Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:16]([C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]>C(O)C>[C:16]([C:18](=[CH:24][NH:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]
Reactant: NNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C#N)=CNNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
4-Trifluoromethyl-2-nitrophenylhydrazine (13.5 g) and ethyl 2-cyano-3-ethoxyacrylate (10.3 g) were heated under reflux in ethanol (300 ml) for 24 hours. The solvent was removed under reduced pressure and the resulting residue triturated with dichloromethane/hexane to give ethyl 2-cyano-3-(2-nitro-4-trifluoromethylphenylhydrazino)acrylate, m.p. 163°-164°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[CH3:11].S([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH2:10]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=[C:8]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:11]
Reactant: Nc1nccnc1C=O
Reactant: CCNc1ccncc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCn1c(-c2nccnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 79.8 %

Procedure:
3-aminopyrazine-2-carbaldehyde (made in example 1(c)) (0.30 g, 2.4 mmol), N4-ethylpyridine-3,4-diamine (made in example 1(b)) (0.36 g, 2.6 mmol), and sodium hydrogensulfite (0.30 g) were combined in 3 mL of dimethylacetamide and heated to 200° C. in a SmithSynthesizer microwave for 10 minutes. The reaction mixture was partitioned between ethyl acetate and water. The reaction was extracted with ethyl acetate (×3), and the combined organic layers were washed with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After filtration, the organics were concentrated in vacuo. Trituration with diethyl ether affords the title compound as tan solids (0.46 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([Cl:12])=[N:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cccc2nc(Cl)ccc12
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-chloroquinoline (1.0 g, 5.6 mmol) was dissolved in 10 mL pyridine and 4-fluorobenzenesulphonylchloride (1.1 g, 5.7 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched by addition of 100 mL water and 6.8 mL acetic acid. The mixture was extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). N-(2-Chloro-quinolin-5-yl)-4-fluoro-benzenesulfonamide was obtained as a brown solid (762 mg, 40%), MS: m/e=337.1 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]([F:36])([F:35])[C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:27]3[C:26]([C:25]([F:36])([F:24])[F:35])=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ncccc1C(F)(F)F
Product: C[C@@]1(c2cc(NC(=O)c3ncccc3C(F)(F)F)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 3-trifluoromethyl-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=397.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[OH-:17].[Na+].Cl>C1COCC1>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([OH:17])[N:7]=1)[CH2:9]2
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1nc(Cl)cc(N2CC3CCC(C2)O3)n1
Temperature: 150 °C
Yield: 221.4 %

Procedure:
In three 2-5 mL microwave vials was each placed 3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 100 mg, 0.384 mmol) in THF (2 ml). A 1N solution of sodium hydroxide (2 ml, 2.000 mmol) was added to each vial. The reaction was heated under microwave irradiation at 150° C. for 30 min. The contents of the three microwave vials were combined, 6 mL 2N HCl was added to acidify (pH˜3). Silica gel was added and the mixture was concentrate purify by silica gel chromatography, using a gradient (0-15%) of MeOH in dichloromethane to give 205 mg (0.85 mmol, 74%) of the title compound as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:12]1[C:10]2=[CH:11][C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:12][C:10]2=[CH:11][C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:12][C:8]2=[CH:9][CH:10]=[CH:11][C:6](=[CH:7]2)[CH2:12][C:8]2=[CH:9][CH:10]=[CH:11][C:6]1=[CH:7]2
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: c1cc2cc(c1)Cc1cccc(c1)Cc1cccc(c1)Cc1cccc(c1)C2
Reaction time: 2 h
Yield: 66 %

Procedure:
Calix(4)arene XXVI is prepared from 4-tert-butylcalix(4)arene (XXV; FIG. 13) as described (Gutsche, Levine, and Sujeeth, 1985). A hot solution of 5.0 g (6.75 mmol) of XXV in 250 ml of toluene is placed in a 500 ml three-necked round-bottom flask fitted with a mechanical stirrer and a gas inlet tube. The solution is cooled to 50°-55° C., treated with 5.0 g (37 mmol) of anhydrous AlCl3, and stirred for 2 h at 50°-55° C. in an inert atmosphere. The mixture is cooled in an ice bath and stirred with 125 ml of 1N HCl for 30 min, the organic phase is separated and washed, dried, and evaporated to leave a yellow residue. This is triturated with 500 ml of ether, and the insoluble material is recrystallized from CHCl3 --CH3OH to yield 1.9 g (66%) of XXVI as off-white microcrystals. m.p. 313°-318° C.
Reaction SMILES: C[Si](I)(C)C.[CH2:6]([O:8][C:9]([C:11]1[CH:44]=[CH:43][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:34]=[C:35]([O:37][C@@H:38]([CH3:42])[CH2:39][O:40]C)[CH:36]=2)[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24](C(OC(C)(C)C)=O)[N:23]=2)=[O:20])=[CH:13][CH:12]=1)=[O:10])[CH3:7].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:40][CH2:39][C@H:38]([CH3:42])[O:37][C:35]1[CH:36]=[C:16]([CH:17]=[C:18]([C:19]([NH:21][C:22]2[CH:26]=[CH:25][NH:24][N:23]=2)=[O:20])[CH:34]=1)[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[CH:44][CH:43]=1
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(C(=O)Nc3ccn(C(=O)OC(C)(C)C)n3)c2)cc1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3cc[nH]n3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
Trimethylsilyl iodide (0.27 mL) was added dropwise under argon to a solution of tert-butyl 3-({3-[4-(ethoxycarbonyl)phenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (167 mg, 0.38 mmol) in acetonitrile (5 mL) and stirred at ambient temperature for 16 hours. Sodium thiosulfate solution was added to quench the reaction and the reaction mixture was extracted into ethyl acetate (3×25 mL). Organic phases were combined and dried (MgSO4) and the filtrate was concentrated in vacuo to give a clear oil (180 mg), which was not purified further.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@@H:21]([CH3:46])[C@H:22]([N:28]([CH3:45])[C:29](=[O:44])[C@@H:30]([N:32]([CH3:43])[C:33](=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:31])[C:23]1[O:24]C=CC=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:47].C(Cl)(Cl)(Cl)Cl.CC#N>CC#N.O>[CH2:35]([O:34][C:33]([N:32]([CH3:43])[C@@H:30]([CH3:31])[C:29]([N:28]([C@@H:22]([C@H:21]([CH3:46])[CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:23]([OH:24])=[O:47])[CH3:45])=[O:44])=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1ccco1)N(C)C(=O)[C@H](C)N(C)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)O)N(C)C(=O)[C@H](C)N(C)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of NalO4 (485.0 mg, 2.30 mmol, 6.0 equiv) in H2O/CCl4/CH3CN (3/2/3, 10.4 mL) was added RuCl3 (26.6 mg, 0.13 mmol, 0.34 equiv) and the mixture was stirred vigorously for 15 minutes. To the mixture was then added a solution of 2.18.1g (242.0 mg, 0.38 mmol) in CH3CN (3 mL). After stirring for 15 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaHSO3 solution, brine, dried over Na2SO4, and concentrated to give product 2.18.1h (242.0 mg) which was used for the next step without further purification. MS m/z (M+1) 619.4.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:32])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C:22]3[N:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:33][O-:34].[Na+]>CO>[O:31]1[C:24]2[CH:23]=[C:22]([CH2:21][NH:20][CH:17]3[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]4[C:10]5[C:5](=[CH:4][CH:3]=[C:2]([O:34][CH3:33])[N:11]=5)[CH:6]=[CH:7][C:8]4=[O:32])[CH2:15][CH2:16]3)[N:27]=[CH:26][C:25]=2[O:28][CH2:29][CH2:30]1
Reactant: O=c1ccc2ccc(Cl)nc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2n1
Yield: 30.6 %

Procedure:
A solution of 7-chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,8-naphthyridin-2(1H)-one (Example 67) (95 mg, 0.21 mmol) in methanol (5 mL) was treated with a solution of sodium methoxide (0.5 M, 1 mL, 0.5 mmol). The reaction mixture was sealed in a tube and heated at 150 C for 1 hour using microwave irradiation. The reaction mixture was concentrated at reduced pressure, partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×10 mL) and chloroform/methanol (4:1) (3×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-50%) gave the product as a colorless solid (29 mg, 31%)
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:10]([O-])=O)=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)cc1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
Iron powder (18.5 g) was added to a solution of 5-bromo-2-fluoro-4-nitrotoluene (9.7 g) in acetic acid (30 ml), and the mixture was stirred at 70° C. for 3 hours. The catalyst was removed by filtration through Celite, and the filtrate was washed with chloroform. The solvent and the like in the filtrate were distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel to conduct elution with chloroform, thereby obtaining the title compound (7.9 g) as a red oil.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Br[CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1>CN(C)C=O>[C:1]([O:9][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CC1(C)OCC(CBr)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COC(=O)c2ccccc2)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
Then, sodium benzoate (50.44 g, 0.35 mol) were added to a mixture of 4-bromomethyl-2,2-dimethyl-1,3-dioxolane (58.52 g, 0.3 mol) and N,N-dimethylformamide (500 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo to give 64.5 g of crude 4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 91%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[NH:4][N:3]=1.[CH3:15]OS(OC)(=O)=O>[OH-].[Na+].O>[CH3:15][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([N:6]([CH3:14])[C:7](=[O:13])[N:8]([CH3:12])[C:9]2=[O:11])=[N:4]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1n[nH]c2c1c(=O)n(C)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Step 4 intermediate (5.2 g, 26.77 mmol) in 1 N sodium hydroxide (52 ml) was added dimetylsulphate (5.2 ml) and stirred at room temperature for 1 h. The reaction mixture was diluted with water and the solid precipitated out was filtered, washed with water and dried to give 3.85 g of the product as off white solid; 1H NMR (300 MHz, CDCl3): δ 2.59 (s, 3H), 3.36 (s, 3H), 3.48 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:16][C:17]1[N:22]=[C:21](F)[C:20]([F:24])=[CH:19][N:18]=1.[F-].[Na+]>CN(C=O)C>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[C:20]([F:24])=[CH:21][N:22]=[C:17]([F:16])[N:18]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ncc(F)c(F)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 27 °C
Reaction time: 0.25 h

Procedure:
A solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (5 g, 26.7 mmol) in DMF (50 mL) was cooled to −5° C. under N2 atmosphere. Internal temperature was monitored and maintained at ca. −5° C. during the portionwise addition of 60% NaH (1.28 g, 32 mmol) over 5 mins (no appreciable exotherm seen, but effervescence observed and cloudy suspension resulted). Added 2,4,5-trifluoropyrimidine (3.76 g, 28 mmol) dropwise whilst still maintaining the temperature at ca. −5° C. After complete addition the reaction mixture was stirred at this temperature for 15 mins before removing the cooling bath and allowing the rm to warm to room temperature (ca. 27° C. internal temp). Left stirring at room temperature for 6 h. Sampled reaction mixture and quenched with water, extracted into EtOAc; TLC and LCMS show significant product but remaining oxazolidinone sm. Cooled reaction mixture to 0° C. and added an additional portion of trifluoropyrimidine (1.2 g, 8.95 mmol), warmed to room temperature and left stirring for 3 h at rt. Still faint residual sm seen by TLC of sample, but quenched reaction mixture at this point. Workup: [Safety Note: NaF salt present. Do not acidify workup] Quenched the reaction mixture with water (100 mL) which resulted in considerable effervescence. Added EtOAc (75 mL) and separated, extracted the aqueous with EtOAc (2×75 mL), combined the organics, washed with water (100 mL), brine (50 mL), dried (MgSO4) and concentrated to dryness to give crude product as a pale yellow oil. Crude was purified by silica gel chromatography (initial neat DCM, then ramp to 20% EtOAc/DCM). Pure product fractions were combined and concentrated to dryness to give a colourless oil which was placed under high vacuum. Upon standing the oil converted into a white solid. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=3, 1 Hz, 1H); 4.73-4.68 (m, 1H); 4.62-4.52 (m, 2H); 4.34-4.28 (m, 1H); 1.20 (s, 9H); 1.11 (d, 3H). MS m/z 302.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>O1CCOCC1>[Cl:32][CH2:33][C:34]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:35]
Reactant: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(OC(=O)CCl)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.8 parts of methyl 3-hydroxy5-oxo-2-styrylcyclopent-1-eneheptanoate and 2 parts of pyridine in 80 parts of dioxane is added, at 0°-5°, a solution of 2.4 parts of chloroacetyl chloride in 20 parts of dioxane. The resulting reaction mixture is stirred at that temperature for about 30 minutes, then at room temperature for about 5 hours. At the end of that reaction period the mixture is poured carefully into ice water and the resulting aqueous mixture is extracted with ether. The ether solution is washed successively with dilute hydrochloric acid and dilute aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. The resulting product is purified by dry column chromatography on silica gel containing 8% of water, using 18% ethyl acetate in benzene, to afford pure methyl 3-chloroacetoxy-5-oxo-2-styrylcyclopent-1-eneheptanoate. This compound is represented by the following structural formula ##SPC7##
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH2:24][CH2:25][N:26]([CH2:48][CH:49]([CH3:51])[CH3:50])[C:27]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=4)=[CH:30][C:28]=3[CH:29]=2)=[O:22])=[CH:16][CH:15]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH2:24][CH2:25][N:26]([CH2:48][CH:49]([CH3:50])[CH3:51])[C:27]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=4)=[CH:30][C:28]=3[CH:29]=2)=[O:22])=[CH:18][CH:19]=1)=[O:60])(=[O:3])[CH3:2]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCOC(C)=O)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of [2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]thio]methyl]-1H-imidazol-1-yl]ethyl acetate (350 mg) in dichloromethane (10 ml) was added dropwise 3-chloroperbenzoic acid (70%, 146 mg) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica get, ethyl acetate:hexane 1:1→ethyl acetate→ethanol:ethyl acetate 1:19), to give [2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]ethyl acetate (Preparation of Compound 411) (278.7 mg) as yellow amorphous.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([C:24]2[C:33]([OH:34])=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[N:31]3)=[C:26]([Cl:35])[CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)=[O:4].[CH3:36][NH:37][CH3:38]>>[Cl:35][C:26]1[CH:25]=[C:24]([CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:37]([CH3:38])[CH3:36])[CH:11]=[CH:10][CH:9]=2)[C:33]([OH:34])=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2
Reactant: O=C(CCl)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Reactant: CNC
Product: CN(C)CC(=O)Nc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 46 %

Procedure:
A solution of 2-chloro-N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)acetamide (100 mg, 0.20 mmol) and dimethylamine (2M/THF, 10 eq.) was heated at 45 C for 18 h. The solvent was removed in vacuo, the residue was dissolved in methylene chloride and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 48 mg (46%) of N-(3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)-N2,N2-dimethylglycinamide as a beige solid.
Reaction SMILES: C(OC([N:11]1[CH2:18][CH2:17][C@@H:16]([CH3:19])[C@@H:12]1[C:13]([OH:15])=[S:14])=O)C1C=CC=CC=1.Br>C(O)(=O)C>[CH3:19][C@@H:16]1[CH2:17][CH2:18][NH:11][C@H:12]1[C:13]([OH:15])=[S:14]
Reactant: C[C@@H]1CCN(C(=O)OCc2ccccc2)[C@H]1C(O)=S
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H]1CCN[C@H]1C(O)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.4 g. (0.024 mole) of (trans)-1-benzyloxycarbonyl-3-methylthio-D,L-proline are treated with 45 ml. of 4 N hydrobromic acid in acetic acid. After stirring for one hour at room temperature the solution is dried in vacuo. A small amount of water is added and this is washed twice with ether. The aqueous solution is applied to a column containing 300 ml. of an ion-exchange resin and water is passed through until the eluate is no longer strongly acidic. The product is then eluted with pH 6.5 (aqueous pyridine acetate) buffer. Fractions positive to ninhydrin are combined and lyophilized to give 3.4 g. (88%) of white fluff. A small sample of this material is crystallized from methanol to give (trans)-3-methylthio-D,L-proline; m.p. 196°-200° (dec.) (s. 192°).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:24]([C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[CH:20][CH:21]=2)[N:16]([CH2:28][CH3:29])[C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:30])=[O:5])=[CH:10][CH:11]=1)#[N:25]
Reactant: CCn1c(-c2ccc(OCC(=O)OC(C)(C)C)cc2)c(C#N)c2ccc(OC)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(-c2ccc(OCC(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Yield: 98.9 %

Procedure:
[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA in CH2Cl2 at room temperature for 3 hours. This is concentrated and the residue is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. The residue is triturated with CH2Cl2 to yield [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634 mg, 99%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=O)[NH:20][C:19]=1[CH3:26])=[O:17]>>[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[NH:20][C:19]=1[CH3:26])=[O:17]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccccc32)c(C)c1C(=O)NCCN(C)C

Procedure:
1,3-Dihydro-indol-2-one was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)amide to give the title compound.