Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][C:19]([OH:21])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][C:19]([Cl:24])=[O:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1nn(Cc2ccccc2)c2ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)COc1nn(Cc2ccccc2)c2ccccc12
Yield: 90 %

Procedure:
[(1-BENZYL-1H-indazol-3-yl)-oxy]acetic acid (Bendazac) (50 g) are suspended in benzene (500 ml) and thionyl chloride (15 ml) is added. The solution is stirred under reflux for about half an hour, cooled, concentrated at room temperature under reduced pressure, the oily residue is treated with further benzene and concentrated again to dryness under vacuum. After addition of hexane, the acidic chloride precipitates as lightly coloured crystals. The solution is filtered and washed with hexane. The substance is colourless and shows m.p. 78°-9°. Yield: 90% of the calculated.
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:30]OS(=O)(=O)OC>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:30])[C:17]2=[O:27])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
0.18 g of 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-yl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added at room temperature in a dimethylformamide solution (2 ml) having suspended therein 0.02 g of sodium hydride (purity: 55%). After standing for 20 minutes, the solution was further added with 0.09 g of dimethylsulfuric acid and stirred overnight. Then dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This crude product was purified by preparative thin-layer chromatography using hexane/ethyl acetate (3:1) as developing solvent to obtain 0.15 g of the objective compound as a colorless viscous oil. It was solidified when left as it was.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[ClH:11].[OH:12][CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14](=O)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].C([BH3-])#N.[Na+]>CO>[ClH:11].[ClH:11].[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH:14]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:12]
Reactant: CC(C)CCC(=O)C(O)c1ccccc1
Reactant: NCCCN1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 28 %

Procedure:
To a solution of 1-(3-aminopropyl)piperidine (285 mg, 2 mmol) in methanol (6 ml) was added 0.1 ml of 6.8N-HCl in MeOH, 1-hydroxy-5-methyl-1-phenylhexan-2-one (413 mg, 2 mmol) and sodium cyanoborohydride (126 mg, 2 mmol). The reaction mixture was stirred for 19 hours at room temperature. The mixture was concentrated under reduced pressure and to the residue was added lN-HCl and ether. The aqueous layer was separated, basified with a 10% NaOH aqueous solution and then extracted three times with ether. The combined ethereal extract was washed twice with water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was dissolved in ethanol (12 ml). To the solution was added 0.70 ml of 6N-HCl in EtOH and the resulting mixture was allowed to stand. Precipitated crystals were collected by filtration to obtain 228 mg of the title compound (yield: 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[CH:16]1([CH2:22]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH2:22][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Reactant: BrCC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(C#N)(CC3CCCCC3)CC2C1
Yield: 41.2 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (3.66 g, 17.6 mmol) was dissolved in 150 mL of tetrahydrofuran with stirring followed by dropwise addition of cyclohexylmethyl bromide (6.2 g, 35.2 mmol) and lithium hexamethyldisilazide (35.2 mL, 32.5 mmol). The reaction mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. Then 150 mL of a saturated aqueous solution of ammonium chloride was added. The mixture was extracted with ethyl acetate (60 mL×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyano-5-cyclohexylmethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15a (2.2 g, yield 41.5%) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([S:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.[CH:31](=O)[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([S:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:4]1)[CH3:32]
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(n2cc(-c3cnc4ccc(Sc5nnc6ccc(C)nn56)cc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (63 mg, 0.152 mmol) in dichloromethane (3.0 mL) was added acetaldehyde (34 uL, 0.608 mmol). The solution was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (80 mg, 0.380) was added. After 1 hour the solution was diluted with dichloromethane (3.0 mL) and washed with sodium bicarbonate (3.0 mL). The aqueous layer was extracted further with dichloromethane (3.0 mL). The combined dichloromethane layers were washed with brine (6 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, dichloromethane:CH3OH:NH4OH, 95:4.995:0.005-80:19.98:0.02) to return 23 mg of 3-[1-(1-ethyl-azetidin-3-yl)-1H-pyrazol-4-yl]-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (34% yield).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([N:11]2[C:16]3[N:17]=[C:18]([S:21][CH3:22])[N:19]=[CH:20][C:15]=3[C:14](O)=[CH:13][C:12]2=[O:24])[CH2:10][CH2:9][CH2:8][CH2:7]1>ClC(Cl)C>[Br:3][C:14]1[C:15]2[CH:20]=[N:19][C:18]([S:21][CH3:22])=[N:17][C:16]=2[N:11]([CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:12](=[O:24])[CH:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: CSc1ncc2c(O)cc(=O)n(C3CCCC3)c2n1
Solvent: CC(Cl)Cl
Product: CSc1ncc2c(Br)cc(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 50 %

Procedure:
Phosphorus oxybromide (11.3 mL) was added to a mixture of 8-cyclopentyl-5-hydroxy-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.56 g, 9.23 mmol) in dichloro-ethane (13 mL) at RT. The reaction mixture was heated to 100° C. in a microwave reactor for 1 h, then cooled to RT. The resulting mixture was partitioned between EtOAc (200 mL) and NaHCO3 (sat'd aq, 200 mL), and the aqueous layer extracted with EtOAc (100 mL). The combined organic layers were washed with NaHCO3 (sat'd aq, 3×100 mL) and water (2×100 mL), dried over MgSO4, filtered and evaporated under reduced pressure to give 1.58 g (50% yield) of 5-bromo-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. MS=340, 342 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29][CH3:30])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]3=[O:28])=[CH:11][CH:12]=2)[CH:7]=[N:6]1>CO.[Pd]>[CH3:30][O:29][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:16][C:15]3=[O:28])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(Cn1ncc2cc(-n3ccc(/C=C/c4ccccc4)cc3=O)ccc21)OC
Agent: [Pd]
Solvent: CO
Product: COC(Cn1ncc2cc(-n3ccc(CCc4ccccc4)cc3=O)ccc21)OC
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
(E)-1-(1-(2,2-dimethoxyethyl)-1H-indazol-5-yl)-4-styrylpyridin-2(1H)-one (2.08 g, 5.19 mmol) was stirred in CH3OH (100 mL) for 2 h under nitrogen atmosphere. Palladium on carbon (3.1 g) was added under nitrogen atmosphere, and the mixture was stirred for 20 min. The nitrogen line was then replaced with a H2 balloon and the reaction mixture was stirred under an H2 atmosphere at room temperature for 2 h and then flushed with nitrogen (10 min). The mixture was filtered through a layer of Celite, and the filtrate was concentrated. The residue was triturated with MeOH and concentrated to gave the title compound (1.77 g, 84%) as a orange solid 1H NMR (300 MHz, CDCl3) 8.04 (s, 1H), 7.68 (d, J=15 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.44-7.36 (dd, J=8.9, 1.9 Hz, 1H), 7.36-7.28 (m, 2H, overlapping with solvent peak), 7.26-7.18 (m, 3H), 6.51 (s, 1H), 6.16-6.06 (dd, J=7.0, 1.8 Hz, 1H), 4.76 (t, J=5.3 Hz, 2H), 4.48 (t, J=5.3 Hz, 2H), 3.36 (s, 6H) 3.01-2.90 (m, 2H), 2.90-2.76 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][CH2:14][C@@:15]([OH:27])([CH3:26])[CH2:16][N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[N:19]=[C:18]1Cl)=[O:12])[CH2:6][CH2:5]2.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][CH2:14][C@:15]1([CH3:26])[O:27][C:18]3=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:17]3[CH2:16]1)=[O:12])[CH2:6][CH2:5]2
Reactant: C[C@](O)(COC(=O)N1CCc2cc(Cl)ccc21)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCc3cc(Cl)ccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 5-chloro-2,3-dihydroindole-1-carboxylate prepared in Example 113 (0.60 g, 1.44 mmol) in DMF (6 ml), sodium hydride (70 mg, 1.73 mmol) was added followed by stirring 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, and the precipitates were filtered off, washed with water and recrystallized from acetonitrile-isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 5-chloro-2,3-dihydroindole-1-carboxylate (0.30 g, yield 55%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:29]4[CH:28]=[N:27][C:26]([NH2:25])=[CH:31][CH:30]=4)[CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.5) (0.185 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.18 g, 85%). MS (ISP) 428.0 [(M+H)+]; mp 227° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: O=c1[nH]cnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(OCCn2cnc3ccccc3c2=O)cc1
Yield: 72.3 %

Procedure:
The title compound (1.5 g, 73%) was prepared from 4-oxo-3,4-dihydroquinazoline (1.03 g, 7.05 mmol) and 4-[2-bromoethoxy]benzaldehyde (1.77 g, 7.7 mmol) in the presence of K2CO3 (2.0 g, 14.5 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:17]=[CH:18][CH:19]=1
Reactant: NCCCc1cccc(Cl)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(3-chloro-phenyl)-propylamine (0.102 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-chloro-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.105 g, 71%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.96 (m, 2H), 2.69 (t, 2H), 3.66 (t, 2H), 4.36 (s, 2H), 7.12-7.58 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 285 (M)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=O)(C)(C)C.C=O>C(O)=O>[Cl:21][C:18]1[N:17]=[CH:16][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:6])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cl)nc1
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@H]1COc1ccc(Cl)nc1

Procedure:
A 625 mg sample of 3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridine, prepared as in Example 45a, was treated with 2 mL of 37% paraformaldehyde and 1 mL of formic acid at reflux for 16 hours. The volatiles were removed by evaporation, and the residue was dissolved in 1 mL of 20% NaOH. The solution was extracted with CH2Cl2 (3X), then the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by chromatography over silica gel, eluting with 100:1 chloroform:methanol to afford 439 mg of the title compound. MS (DCI/NH3) m/e: 227/229 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.09 (dd, J=2.1, 2.1 Hz, 1H), 7.24-7.21 (m, 2H), 4.02 (dd, J=11.0, 3.0 Hz, 1H), 3.93 (dd, J=11.0, 5.8 Hz, 1H), 3.21-3.10 (m, 1H), 2.76-2.64 (m, 1H), 2.51 (s, 3H), 2.40-2.28 (m, 1H), 2.12-1.98 (m, 1H), 1.97-1.68 (m, 4H).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:41][CH2:42][C:43](O)=[O:44])(OC(C)(C)C)=O>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:43](=[O:44])[CH2:42][NH2:41])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: NCC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and Boc-glycine (21.0 mg) were reacted and treated in the same manner as in the method described in Example 29 to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:17])=[CH:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.[OH-].[K+].O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:17])=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C(C)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=CC(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 16.6 g. of ethyl 3-(4-nitrophenyl)-2-butenoate, 75 ml. of ethanol and 94.7 ml. of 1.5 N potassium hydroxide was heated on a steam bath for 70 minutes, and then it was cooled to room temperature. To the reaction mixture was added 200 ml. of water and 200 ml. of ethyl acetate. The aqueous phase was removed and acidified with concentrated hydrochloric acid, and then the solid was recovered by filtration. This latter solid was recrystallized from aqueous ethanol to give 9.8 g. (67% yield) of the title compound, m.p. 167°-169° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)c1cccc(C23CC4CC(CC(C4)C2)C3)c1
Reactant: C=CCOC(=O)c1ccc(O)cc1
Product: C=CCOC(=O)c1ccc(OC(=O)c2cccc(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 65.5 %

Procedure:
In a manner analogous to Example 9(a) by reacting 1.5 g (5.5 mmoles) of 3-(1-adamantyl)benzoyl chloride with 980 mg (5.5 mmoles) of allyl 4-hydroxybenzoate, 1.5 g (68% yield) of the expected ester in the form of a colorless oil are obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27](=[O:45])[NH:28][CH:29]1[CH2:36][CH2:35][CH2:34][CH:33]([O:37][Si](C(C)(C)C)(C)C)[CH2:32][CH2:31][CH2:30]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27](=[O:45])[NH:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH:33]([OH:37])[CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(NC(=O)OCc2ccccc2)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NC1CCCC(O)CCC1)OCc1ccccc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
Benzyl chloroformate (4 mL, 28.02 mmol) was added to a stirred and cooled (0° C.) solution of the product of Example 5C (14.01 mmol) and diisopropylethyl amine (7.5 mL, 42.03 mmol) in dry dichloromethane (50 mL). After the addition, the solution was warmed to room temperature and stirred for another three hours. It was quenched with NaHCO3 solution. The phases were separated and the organic phase was washed with NaHSO4 solution brine, dried (Na2SO4), filtered, and evaporated. The crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester was isolated as an oil and was used without further purification. Tetrabutyl ammonium fluoride (42 mL, 1 M in tetrahydrofuran, 42.03 mmol) was added to a solution of crude [5-(tert-Butyl-dimethyl-silanyloxy)-cyclooctyl]-carbamic acid benzyl ester (about 14.01 mmol) in tetrahydrofuran (35 mL). The resulting solution was stirred for two hours at 23° C. before it was partitioned with diethyl ether and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-50% ethyl acetate in hexanes to give (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester as an oil. (5-Hydroxy-cyclooctyl)-carbamic acid benzyl ester (2.68 g, 9.66 mmol) was stirred in the presence of Pd(OH)2/C (0.5 g) in methanol under H2 (balloon) for two hours at 23° C. before it was filtered through a pad of Celite and the solvent was evaporated. The title compound was isolated as an oil and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCCO
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CCO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 97.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)ethanol (40 mg, 0.53 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving the title compound (106 mg) as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][C:11]2([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:14][CH2:15][CH:10]2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH2:9]1[CH:10]2[CH2:15][CH2:14][CH2:13][C:11]2([C:16]([O:18][CH3:19])=[O:17])[CH2:12][NH:8]1
Reactant: COC(=O)C12CCCC1CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C12CCCC1CNC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 2-benzyloctahydrocyclopenta[c]pyrrole-3a-carboxylate (2.0 g, 7.69 mmol) in MeOH (15.0 mL) was added palladium hydroxide (0.20 g, 10% w/w) and the mixture stirred at rt for 16 h under H2 atmosphere. After completion of reaction (by TLC), the reaction mixture was passed through celite and the solvent evaporated. The crude (1.50 g) residue was carried forward for the next step without further purification. MS: 170.18 [M+H]+.