Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[CH2:11][CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[CH2:11][CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-(4-chlorophenyl)-5,5-dimethyl-2-pyridin-4-yl-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (240 mg, 0.65 mmol) was placed in a 100 mL round bottomed flask and dissolved in 1,2-dichloroethane (10 mL). To the solution were added trifluoroacetic acid (1 mL, 10 mmol) and triethylsilane (1 mL, 6 mmol). The resulting yellow solution was stirred for 16 hr at 90° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and the resulting solution was washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was separated and extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (24 g) column chromatography, eluting with a 30% to 100% EtOAc in hexane to obtain product as colorless syrup. LCMS: (FA) ES+354, 356; 1H NMR (400 MHz, d-chloroform) δ ppm 8.49 (dd, 2H), 7.31 (dd, 2H), 7.20 (d, 2H), 7.03 (d, 2H), 6.84 (s, 1H), 3.67 (s, 1H), 2.83-3.00 (m, 2H), 1.77-1.82 (m, 1H), 1.63-1.70 (m, 1H), 1.04 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[OH:17]P([O-])(O)=O.[K+].[OH:23]P(O)(O)=O.[Na+].[Cl-]>O>[OH:17][CH:3]1[CH2:4][C:5](=[O:1])[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:2]1.[OH:23][CH:2]1[CH:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5](=[O:1])[CH:4]=[CH:3]1
Reactant: COc1cccc(CC(O)c2ccco2)c1
Reactant: O=P([O-])(O)O
Reactant: O=P(O)(O)O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cccc(CC2=CC(O)CC2=O)c1
Product: COc1cccc(CC2C(=O)C=CC2O)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-(Furan-2-yl)-2-(3-methoxyphenyl)ethan-1-ol (20 g, 91.7 mmol) and KH2PO4 (0.4 g, 0.02 mmol) was added to H2O (400 mL) and H3PO4 was added until pH=3.0. The reaction was kept being stirred at 120° C. overnight. After being cooled, NaCl (300 g) was added, and the reaction was extracted with EtOAc, dried over MgSO4, and evaporated to give the crude 4-Hydroxy-2-(3-methoxybenzyl)cyclopent-2-enone and 4-Hydroxy-5-(3-methoxybenzyl)cyclopent-2-enone as black oil: 19 g (crude yield: 95%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)([CH3:3])[CH3:2].[C:11](O)(=O)C.[CH:15]([NH2:17])=[NH:16]>C(O)CCC>[CH:1]([CH:4]1[C:5]2[N:17]=[CH:15][N:16]=[CH:11][C:6]=2[CH2:7][CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1CCCCC1=O
Reactant: N=CN
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC(C)C1CCCc2cncnc21
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.5 %

Procedure:
A 100 mL reaction flask is charged with 2-isopropyl-cyclohexanone (10 g, 0.07 mol), formamidine acetate (40 g, 0.4 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 8-isopropyl-5,6,7,8-tetrahydro-quinazoline (˜5 g) is obtained.
Reaction SMILES: [OH:1]O.[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>O.C(O)(C(F)(F)F)C(F)(F)F>[OH:3][C@:4]1([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([S:30]([CH3:31])=[O:1])=[CH:28][CH:29]=3)[CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: OO
Reactant: CSc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Solvent: O
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CS(=O)c1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35% Hydrogen peroxide in water (48 μL) is added to 4-(β-D-glucopyranos-1-yl)-2-(4-methylsulfanyl-benzyl)-benzonitrile (83 mg) in 1,1,1,3,3,3-hexafluoroisopropanol (2 mL). The resulting solution is stirred at ambient temperature for 1 h and then quenched by the addition of aqueous Na2S2O3 solution and aqueous NaHCO3 solution. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[C:22]([CH:29]([NH2:32])[CH:30]=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH:11][CH2:30][CH:29]([NH2:32])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(N)C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](NCC(N)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 143.1 %

Procedure:
Alanine benzyl ester (10, 8.82 g, 49 mmol, 1 eq) was dissolved in MeOH (100 ml) and glacial acetic acid (10.34 g, 172 mmol, 3.5 eq) was added. The mixture was stirred at 0° C. under nitrogen and sodium cyanoborohydride (10.82 g, 172 mmol, 3.5 eq) was added. Boc-aminoacetaldehyde (15.67 g, 98 mmol, 2 eq) in MeOH (200 ml) was added dropwise during 2 h. The reaction mixture was stirred at 0° C. for 35 min. and then at 4-5° C. overnight. Water (300 ml) was added to the reaction mixture and the pH was adjusted to 9 by addition of solid sodium carbonate. The saturated solution was filtered and subsequently extracted with ether (3×500 ml). The organic phase was washed with a 1:1 mixture of saturated aqueous solutions of sodium chloride and sodium bicarbonate (1×450 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give 22.60 g of crude N-(2-Boc-amino-ethyl)alanine benzyl ester as a slightly golden oil. The crude product was dissolved in dry ether (500 ml) and stirred at 0° C. HCl in ether (60 ml) was then added to the solution, and the resulting precipitate was collected by filtration and washed with cold dry ether (3×20 ml) affording 7.21 g (41%) of 11 as white crystals. A second crop of 2.12 g (12%) could be collected as a white semicrystalline material by keeping the mother liquor in the freezer overnight. This second crop was slightly less pure than the first crop. 1H-NMR (D2O/TMS): δ 1.36 (s, 9H, Boc); 1.52 (d, J=7.2 Hz, 3H, Me); 3.16 (m, 2H, NCH2); 3.35 (m, 2H, NCH2); 4.17 (q, J=7.2 Hz, 1H, CH); 5.26 (s, 2H, CH2Ph); 7.40 (s, 5H, Ph). 13C-NMR (D2O/TMS): δ 13.5 (Me); 27.3 (Box); 36.4 (CH); 45.5 (NCH2); 55.2 (NCH2); 68.4 (CH2Ph); 128.3, 128.7, 128.8 (Ph). MS(FAB+) m/z (%): 323 (100, M-HCl+H) Anal. Calcd for C17H27CIN2O4 : C, 56.90; H, 7.58; N, 7.81; Cl, 9.88. Found: C, 55.11; H, 7.52; N, 7.93; Cl, 10.45.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1>>[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]3)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)OCCO3)c1
Yield: 69.9 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and 2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (352 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 258 mg, 70%).
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])[CH:21]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].[C:33]1([C:44](O)=[O:45])[CH:34]=[CH:35][CH:36]=[C:37]2[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:44]([C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39][C:38]=23)=[O:45])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30])[CH:21]=2)=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-[4-(benzyloxy)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]propan-1-ol (617 mg, 1.37 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (258 mg, 1.37 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2.06 mmol) and 1-hydroxybenzotriazole hydrate (210 mg, 1.37 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (474 mg, 56%).
Reaction SMILES: [Mg:1].[Br:2]C(Br)C.Br[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:8]=1[CH2:20][CH3:21]>O1CCCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:10]=[CH:9][C:8]([CH2:20][CH3:21])=[C:7]([Mg:1][Br:2])[CH:12]=2)=[CH:18][CH:17]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: [Mg]
Reactant: CC(Br)Br
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[Mg]Br
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a 50 ml volume three-necked flask, magnesium (cutting chip) (296 mg) and anhydrous tetrahydrofuran (6.75 ml) were added under a nitrogen atmosphere. Dibromoethane (95 mg) was added dropwise, and stirred at 50° C. for 30 minutes. To the mixture, 2-bromo-4-(4-chlorophenyl)-1-ethylbenzene (10-c) (3.0 g) dissolved in tetrahydrofuran (6.75 ml) was added dropwise over 10 minutes, stirred for 2.5 hours, and cooled to room temperature to give a solution of 5-(4-chlorophenyl)-2-ethylphenylmagnesium bromide in tetrahydrofuran.
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH3:12])[CH:10]=[C:9]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:34])[C@@H:23]4[C@H:27]([O:29][Si](C)(C)C)[CH3:28])[C:20]=3[C:35]([O:37]CC=C)=[O:36])[S:16][CH:17]=2)[CH2:8]1)=O)C=C.O.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C1COCC1>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:34])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:9]3[CH2:8][NH:7][C@H:11]([CH3:12])[CH:10]=3)[N:14]=1)=[C:20]2[C:35]([OH:37])=[O:36])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@@H](C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C=C(c2csc(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)n2)CN1
Reaction time: 0.17 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(4-{(5R)-1-[(allyloxy)carbonyl]-5-methyl-2,5-dihydro-1H-pyrrol-3-yl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-[(1R)-1-[(trimethylsilyl)oxy]ethyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (42 mg, 0.070 mmol) in ethyl acetate (4 ml) was added water and then 2N hydrochloric acid and the solution was adjusted to pH 2. After stirring for 10 minutes, THF was further added thereto and the solution was stirred for 20 minutes. To the obtained mixture was added a saturated aqueous sodium hydrogen carbonate solution and the solution was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To a solution of the residue (37.6 mg) in dichloromethane (2 ml) were added at 0° C. tributyltin hydride (0.17 ml), acetic acid (10 μl) and bis(triphenylphosphine)palladium chloride(5 mg) and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture were added phosphate buffer (50 mM, pH7, 25 ml) and dichloromethane (20 ml). The aqueous layer was separated and the dichloromethane layer was extracted twice with water. The combined aqueous layer was washed with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-({4-[(5R)-5-methyl-2,5-dihydro-1H-pyrrol-3-yl]-1,3-thiazol-2-yl}sulfanyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: NCc1ccccn1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: C1COCCO1
Product: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (1.5 g, 3.5 mmol) and 2-(aminomethyl)pyridine (1.46 g, 13.5 mmol) in dioxan (10 ml) was stirred at room temperature for 2 h. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed [50-100% ethyl acetate/cyclohexane] to give the title compound as a yellow solid (1.5 g, 3.70 mmol, 82% yield). LCMS (formate) Rt 0.86 min, MH+ 406.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>CN(C=O)C>[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][O:17][C:13]1[CH:12]=[C:11]([C:10]2[N:9]=[C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Reactant: BrCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4Br)c3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (100 mg, 0.36 mmol) in DMF (1.8 mL) was charged with Cs2CO3 (174 mg, 0.54 mmol) and stirred at rt for 30 min. A solution of 2-bromobenzyl bromide (89.2 mg, 0.36 mmol) in DMF was added to the reaction mixture. Reaction mixture was stirred overnight at rt under nitrogen. The crude product was left under high vacuum to remove the DMF for 2 h. The product was then purified by silica gel column chromatography (3% NH3 in MeOH):CH2Cl2 to yield the title compound as a brown/red solid; 1H NMR (CDCl3, 400 MHz) δ 2.02-2.08 (m, 1H), 2.14-2.21 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1H), 5.21 (s, 2H), 7.00 (d, J=5.6 Hz, 1H), 7.04-7.07 (m, 1H), 7.11 (d, J=5.2 Hz, 1H), 7.18-7.23 (m, 1H), 7.25-7.30 (m, 2H), 7.33-7.37 (m, 1H), 7.42 (t, J=16 Hz, 1H), 7.55-7.61 (m, 2H); MS (ES+): m/z 450.81 (100) [MH+].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl[CH2:24][CH2:25][N:26]=[C:27]=[O:28].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([N:6]2[CH2:24][CH2:25][NH:26][C:27]2=[O:28])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C=NCCCl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1NCCN1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 25.5 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)aniline (21.1 g) and triethylamine (13.9 mL) in toluene (200 ml) was slowly added 2-chloroethyl isocyanate (10.0 g) at 0° C., and the mixture was stirred at 60° C. for 4 hr. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (250 ml), sodium hydride (4.0 g) was slowly added at 0° C., and the mixture was stirred at room temperature for 3 hr. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over sodium sulfate. The solvent was concentrated under reduced pressure to give the title compound as a white solid (7.0 g, yield 26%).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 14 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and methyl 3-bromopropionate (121 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 1% methanol in dichloromethane with a 30:1 silica ratio) to obtain the title product (32.6 mg, 0.092 mmol, 14% yield); LCMS; m/z 353.47, found 354.3 (M+1); 1H NMR (400 MHz, CDCL3) δ 3.92 (s, 1H), 1.59 (s, 2H), 1.76-1.78 (m, 1H), 1.93-2.00 (m, 1H), 2.28-2.30 (m, 1H), 2.52-2.55 (m, 2H), 2.67-2.74 (m, 1H), 2.84-2.91 (m, 1H), 3.11-3.15 (m, 1H), 3.20-3.27 (m, 1H), 3.66 (s, 3H), 3.73-3.77 (m, 1H), 3.91-3.92 (m, 2H), 6.81-6.84 (m, 2H), 7.07-7.09 (m, 2H), 7.16-7.29 (m, 5H).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=S.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CCOCC.O.C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][NH:7][C:8]1=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCNC(=S)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: c1ccc(N=C2NCCCO2)cc1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of sodium hydroxide (23.8 mg) and water (0.6 ml) was added under argon and with stirring to a solution of 1-(3-hydroxypropyl)-3-phenylthiourea (50 mg) and THF (1.5 ml). Subsequently, a solution of p-toluenesulfonyl chloride (49.9 mg) and THF (0.5 ml) was added dropwise over fifteen minutes. After stirring for 30 minutes, the reaction mixture was added to water, and extraction was effected three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Chromatography using silica gel (initially 50:1 methylene chloride/methanol, at the end 100:1 methanol/saturated ammonia solution) afforded 27.4 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Yield: 84 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (1.81 g) described in Preparation Example 76 and 1-(2,4-dimethylphenyl)piperazine (1.67 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.68 g) was obtained.
Reaction SMILES: [Na].C(O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]4[C@@:25]5([CH2:31][C:32]6C=CC=CN=6)[CH2:26][CH2:27][C:28](=[O:30])[CH2:29][C@H:24]5[CH2:23][CH2:22][CH2:21][C:18]=4[CH:19]=3)[CH:14]=[N:13]2)=[CH:8][CH:7]=1.FC1C=CC(N2[C:53]3[C:48](=[CH:49][C:50]4[C@]5(CC6C=CC=CN=6)CCC(=O)C[C@@H]5CCC[C:51]=4[CH:52]=3)[CH:47]=N2)=CC=1.C(=O)C1C=CC=CC=1>C1COCC1>[CH:47](=[C:27]1/[CH2:26][C:25]2([CH2:31][CH3:32])[C:17]3=[CH:16][C:15]4[CH:14]=[N:13][N:12]([C:9]5[CH:8]=[CH:7][C:6]([F:5])=[CH:11][CH:10]=5)[C:20]=4[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][C:28]/1=[O:30])/[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C1CC[C@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@@H]2C1
Reactant: O=C1CC[C@@]2(Cc3ccccn3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCC[C@H]2C1
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: CCC12C/C(=C\c3ccccc3)C(=O)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Sodium (0.092 g, 4.0 mmol) was added to ethanol (20 mL) and mixed at rt until the sodium was completely consumed. A solution of rac-(4aS,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (10, R1=4-Fluorophenyl, R2=Ethyl) (1.00 g, 2.66 mmol) in THF (10 mL) was added in one portion. Benzaldehyde (0.310 g, 2.92 mmol) was added and the reaction mixture was stirred at rt for about 3 h. The organic volatiles were removed under reduced pressure. The residue was partitioned between EtOAc (70 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 5-18% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3(2H)-one (53, R1=4-Fluorophenyl, R2=Ethyl) (1.00 g, 81% yield); LC/MS, method 3, Rt=3.11 min.; MS m/z: 465 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.98-7.96 (m, 1H), 7.80-7.73 (m, 2H), 7.73-7.67 (m, 2H), 7.62-7.55 (m, 3H), 7.53-7.46 (m, 2H), 7.44-7.35 (m, 2H), 6.99 (s, 1H), 3.72-3.62 (m, 1H), 3.27-3.15 (m, 1H), 3.01-2.91 (m, 1H), 2.90-2.81 (m, 1H), 2.58-2.52 (m, 1H), 2.48-2.37 (m, 1H), 2.36-2.25 (m, 1H), 2.25-2.14 (m, 1H), 2.11-1.97 (m, 1H), 1.87-1.45 (m, 4H), 0.65 (t, J=7.3 Hz, 3H).