Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][C@H:11]1[CH2:12][CH2:13][C@@H:9]([OH:8])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](OC2CCCCO2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1CC[C@H](OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of (1R,3S)-1-(tert-butyldimethylsilyl)oxy-3-tetrahydropyranyloxycyclopentane (11.3 g, 33.0 mmol) in dry THF (40 ml) was added a 1.0M solution of tetrabutylammonium fluoride in THF (50 ml, 50.0 mmol). After stirring for 1 h at room temperature, the reaction mixture was poured into water (200 ml) and the whole extracted with ether (200 ml). The ether phase was washed with brine (200 ml), dried (MgSO4) and concentrated under reduced pressure. Chromatographic purification of the residue {SiO2, 800 g; hexane/ethyl acetate (2:1) with 1% of triethylamine} provided 5.47 g (73%) of the title compound as a colorless oil: 1H NMR δ4.73-4.64 (m, 1H), 4.42-4.23 (m, 2H), 3.95-3.81 (m, 1H), 3.59-3.44 (m, 1H), 2.20-1.20 (m, 13H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([Sn](CCCC)(CCCC)[C:18]1[N:19]=[CH:20][S:21][CH:22]=1)CCC.O.CCOC(C)=O>C1COCC1.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>[S:21]1[CH:22]=[C:18]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=[CH:20]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2cscn2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available ethyl 3-iodobenzoate (650 mg; 2.35 mmol), 4-(tributylstannyl)thiazole (894 mg; 2.39 mmol), and PdCl2(PPh3)2 (165 mg; 0.23 mmol) in anh. THF (20 ml) was heated to 75° C., under nitrogen, for 17 h. Water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded ethyl 3-(thiazol-4-yl)benzoate as a yellow oil. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 233.94 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1.Cl.C(=O)([O-])[O-].[NH4+:45].[NH4+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)(=[O:19])=[O:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](=[NH:45])[NH2:39])=[CH:36][CH:37]=1
Reactant: [NH4+]
Reactant: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)CN(c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(methoxycarbonylmethyl)-quinoline-8-sulphonylamino)-benzimidazole and methanolic hydrochloric acid, methanol and ammonium carbonate.
Reaction SMILES: C[Al](C)C.[O:5]1[C@H:9]2[O:10][CH2:11][CH2:12][C@H:8]2[C:7](=[O:13])[CH2:6]1.[Si](C=[N+]=[N-])(C)(C)[CH3:15].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1.CC(O)=O>[O:10]1[C@@H:9]2[O:5][CH2:6][C:7](=[O:13])[CH2:15][C@@H:8]2[CH2:12][CH2:11]1
Reactant: O=C1CO[C@H]2OCC[C@@H]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CO[C@H]2OCC[C@H]2C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
AlMe3 (25% w/w hexanes, 250 μL, 0.6 mmol) was diluted in dry CH2Cl2 (5 mL) under argon and the solution was cooled to −78° C. A solution of ketone 28 (64 mg, 0.5 mmol) in dry CH2Cl2 (5 mL) was slowly added dropwise. After 10 min, TMSCHN2 (2 M solution in Et2O, 275 μL, 0.55 mmol) was added. The reaction was stirred for 2 h while warmed to −30° C. Saturated Rochelle's salts solution (5 mL) was added and the mixture was stirred for 1 h. The phases were separated, the aqueous phase extracted with CH2Cl2, and the combined organic phase was dried (MgSO4). The solution was filtered on a small silica gel pad, flushing with Et2O, and the collected organic phase evaporated. A crude mixture of the desired ketone along with α-silylated derivatives and isomers was then obtained. The mixture was re-dissolved in THF (5 mL). AcOH (6 drops) and TBAF (0.5 mL, 0.5 mmol) were successively added. The resulting mixture was stirred at 23° C. for 3 h and evaporated to dryness. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc (5:1) as the eluent to give ketone 29 (45 mg, 63%). TLC: Rf=0.35 (hexanes/EtOAc=2:1); 1H NMR (CDCl3, 400 MHz) δ 5.49 (d, J=6.8 Hz, 1H), 4.11 (d, J=18.2 Hz, 1H), 4.10 (m, 1H), 3.92 (d, J=18.2 Hz, 1H), 3.74 (dt, J=6.5, 8.9 Hz, 1H), 2.85 (m, 1H), 2.71 (d, J=6.3, 15.6 Hz, 1H), 2.48 (d, J=3.9, 15.6 Hz, 1H), 2.15 (m, 1H), 1.55 (ddt, J=7.7, 8.9, 12.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 210.7, 100.9, 67.5, 67.1, 39.2, 36.2, 31.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3(CCOC[CH2:19]3)[O:10][C:9]2=[O:24])[CH:5]=[CH:4][N:3]=1.[O:25]1CC(=O)[CH2:26]1>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:11]3([CH2:19][O:25][CH2:26]3)[O:10][C:9]2=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1COC1
Reactant: O=C1OC2(CCOCC2)C(c2ccccc2)N1c1ccnc(Cl)n1
Product: O=C1OC2(COC2)C(c2ccccc2)N1c1ccnc(Cl)n1

Procedure:
Prepared using similar methods as described above for 3-(2-chloropyrimidin-4-yl)-4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one, but starting with oxetan-3-one. LCMS m/z 318.1 (M+H)+, Rt 0.78 min.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].C(Cl)(=O)C>>[CH:1](=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH3:2]
Reactant: CCC1(O)c2ccccc2C=Cc2ccccc21
Solvent: CC(=O)Cl
Product: CC=C1c2ccccc2C=Cc2ccccc21

Procedure:
5-Ethyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene (13.7 g., 0.058 mole) is dissolved in 80 ml. of acetyl chloride and the solution heated to refluxing for 90 minutes. The acetyl chloride is evaporated under reduced pressure and the residue dissolved in benzene. After washing with alkali followed by a water wash, the benzene is removed and the product distilled under reduced pressure. The desired 5-ethylidene-5H-dibenzo[a,d]cycloheptene is obtained as the fraction boiling at 130°-135° C. (0.02 mm.). It is crystallized on cooling. The compound was purified further by recrystallization from 95% alcohol.
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH2:14][Br:15])=[O:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[S:18][C:19]2[CH2:25][CH2:24][CH2:23][CH2:22][C:20]=2[N:21]=1>>[BrH:15].[NH:16]=[C:17]1[N:21]([CH2:14][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N:4]3[CH2:5][CH2:1][CH2:2][CH2:3]3)=[CH:7][CH:8]=2)=[O:13])[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18]1
Reactant: Nc1nc2c(s1)CCCC2
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Product: Br
Product: N=c1sc2ccccc2n1CC(=O)c1ccc(N2CCCC2)cc1
Yield: 43 %

Procedure:
The title compound is prepared from α-bromo-4-(1-pyrrolidino)acetophenone and 2-amino-4,5,6,7-tetrahydrobenzothiazole using method A in 43% yield: mp 285-290° C. (dec); 1H-NMR (DMSO-d6) 2.00 (s, 4H), 3.38 (m, 4H), 5.93 (s, 2H), 6.68 (d, 2H), 7.43 (t, 1H), 7.50 (t, 1H), 7.57 (d, 1H), 7.90 (d, 2H), 8.03 (d, 1H); Anal. C19H20BrN3OS (C, H, N).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27](O)=[O:28])[CH:20]=[N:19]2)[CH2:14][C@H:13]1[CH3:30])=[O:11])[CH3:8].[Cl:31][C:32]1[C:33]([O:47][CH3:48])=[N:34][CH:35]=[C:36]([Cl:46])[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:31][C:32]1[C:33]([O:47][CH3:48])=[N:34][CH:35]=[C:36]([Cl:46])[C:37]=1[CH2:38][CH2:39][N:40]([CH2:41][C:42]([CH3:45])([CH3:43])[CH3:44])[C:27]([C:21]1[CH:20]=[N:19][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[C@H:13]([CH3:30])[CH2:14]2)[C:22]=1[C:23]([F:24])([F:26])[F:25])=[O:28]
Reactant: COc1ncc(Cl)c(CCNCC(C)(C)C)c1Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CCc3c(Cl)cnc(OC)c3Cl)CC(C)(C)C)c2C(F)(F)F)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Oxalyl chloride (2.0M in DCM, 0.52 mL, 1.03 mmol) was added to a solution of 1-((1S,3R,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (239 mg, 0.687 mmol) in DCM (2.0 mL) followed by 1 drop of DMF while cooling in an ice bath. The solution was removed from the ice bath and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was treated with DCM (2.0 mL) and cooled to 0° C. The stirring solution was then treated with N-(2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)-2,2-dimethylpropan-1-amine (200 mg, 0.687 mmol) in DCM (2 mL) followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and allowed to warm to room temperature and stirred overnight (16 h). The reaction mixture was concentrated to dryness under reduced pressure (rotary evaporator) and the crude residue was purified on an ISCO Combiflash™ RF (25 g Grace Reveleris column, using a gradient of 0-50% EtOAc in heptane) affording (1S,2R,4S)-ethyl 4-(4-((2-(3,5-dichloro-2-methoxypyridin-4-yl)ethyl)(neopentyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-methylcyclohexanecarboxylate (350 mg, 0.56 mmol, 82% yield) as a white crystalline solid. MS (ESI) 621.2, 623.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.[ClH:32].N>C1COCC1.O.CO>[ClH:32].[ClH:32].[NH2:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in THF and water and cooled to 0° C. was added HCl (1 N in Et2O). After 30 min the mixture was warmed to room temperature and the solution was stirred for 48 h. 2 M NH3 in MeOH was added. The solvents were evaporated and the mixture purified by column chromatography (SiO2, 0-5-10% (2 M NH3 in MeOH)/CH2Cl2). The compound was dissolved in DCM/MeOH and 1 N HCl in Et2O added. The solvents were evaporated to give pure 3-amino-2-(4-(hydroxymethyl)phenyl)-N-(isoquinolin-6-yl)propanamide dihydrochloride (E144).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=O)[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16][O:17][CH2:18][F:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O1CCCC1.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[S:40])[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16][O:17][CH2:18][F:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(CCNC(=O)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCNC(=S)C(=COCF)c2ccc3c(c2)CCCC3)cc1OC
Yield: 56.2 %

Procedure:
A mixture of 380 mg (0.920 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 420 mg (1.01 mmol) of Lawesson's Reagent and 5 ml of anhydrous tetrahydrofuran was refluxed by heating for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was washed with aqueous sodium hydroxide solution, aqueous ammonium chloride solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=3:1) to give 222 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylthioamide (the present compound 1160).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N+:40]([O-])=[C:39]([CH3:45])[CH:38]=1.C(BC(C(C)C)C)(C(C)C)C>>[CH3:43][C:41]1[CH:42]=[C:37]([C:20]2[CH:19]=[CH:18][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:22][CH:21]=2)[CH:38]=[C:39]([CH3:45])[N:40]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Agent: CC(C)C(C)BC(C)C(C)C
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide using a procedure analogous to that described in Example 14, followed by treatment with disiamyl borane. LC-MS Method 1 tR=1.1 min, m/z=463 (M+1); 1H NMR (CDCl3) 7.50 (s, 2H), 7.45 (d, 1H), 7.25 (m, 3H), 7.17-6.99 (m, 4H), 5.73 (q, 1H), 4.28 (t, 1H), 3.04 (m, 1H), 2.82 (s, 6H), 2.31 (m, 3H), 1.91 (m, 3H), 1.58 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[C:5]2[CH:6]=[C:7]3[CH:17]=[C:16]([F:18])[C:15](F)=[CH:14][C:8]3=[N:9][C:10]=2[N:11]([CH3:13])[CH:12]=1)#[N:2].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[C:1]([C:3]1[C:4](=[O:20])[C:5]2[CH:6]=[C:7]3[CH:17]=[C:16]([F:18])[C:15]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[CH:14][C:8]3=[N:9][C:10]=2[N:11]([CH3:13])[CH:12]=1)#[N:2]
Reactant: CN1CCNCC1
Reactant: Cn1cc(C#N)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C#N)cn4C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 2.1 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 100 cm3 of dimethyl sulphoxide is heated to 80° C. in the presence of 2 cm3 of N-methylpiperazine. The reaction mixture is maintained at this temperature for 8 hours. The solution obtained is cooled to room temperature and stirred at this temperature for 15 hours. The precipitate formed is filtered off, washed with 3 times 20 cm3 of water and dried under vacuum (20 kPa) at 50° C. 2.6 g of 3-cyano-7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxobenzo[b][1,8]naphthyridine are obtained in the form of a yellow precipitate, melting point 335° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=1
Reactant: COC(=O)c1ccc2c(=O)[nH]cnc2c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(=O)n(Cc3cccc(C(F)(F)F)c3)cnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.100 g, 0.49 mmol) in DMF (5 mL) was added potassium carbonate (0.135 g, 0.98 mmol) and 3-(trifluoromethyl)benzyl bromide (0.11 mL, 0.74 mmol). The reaction mixture was heated to 60° C. and stirred overnight. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (15 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+ 363.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)(OC(C)(C)C)=O.Br[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:1]([CH:19]2[CH2:18][CH2:17][NH:16][CH2:21][CH2:20]2)[CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: BrCc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Clc1ccc(N(Cc2ccsc2)C2CCNCC2)cn1

Procedure:
Using general procedure A with 5-amino-2-chloropyridine (254 mg, 1.98 mmol) and 1-Boc-4-piperidone (590 mg, 2.96 mmol), then general procedure H with the resulting amine and 3-(bromomethyl)thiophene (517 mg) and then using general procedure C gave (6-chloro-pyridin-3-yl)-piperidin-4-yl-thiophen-3-ylmethyl-amine as a green oil (65 mg, 10% over 3 steps).
Reaction SMILES: [C:1]([C:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]([CH3:16])([CH3:15])[C:4]=1O)#[N:2].O.[NH2:19][NH2:20].CC(O)=O>C(O)C>[NH2:2][C:1]1[NH:20][N:19]=[C:4]2[C:5]([CH3:16])([CH3:15])[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC(C#N)=C(O)C1(C)C
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
32 g of tert-Butyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate (0.134 mol) were added to 430 ml of absolute ethanol. To this solution, 9 ml (0.18 mol) of hydrazine hydrate were added, followed by 12 ml of glacial AcOH (1.5 eq); The mixture was stirred at 60° C. for 48 hours, the ethanol was removed, the residue was taken up with 400 ml of sodium hydrogencarbonate solution, and extracted several times with ethyl acetate up to total extraction of the desired product. The organic phases were dried and evaporated. After purification by flash chromatography (eluent: CHCl3/EtOH 97/3) and trituration with a mixture of hexane/ethyl acetate 9/1, 25 g of title compound were obtained. Total yield 30.5 g (yield: 88%)
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:19]=[N:20][CH:21]=[C:22]([N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[N:23]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: Clc1cncc(N2CCOCC2)n1
Product: c1cc2c(cc1Oc1cncc(N3CCOCC3)n1)CCN(C1CCC1)CC2

Procedure:
Example (E288) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 4-(6-chloro-2-pyrazinyl)morpholine [Zagulyaeva, O. A., J. Org. Chem. USSR, EN, 14; 1978; 377-380] using an analogous method to that described for Example 242 (E242); MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: C([C:3]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1)#N.S(=O)(=O)(O)O.O.[OH-].[Na+]>C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:3]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH2:8][CH2:7]1
Reactant: COc1ccccc1N1CCN(CCC(C#N)(c2ccccn2)c2ccccn2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCC(c2ccccn2)c2ccccn2)CC1
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A mixture of 2.44 g of compound of Example 6 and 12 mL of 70% sulphuric acid was stirred for 1.5 h at 125° C. The obtained reaction mixture was then cooled to room temperature, followed by careful pouring into 100 g of ice, dilution with water, alkalinization with 35% sodium hydroxide, and extraction with ethyl acetate (3×40 mL). The combined organic phases were then washed with water, dried on anhydrous sodium sulphate, and then evaporated to complete dryness under vacuum. The obtained crude was then purified by flash chromatography (ethyl acetate-2.2 N solution of ammonia in methanol 9.6:0.4). The recovered fractions were then evaporated to complete dryness, affording 1.87 g of the title product (82%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]1=[O:24].[CH3:25][C:26]([CH3:44])([CH3:43])/[CH:27]=[CH:28]/[C@H:29]1[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]2[CH:37]([O:41][CH3:42])[C:38](=[O:40])[O:39][C@H:30]12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@H:6]1[CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3](=[O:24])[C@@H:2]([NH:1][C:38](=[O:40])[C@@H:37]([C@H:31]2[C@H:30]([OH:39])[C@@H:29](/[CH:28]=[CH:27]/[C:26]([CH3:43])([CH3:25])[CH3:44])[O:34][C:33]([CH3:36])([CH3:35])[O:32]2)[O:41][CH3:42])[CH2:8][CH2:7]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C(=O)N(Cc2cccnc2)C1
Reactant: COC1C(=O)O[C@H]2C1OC(C)(C)O[C@@H]2/C=C/C(C)(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Yield: 57.2 %

Procedure:
A solution of (3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-one (1.84 g, 5.3 mmol), (4R,4aR)-4-((E)-3,3-Dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one (1.0 g, 3.5 mmol) and diisopropylethylamine (1.37 g, 11.0 mmol) in isopropanol (10 mL) is refluxed for 16 h. The solution is evaporated and chromatographed on silica (95% CH2Cl2/5% CH3OH) to give 1.27 g (57.0%) of (R)-N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a white solid. MS (ESI) 634.3 (M+H)+