjusted with solid sodium hydrogen carbonate until neutral. The mixture was then extracted with ethyl acetate (100 mL); the organic phase was dried over magnesium sulphate. The resulting mixture was filtered and concentrated under reduced pressure to give a brown oil. This crude product was purified by chromatography on silica gel eluting with 10% ethyl acetate in pentane (by volume) to produce the title compound as a pale yellow solid (0.91 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1)([O-:35])=[O:34]>ClCCl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.2 g, 0.54 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.135 g, 1.34 mmol) (Aldrich), followed by the addition of 1-nitro-4-isocyanato-benzene (0.105 g, 0.64 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with wthyl acetate. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide as a yellow solid (Yield 0.19 g, 68%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][CH:7]=1)=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.Cl>C1COCC1.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:4]([C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][CH:7]=2)=[O:5])=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1csc(C)c1C
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1scc(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a cooled (−40° C.) solution of N-methoxy-N,4,5-trimethylthiophene-3-carboxamide (1.77 g, 8.88 mmol) in THF (10 mL) was slowly added (over 10 min) a solution of 4-chlorophenylmagnesium bromide (17 mL, 17.00 mmol, 1 M) in diethyl ether. The reaction mixture was allowed to gradually warm to room temperature and age for several hours. To the mixture was added 1 N HCl and the aqueous layer was extracted with EtOAc (2×). The combined organic layer was washed with saturated NaHCO3, water, dried over Na2SO4, and concentrated to give an oil. The resultant oil was purified on Biotage system (gradient elution 1% EtOAc:99% Hexanes to 4% EtOAc:96% Hexanes) to give the titled compound as white solids (2.00 g, 7.96 mmol, 90% yield). LC/MS m/z 251 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([F:34])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15]([F:26])=[CH:14][C:13]=1[F:27])[CH:9]=[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:7]2=[O:33].[N-:36]=[N+:37]=[N-:38].[Na+].CN(C)C=O>C(OCC)(=O)C>[N:36]([C:3]1[C:2]([Br:1])=[C:11]2[C:6]([C:7](=[O:33])[C:8]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:9][N:10]2[C:12]2[CH:17]=[C:16]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:15]([F:26])=[CH:14][C:13]=2[F:27])=[CH:5][C:4]=1[F:34])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Br)c(N=[N+]=[N-])c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
Ethyl 8-bromo-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1,000 mg) and sodium azide (180 mg) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred overnight at 60° C. After the reaction mixture was cooled back to room temperature, ethyl acetate (100 ml) was added to the reaction mixture, and the resultant mixture was washed 3 times with water (100 ml). After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (428 mg) as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:15][CH2:14]1
Reactant: CCS(=O)(=O)Cl
Reactant: N#Cc1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
The crude 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carbonitrile (Intermediate 9) (0.222 g, 0.493 mmol) was suspended in dichloromethane (5 mL) and treated with diisopropylethyl amine (0.257 mL, 1.48 mmols), and ethane sulfonyl chloride (0.070 mL, 0.74 mmols) at ambient temperature. After 2 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (25 mL), and extracted with dichloromethane (100 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified by combiflash (column 10 g, eluting with 100% dichloromethane, 5% ethyl acetate/dichloromethane, 30% ethyl acetate/dichloromethane) to give the title compound (0.083 g, 24%).
Reaction SMILES: C1COCC1.[CH2:6]([N:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]2[C:27]([O:29]CC)=[O:28])=[CH:10][C:9]1=[O:32])[CH3:7].[OH-].[Li+]>CO>[CH3:24][C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([C:11]2[CH:12]=[CH:13][N:8]([CH2:6][CH3:7])[C:9](=[O:32])[CH:10]=2)[C@H:15]([C:27]([OH:29])=[O:28])[CH2:16]1)=[O:21])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccn(CC)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.07 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1-ethyl-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3.1 eq.). The resulting cloudy solution was stirred vigorously at RT for 18 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12]CC=C)=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:16])[CH3:2].C(N(CC)[C:20]1[CH:25]=CC=C[CH:21]=1)C>>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:25][CH:20]=[CH2:21])[C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:16])[CH3:2]
Reactant: C=CCOc1ccc2c(c1)CC(=O)N2CC
Reactant: CCN(CC)c1ccccc1
Product: C=CCc1c(O)ccc2c1CC(=O)N2CC
Temperature: 0 °C
Yield: 12 %

Procedure:
A solution of 1.09 g. (5.02 mmoles) of 1-ethyl-5-allyloxyoxindole in 5 ml. of N,N-diethylaniline was heated at reflux for 1 hour. The cooled reaction was added to ice cold 1N hydrochloric acid and the mixture extracted with methylene chloride. The extract was washed with water (3×), saturated brine solution (1×) and dried over magnesium sulfate. The residue remaining after the solvent was removed was chromatographed on 22 g. of silica gel using 50-100% diethyl ether-hexane as the eluent to give 134 mg. (12% yield) of 1-ethyl-4-allyl-5-hydroxyoxindole and 644 mg. (59% yield) of 1-ethyl-5-hydroxy-6-allyloxindole, m.p. 130°-131° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][CH:26]3[CH2:29][CH2:28][CH2:27]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:32]>>[CH:26]1([NH:25][CH:8]2[C:7]3[S:6][C:5]([C:3]([NH2:32])=[O:2])=[N:14][C:13]=3[C:12]3[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[CH2:29][CH2:28][CH2:27]1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(NC1CCC1)CO2
Yield: 54 %

Procedure:
A solution of 4-Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (80 mg, 0.19 mmol), in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. Then the mixture was filtered to afford 4 Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (42 mg, 54%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12]([O:14][C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:22][CH:23]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: Cc1cc2c(cc1C(=O)O)C(C)(C)CCS2
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2cc3c(cc2C)SCCC3(C)C)cc1
Reaction time: 24 h

Procedure:
A solution of 83.7 mg (0.35 mmol) of 4,4,7-trimethyl-6-carboxythiochroman and 59.1 mg (0.35 mmol) of ethyl-4-hydroxybenzoate in 2 ml of methylene chloride was treated sequentially with 74.5 mg (0.36 mmol) of 1,3-dicyclohexylcarbodiimide and 11.1 mg (0.09 mmol) of 4-dimethylaminopyridine. The mixture was stirred under nitrogen for 24 h and then filtered. The fillrate was concentrated in-vacuo and the residue purified by flash chromatography (silica; 15% ethyl acetate in henane) to give the title compound as a pale yellow oil. PMR (CDCl3): δ1.37 (6H, s), 1.41 (3H, t, J~7.1 Hz), 1.92-2.00 (2H, m), 2.56 (3H, s), 3.02-3.10 (2H, m), 4.40 (2H, q, J~7.1 Hz), 7.03 (1H, s), 7.29 (2H, d, J~8.7 Hz), 8.13 (2H, d, J~8.7 Hz), 8.18 (1H, s).