Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:7]([C:6]1[CH:9]=[C:2]([O:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (84.0 g) and ethyl 4bromobutyrate (86 ml) in dry dimethylformamide (500 ml) blanketed under dry nitrogen was added potassium carbonate (76.0 g). The reaction mixture was heated to 100° C. for 1 hour. This mixture was cooled, and the solvent removed by evaporation to give a dark brown syrup. This residue was partitioned between ethyl acetate and saturated sodium carbonate (500 ml each). The organic layer was washed with additional saturated sodium carbonate (3×500 ml), and with brine (2×500 ml), dried, filtered and evaporated to give a dark brown syrup. Kugelrohr distillation (180° C., 0.2 mm) afforded ethyl 4-((3-formyl-4-nitrophenyl)oxy)butyrate (95 g) as a bright yellow syrup which slowly darkened upon standing.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]3[C@@H:18]([C:26]([OH:28])=[O:27])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29](OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CO>[CH3:29][O:27][C:26]([C@@H:18]1[C@@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[O:17]1)=[O:28]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Solvent: CO
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Yield: 74.2 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (3.018 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.66 g) in methanol (120 ml) was heated under reflux for 17 h. The resulting mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (150 ml). The solution was washed with 0.5M aqueous citric acid solution (3×25 ml) and brine (50 ml), dried (magnesium sulphate), and evaporated in vacuo to give a white foam. Purification by column chromatography on silica gel, eluting with ethyl acetate:cyclohexane (1:1), gave the title compound as a white solid (2.32 g).
Reaction SMILES: C(O)C.C([O:11][C:12](=[O:29])[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[O:21]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].O1CCCC1>[C:19]([C:17]1[CH:18]=[C:13]([C:12]([OH:29])=[O:11])[C:14]([OH:21])=[CH:15][CH:16]=1)#[N:20]
Reactant: N#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(O)c(C(=O)O)c1
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethanol (10 mL) and tetrahydrofuran (10 mL) were added to 2-benzyloxy-5-cyanobenzoic acid benzyl ester (446 mg, 1.3 mmol) and 5% palladium on carbon (45 mg), and the mixture was hydrogenated at room temperature for 2 hours. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure to give the title compound (212 mg, 100.0%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[O:27][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-benzyl-2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-4-amine (890 mg, 2.5 mmol) in methanol (10 mL) was stirred at room temperature for two minutes, and sodium methoxide (5 mL of a 25% w/w solution in methanol) was added. The resulting suspension was stirred at room temperature for one hour and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was separated and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.3:4.7:95). The resulting off-white solid was triturated with hot acetonitrile, isolated by filtration, and dried under vacuum to provide 50 mg of 1-benzyl-2-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 240-242° C.
Reaction SMILES: [N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:15][CH2:14][C@H:12]2[O:13][C@H:7]3[C@H:8]([N:9]=[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)[S:6]3)[C@@H:10]([OH:17])[C@@H:11]2[OH:16])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](O)[C@@H]2O)cc1
Yield: 12.7 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5.0 g, 19 mmol) and triethylamine (3.88 g, 38 mmol) in DMF (50 mL) was treated with 4-methylbenzene-1-sulfonyl chloride (4.4 g, 23 mmol) overnight at room temperature. The reaction mixture was quenched by water (100 mL), extracted with dichloromethane (3×80 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 1%-5% methanol in dichloromethane to give crude compound 4 as a light yellow solid (1.0 g). This material was employed in the next step without further purification. (ES, m/z) [M+H]+ 415.0.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:35][C:34](=O)[C:32]=2[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:35]/[C:34](=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])/[C:32]=2[CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C=C1\Cc2ccc(OCc3ccccc3)cc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
At −78° C., Lithium bis(trimethylsilyl)amide (1.0 M in THF) (7.1 mL, 7.1 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (1.2 mL, 7.1 mmol) in THF (6 mL). It was maintained at −78° C. for 12 min. 5-(Benzyloxy)cyclobutabenzen-1(2H)-one (3.2) (0.88 g, 3.9 mmol) in THF (3 mL) was added in one portion. It was stirred at −78° C. and allowed to r.t. overnight. EtOAc (300 mL) was added and it was washed with brine and dried over Na2SO4. After removing solvent, the residue was purified by chromatography (silica gel, 1:6 EtOAc/hexane) to give 3.4 in 14% yield.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCCCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.711 g (5.0 mmol) of 1-nonanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=3/1) to yield 1.96 g (88.0%, yellow oily substance) of the desired product.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]#[N:29])=[CH:22][C:21]=2[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=[CH:16][C:17]=1[O:18]C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]#[N:29])=[CH:22][C:21]=2[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=[CH:16][C:17]=1[OH:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(O)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
2.20 ml (2.20 mmol, 3 eqv) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 279 mg (0.73 mmol) 3-(3′-Benzyl-2-isobutyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile (24) in 12 ml dry CH2Cl2 at 0° C. via syringe. After that, the solution was stirred for 2 h at 0° C. and then for 7 h at rt. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (2+1)) yielded 258.5 mg (0.70 mmol, 96%) 25 as a pale yellow oil: Rf (Hexanes/EtOAc (2+1)) 0.53; 1H NMR (500 MHz, CDCl3) δ 0.65 (d, 6H, J=6.62 Hz), 1.57 (m, 1H), 2.38 (d, 2H, J=7.25 Hz), 2.57 (t, 2H, J=7.41 Hz), 2.89 (t, 2H, J=7.41 Hz), 3.95 (s, 2H), 4.62 (s, br., 1H), 6.74 (d, 1H, J=8.04 Hz), 6.94-7.24 (m, 10H); LRMS (EI) m/z 369 (8), 335 (10), 293 (15), 161 (13), 160 (66), 91 (35), 86 (63), 84 (100); HRMS (EI) Calcd. for C26H27NO: 369.209264. Found: 369.209026.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].C(=O)(O)[O-].[Na+].Br[CH:19]([CH2:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]>>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:1][CH:19]([CH2:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]
Reactant: Cc1ccc2ccccc2c1N
Reactant: CCC(Br)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(Nc1c(C)ccc2ccccc12)C(=O)OC
Yield: 86.3 %

Procedure:
144.2 g (0.92 mole) of 1-amino-2-methylnaphthalene are stirred with 90.2 g (1.08 moles) of sodium bicarbonate and 507 g (2.8 moles) of methyl 2-bromobutyrate at from 120° to 125° C. for 18 hours. The mixture is cooled, and thereafter the precipitate is filtered off under suction, the filtrate is concentrated under reduced pressure, and the residue is distilled under reduced pressure. 204.3 g (79.5% of theory) of methyl 2-(2-methylnaphth-1-ylamino)-butyrate are obtained as a colorless oil. Boiling point: 148°-150° C./0.25 mbar; nD25 =1.5779.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])(C)(C)C.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)[Cl:13]>CCOCC>[Cl:13][CH2:12][C@H:14]([OH:16])[CH2:15][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: ClC[C@H]1CO1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O[C@@H](CCl)Cc1cccs1
Reaction time: 1.5 h
Yield: 25.8 %

Procedure:
To a solution of 2-bromothiophene (0.95 mL, 9 mmol) in ether (60 mL) cooled to −100° C. was added t-butyl lithium (5.41 mL of 1.7 M in pentane, 9 mmol) by dropwise addition. The reaction mixture was stirred at this temperature for 30 min. (R)-Epichlorohydrin (1.08 mL, 14 mmol) was added and the −100° C. bath was replaced with an ice/ethanol bath. The reaction was stirred at this temperature for 1.5 h and then stirred in an ice-bath for an additional 1.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (50% EtOAc in heptane eluent) to afford (R)-1-chloro-3-thiophen-2-yl-propan-2-ol (410 mg, 25%) as a brown oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.28 (d, J=4.14 Hz, 1H) 3.06-3.21 (m, 2H) 3.46-3.73 (m, 2H) 4.08 (d, J=5.65 Hz, 1H) 6.91 (dd, J=3.39, 0.94 Hz, 1H) 6.98 (dd, J=5.09, 3.39 Hz, 1H) 7.21 (dd, J=5.18, 1.22 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH2:5]O>[Pd]>[CH3:1][N:2]([CH3:1])[C@@H:3]1[CH2:4][CH2:5][CH2:5][CH2:4][C@H:3]1[NH2:2]
Reactant: CCO
Reactant: CNC
Agent: [Pd]
Product: CN(C)[C@@H]1CCCC[C@H]1N
Reaction time: 19 h

Procedure:
A solution of the benzylamino compound was hydrogenated in two batches each containing 30.5 g. (0.131 mole), 175 ml. EtOH, 3.4 g Pd-C and 56.5 g. (0.394 mole) of 70% HClO4, at initial pressure of 51.5 p.s.i. for 19 hours. The two batches were combined, filtered through Celite and evaporated in vacuo at 45°. The residue was cooled in ice, basified with 40% KOH to pH 11. The resulting thick suspension was extracted with ether (5 × 200 ml), the ether extract was dried (MgSO4) and evaporated through a 9 inches Vigreux. The residue was distilled at 13 mm to give 32.5 g. (87% yield), b.p. 77°-78.5°. Vpc 100% at 3.8 mm. ir and nmr was identical to those of the sample prepared by the reaction of 7-azabicyclo[3.1.0]heptane with dimethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([C:34]([F:35])([F:37])[F:36])[CH:28]=4)[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: Cc1ccc(C2CCCC(Br)C2=O)cc1C(F)(F)F
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(C)c(C(F)(F)F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 17 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (52 mg, 0.20 mmol) and of crude 6-bromo-2-(4-methyl-3-trifluoromethyl-phenyl)-cyclohexanone (70 mg, 0.21 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (17 mg, 15%) as a pale-brown oil. MS ISP (m/e): 499.0 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 7.20 (s, 2H), 7.09 (d, 1H), 6.82 (s, 1H), 6.65 (d, 1H), 4.04 (m, 1H), 3.52 (s, 3H), 2.77 (m, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 2.22 (m, 1H), 1.78-2.03 (m, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:4])=[O:3].C(O)C.CN.FC1C=C(C=CC=1F)CO[C:41]1N=C(NC)C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)[N:42]=1>C(#N)C>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH2:41][NH2:42])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:3])=[O:4]
Reactant: CNc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: CN
Solvent: CC#N
Solvent: CCO
Product: CS(=O)(=O)c1nc(CN)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 1 h

Procedure:
To a round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 2,4-bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]-pyrimidine (Reference Example 5, Step A, 50 mg, 0.1 mmol), and 1 mL each of ethanol and acetonitrile. The mixture was cooled to 0° and methylamine (2 eq., 400 μL, 1M in THF) was added via syringe. The mixture was stirred for 1 h, the solvents removed under reduced pressure and the product chromatographed (77/23 hexanes/ethyl acetate) to give two products: a higher Rf product (unidentified) and 2-(3,4-difluorobenzyloxy)-4-(N-methylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine as the lower Rf product. HPLC/MS: m/e=442 (M+−1); Rt=3.58 min. 1H-NMR 500 MHz (CDCl3): δ 3.13 (d, J=5 Hz, 3H), 3.37 (s, 3H), 7.07 (d, J=8 Hz 1H), 7.10 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.38-7.40 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[N:38]=[C:39]=[O:40]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:39]([NH:38][C:32]3[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])=[O:40])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1c(F)cccc1F
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1c(F)cccc1F

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2,6-difluorophenyl isocyanate according to the procedure of Example 65. HRMS: calcd for C30H18F5N3O2, 547.1319; found (ESI, [M+H]+), 548.1425.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([NH:9][C:10](=[O:21])[O:11][CH2:12][C:13]23[CH2:20][CH2:19][N:16]([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[N:8]=1)(=O)[NH2:2].P(Cl)(Cl)([Cl:30])=O.C([O-])(O)=O.[Na+].Cl.CCOC(C)=O>CN(C=O)C.CCOC(C)=O>[ClH:30].[C:1]([C:4]1[S:5][C:6]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:7]([NH:9][C:10](=[O:21])[O:11][CH2:12][C:13]23[CH2:14][CH2:15][N:16]([CH2:17][CH2:18]2)[CH2:19][CH2:20]3)[N:8]=1)#[N:2]
Reactant: NC(=O)c1nc(NC(=O)OCC23CCN(CC2)CC3)c(-c2ccccc2)s1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(NC(=O)OCC23CCN(CC2)CC3)c(-c2ccccc2)s1
Reaction time: 1 h

Procedure:
To a solution of 1-azabicyclo[2.2.2]oct-4-ylmethyl (2-carbamoyl-5-phenyl-1,3 thiazol-4-yl)carbamate (100 mg) in DMF (5 mL) was added phosphorous oxychloride (48 μL) at 0° C., followed by stirring for 1 hour. To the reaction mixture was added EtOAc, followed by dilution, addition of an aqueous NaHCO3 solution, and extraction with EtOAc. The organic layer was washed with water and brine in this order, then dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH:28% aqueous ammonia=9:1:0.1), and the brown oily substance obtained was dissolved in EtOAc, followed by addition of 4 M HCl/EtOAc and stirring. The mixture was concentrated under reduced pressure, EtOAc was added thereto, and the solid precipitated was collected by filtration to obtain 1-azabicyclo[2.2.2]oct-4-ylmethyl (2-cyano-5-phenyl-1,3-thiazol-4-yl)carbamate hydrochloride (33 mg) as a pale brown solid.
Reaction SMILES: CC(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[C:10]([N+:33]([O-:35])=[O:34])[CH:9]=1)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N+:33]([C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1)([O-:35])=[O:34]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OC(C)(C)C)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc([N+](=O)[O-])c1
Reaction time: 3.5 h
Yield: 97.5 %

Procedure:
To a solution of 4.6 g of 3-nitro-5-(octadecyloxy)phenylcarbamic acid dimethylethyl ester in 100 ml of methylene chloride stirred at room temperature was added 20 ml of trifluoroacetic acid. The reaction mixture was kept at room temperature for 3.5 hours and the solvent was then removed at reduced pressure. The residue was treated with water and the product was filtered and recrystallized from ethyl acetate-hexane to give 3.6 g (97% yield, mp 106°-108°) of 3-nitro-5-(octadecyloxy)benzenamine.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:19][S@](C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])(C(C)(C)C)(C)C.[ClH:26].O1CCOCC1>CO>[ClH:26].[NH2:19][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:9][OH:8]
Reactant: CC(C)(C)[S@](=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](CO)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a mixture of (S)—N—((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.08 g, 2.76 mmol) in MeOH (8 mL) was added 4N HCl in dioxane (6.9 mL, 28 mmol) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 4 hours. The solvents were evaporated in vacuo to give (R)-2-amino-2-(2,4-difluorophenyl)ethanol hydrochloride (0.58 g, 100%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was treated with hydrochloric acid to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride. 1H NMR 400 MHz (DMSO-d6) δ: 9.08 (2H, s), 8.37 (1H, d, J=8.30 Hz), 8.18 (1H, s), 8.07 (1H, s), 7.06 (1H, dd, J=8.35, 1.80 Hz), 6.91 (1H, d, J=1.80 Hz), 5.85 (1H, m), 4.53 (4H, m), 3.35 (2H, d, J=12.46 Hz), 2.98 (2H, m), 2.87 (1H, m), 1.93 (4H, m), 1.50 (6H, d, J=6.57 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: Cc1cccc(C(OC2CCNCC2)c2ccccc2)c1
Product: Cc1cccc(C(OC2CCN(CCCOc3ccccc3[N+](=O)[O-])CC2)c2ccccc2)c1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(3-methylphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(3-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.