Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl>N1C=CC=CC=1>[C:32]1([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]3[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=3)=[CH:4][C:3]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccccc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.995 g, 0.00181 mol) and phenylsulfonyl chloride (0.484 g, 0.00274 mol) 40 mL of methylene chloride was added 5 mL of pyridine. The reaction mixture was stirred overnight at room temperature, washed with 1N HCl and 1N NaOH, dried over Na2SO4 and concentrated. A crystallization from ethyl acetate-hexanes gave an oil. It was solidified under standing. Yield 1.043 g (83%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH2:13][OH:14])=[CH:10][CH:9]=[CH:8]2.P(=O)(O)(O)O.O>C(Cl)Cl>[CH2:2]1[C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:13][O:14]1)[CH:6]=[CH:5][CH:4]=2
Reactant: OCc1cccc2cccc(CO)c12
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Product: c1cc2c3c(cccc3c1)COC2
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A 1-L 3-neck flask equipped with an overhead stirrer, a condenser, and a thermocouple was charged with (8-hydroxymethyl-naphthalen-1-yl)-methanol (33.0 g, 0.175 mol), concentrated phosphoric acid (225 mL), and water (5 mL). The reaction mixture was stirred at 140° C. for 3 h, cooled to room temperature, diluted with CH2Cl2 (800 mL) and transferred to a 2-L separatory funnel. After washing the organic layer with water and saturated NaHCO3 it was dried over MgSO4 and evaporated to yield 1H,3H-Benzo[de]isochromene as a solid.
Reaction SMILES: C1C=CN=CC=1.F.[Si:8]([O:15][C@@H:16]([CH2:42][C@H:43]([O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])/[CH:44]=[CH:45]\[C@H:46]([CH3:70])[C@H:47]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:48]([CH3:61])[CH2:49][C@@H:50]([CH3:60])[CH2:51][O:52][Si](C(C)(C)C)(C)C)[C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>N1C=CC=CC=1.C1COCC1>[Si:63]([O:62][C@@H:47]([C@@H:46]([CH3:70])/[CH:45]=[CH:44]\[C@@H:43]([O:71][Si:72]([C:75]([CH3:78])([CH3:76])[CH3:77])([CH3:74])[CH3:73])[CH2:42][C@H:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:48]([CH3:61])[CH2:49][C@@H:50]([CH3:60])[CH2:51][OH:52])([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@@H](CO)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 21 h
Yield: 66.9 %

Procedure:
HF-pyridine in pyridine (40 mL, prepared by slow addition of 12 mL pyridine to 3 mL HF-pyridine complex followed by dilution with 25 mL THF) was slowly added to a solution of TBS ether 35 (4.27 g, 4.10 mmol) in THF (5 mL) at 0° C. The mixture was stirred for 21 h at 0° C. and quenched with saturated aqueous NaHCO3 (100 mL). The aqueous layer was separated and extracted with Et2O (3×50 mL). The combined organic layers were washed with saturated aqueous CuSO4 (3×50 mL), dried over MgSO4, filtered and concentrated. Flash column chromatography (EtOAc/hexane 1:4) afforded 2.55 g (67%) of the alcohol 36 as a colorless oil: IR (CHCl3) 3350, 2956, 2928, 2856, 1471, 1448, 1254, 1086, 836, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.52 (m, 6H), 7.32 (m, 9H), 5.68 (m, 2H), 5.50 (t, J=10.6 Hz, 1H), 5.35 (dd, J=10.9, 8.5 Hz, 1H), 4.61 (t, J=8.5 Hz, 1H), 4.00 (t, J=8.1 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.58 (dd, J=10.6, 4.3 Hz, 1H), 3.45 (m, 1H), 3.36 (dd, J=9.9, 7.3 Hz, 1H), 2.66 (m, 1H), 2.48 (m, 1H), 1.70 (m, 3H), 1.49 (m, 3H), 1.04 (d, J=6.6 Hz, 6H), 0.97 (s, 18H), 0.93 (m, 6H), 0.87 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H), 0.11 (s, 6H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.3, 134.4, 133.0, 132.1, 128.7, 127.7, 126.8, 86.7, 79.8, 72.3, 67.7, 66.5, 65.1, 42.4, 41.5, 37.3, 35.7, 35.5, 33.3, 26.2, 26.0, 25.9, 19.6, 18.4, 18.14, 18.06, 17.98, 15.7, 13.2, −2.9, −3.6, −3.7, −4.1, −4.2, −4.3; LRMS (ESI) 951.8 [M+Na]+, 771.6, 328.3; HRMS (ESI) calcd for C56H92O5Si3Na 951.6150 [M+Na]+, found 951.6162; [α]20D−12.0 (c 0.71, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[ClH:26].C(OCC)(=O)C>CO>[ClH:26].[ClH:26].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Cc1[nH]cnc1CSCCNc1ncccc1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]cnc1CSCCNc1ncccc1O
Reaction time: 48 h

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]amino-3-benzyloxypyridine (1.3 g; 0.0036 moles) was treated with conc. hydrochloric acid (10 ml) and heated to 60° for 4 hours. The reaction mixture was stripped in vacuo to a green oil, dissolved in methanol, treated with ethyl acetate and left to stand for 2 days. The red crystals obtained were filtered off and recrystallised from methanol/ethyl acetate to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-hydroxypyridine dihydrochloride as dark red crystals (0.17 g, mp 210°-212°).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]1[CH2:19][OH:20])=O)(C)(C)C.C1COCC1.Cl.[OH-].[Na+]>CO>[C:13]1([C@H:10]2[CH2:11][CH2:12][NH:8][C@H:9]2[CH2:19][OH:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@@H]1NCC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
rac-(cis)-3-Phenylpyrrolidin-2-yl)methanol. To a stirred solution of rac-(cis)-tert-butyl-2-(hydroxymethyl)-3-phenylpyrrolidine-1-carboxylate, racemic (0.2133 g, 769 μmol) in THF (2.0 mL, 24409 μmol) was added hydrogen chloride (4.0 N solution in 1,4-dioxane) (1.9 mL, 7690 μmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The entire mixture was neutralized with SN NaOH and concentrated to give rac-(cis)-3-phenylpyrrolidin-2-ylmethanol (76 mg, 56% yield) as a white solid, which was pure enough to be used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].C[O:10][C:11](=O)[C:12]([OH:23])([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[Na]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:11](=[O:10])[C:12]([OH:23])([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN1CCC[C@H]1CO
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1CCC[C@H]1COC(=O)C(O)(c1cccs1)c1cccs1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
To a mixture of molecular sieve 4A, ((S)-1-Methyl-pyrrolidin-2-yl)-methanol (3.71 g, 31.2 mmol) and Hydroxy-di-thiophen-2-yl-acetic acid methyl ester (3.96 g, 15.6 mmol) in toluene (40 ml) is added sodium (65 mg) and the suspension is heated under stirring to 80° C. for 3.5 hours. Additional sodium (65 mg) is then added and the reaction mixture stirred at 80° C. for 16 hours. The reaction mixture is cooled to room temperature, diluted with diethylether (100 ml) and extracted with HCl 1 M (2×100 ml). The combined acidic aqueous layers are washed with diethylether (50 ml) and basified with sodium hydroxide 4 M whilst cooling in ice. The solution is then extracted with ethylacetate and diethylether. The combined organic layers are dried over magnesium sulphate, filtered and evaporated to dryness to give the title product.
Reaction SMILES: [CH:1]([S:4]([C:7](=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)SC)[C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:22][CH:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24]>>[CH:1]([S:4]([C:7](=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[NH:22][CH:23]([CH3:24])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(N)C(C)(C)C
Reactant: COc1cccc(NC(SC)=C(C#N)S(=O)(=O)C(C)C)c1
Product: COc1cccc(NC(NC(C)C(C)(C)C)=C(C#N)S(=O)(=O)C(C)C)c1
Yield: 80 %

Procedure:
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-propenenitrile(0.500 g, 1.53 mmol) was stirred in 2-amino-3,3-dimethylbutane (2 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane,washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and evaporated to afford 450 mg (80%) of the title compound as white crystals. Mp 59-62 ° C.1H NMR (200 MHz, CDCl3): δ=0.84 (s, 9H), 0.96 (d, 3H), 1.40 (d, 6H), 3.00-3.33 (m, 2H), 3.82 (s, 3H), 6.70 (dd, 1H), 6.81 (dd, 1H), 7.31 (dd, 1H), 7.73-7.94 (m, 1H) 8.95 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]([N:32]1[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]1[C:38]#[N:39])=[O:31]>C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:29][C:30]([N:32]3[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]3[C:38]#[N:39])=[O:31])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Reaction time: 4 h
Yield: 79.6 %

Procedure:
2-Tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (62.9 mg) was suspended in acetonitrile (1 mL). To this solution, diisopropylethylamine (47 μL) was added and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) in acetonitrile (0.8 mL) was added while the mixture was chilled in an ice bath. The mixture was stirred for 4 hours and concentrated. To the resulting residue, ethyl acetate and water were added, followed by an aqueous sodium bicarbonate solution to make the pH basic. The solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant:dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].[O:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH2:33][NH2:34]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:25])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:34][CH2:33][C@H:29]2[CH2:30][CH2:31][CH2:32][O:28]2)=[O:19])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: NC[C@H]1CCCO1
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC[C@H]2CCCO2)C1(C)C

Procedure:
The product from Example 173 and (R)-(tetrahydrofuran-2-yl)methanamine (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.24 (s, 3H), 1.26-1.52 (m, 5H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.74-1.89 (m, 3H), 1.95-2.08 (m, 1H), 2.62-2.83 (m, 4H), 2.91-2.99 (m, 1H), 3.22-3.33 (m, 2H), 3.56-3.84 (m, 2H), 7.58-7.62 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 478 (M+H)+. Anal. calcd. for C26H43N3O3S: C, 65.37; H, 9.07; N, 8.80. Found: C, 65.39; H, 8.91; N, 8.66.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:30]([CH:27]5[CH2:29][CH2:28]5)=[O:31])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: O=C(Cl)C1CC1
Product: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4NC(=O)C4CC4)[nH]c3cc21
Yield: 16.6 %

Procedure:
Cyclopropanecarboxylic acid[3-(7,7-diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-Amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and cyclopropanecarbonyl chloride (45 mg, 0.43 mmol). 30 mg (17%) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C:19]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1(c2ccccc2)C(=O)NCc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared. The product was purified by LC 2000 chromatography, eluting with ethyl acetate.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CS(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([C:11]2[CH:12]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:8]([OH:17])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 90 °C
Reaction time: 17 h
Yield: 68.1 %

Procedure:
A mixture of 12.0 g (300 mmol) of powdered sodium hydroxide, 24.7 g (120 mmol) of 2,6-di-tert-butylphenol, 15.7 g (100 mmol) of 1-chloro-4-nitrobenzene, and 120 mL of DMSO was stirred for 17 hours at 90° C. and poured into one liter of IN HC1. The resulting aqueous mixture was extracted with three 250 mL portions of diethyl ether. Combination, drying (MgSO4), and concentration of the organic layers afforded a residue which was purified by two recrystallizations from ethanol-dichloromethane to give 22.3 g (68% yield) of 4-(4'-nitrophenyl)-2,6-di-tert-butylphenol which can also be named 3,5-bis-(1,1-dimethylethyl)-4'-nitro-(1,1'-biphenyl)-4ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:17].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[C:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]3[CH:20]=[C:19]([Cl:18])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])=[C:3]([F:17])[CH:4]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)c(F)c1
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1F

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 5 step (i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[OH:1][CH:2]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)COCc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(O)COCc1cccc(CN2CCCCC2)c1
Yield: 75.9 %

Procedure:
8.60 g (0.021 mol) of 2-[2-hydroxy-3-[3-(1-piperidylmethyl)-benzyloxy]propyl]-1H-isoindole-1,3-dione and 3.3 ml of hydrazine hydrate (80%) are boiled in 80 ml of ethanol for 3 hours. The residdue left after concentration of the mixture by evaporation is taken up in 50 ml of water; 8 ml of conc. hydrochloric acid are added and the reaction mixture is filtered. The filtrate is adjusted to pH 12 with conc. sodium hydroxide solution and extracted with 3×40 ml methylene chloride. The organic phase is dehydrated with Na2SO4 and concentrated by evaporation under vacuum. The residue is distilled in a high vacuum. 4.44 g (76%) of a colourless oil, boiling point 145°-155° C./1×10-2 mbar are obtained. ##STR4##
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH:20]4[CH:15]([CH2:16][CH2:17][NH:18][CH2:19]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].CCN(CC)CC>C(Cl)Cl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[S:29]([N:18]1[CH2:17][CH2:16][CH:15]2[CH:20]([N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:19]1)(=[O:30])=[O:31]
Reactant: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(S(=O)(=O)N2CCC3CN(c4nccc(-c5ccccc5)n4)C3C2)c1
Yield: 31.7 %

Procedure:
A mixture of 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 6, 110 mg, 0.29 mmol), 2,5-dimethyl-benzenesulfonyl chloride (83 mg, 0.41 mmol) and Et3N (91 mg, 0.9 mmol) was stirred in DCM (5.0 mL) at RT for 18 h. The reaction mixture was diluted with more DCM (15 mL) and washed with water. The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield crude product. The crude product was purified on HPLC (basic system) to yield the title compound (40 mg, 35%). MS (ESI) mass calcd. for C24H26N4O2S, 434.55; m/z found 435.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.26 (s br, 1H), 7.87 (s br, 2H), 7.70 (s, 1H), 7.51-7.34 (m, 3H), 6.94 (d, J=5.3, 1H), 6.91-6.73 (m, 2H), 4.62-4.52 (m, 1H), 4.16 (t, J=8.3, 1H), 4.04 (dd, J=13.5, 2.9, 1H), 3.93 (dd, J=8.6, 3.9, 1H), 3.85-3.73 (m, 1H), 3.74-3.59 (m, 1H), 3.40 (dd, J=13.5, 2.8, 1H), 2.95-2.89 (m, 1H), 2.45 (s, 3H), 2.28-2.12 (m, 1H), 2.21-1.85 (m, 4H).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH:4]12[NH:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH2:7][CH:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5]2>C(Cl)Cl>[CH2:1]([N:12]1[CH:4]2[CH2:11][CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:5]2)[CH3:2]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC1CC2CCCC(C1)N2
Solvent: ClCCl
Product: CCN1C2CCCC1CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 30 h
Yield: 44.4 %

Procedure:
Ethyl iodide (50 μL, 0.63 mmol) was added to a solution of the amine from Step B (100 mg, 0.42 mmol) in methylene chloride (2 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 h. The mixture was quenched with a saturated solution of sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford tert-butyl 9-ethyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate (50 mg, 45%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 4.28 (br s, 1H), 3.99 (br s, 1H), 3.13-3.10 (m, 2H), 2.63 (q, J=7.0 Hz, 2H), 2.38-2.30 (m, 2H), 1.90-1.82 (m, 3H), 1.48-1.46 (m, 1H), 1.44 (s, 9H), 1.16-0.95 (m, 7H); MS (ESI+) m/z 269 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]1([CH:14]=[CH:13][CH:12]=[C:10]([OH:11])[CH:9]=1)[OH:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:2]([O:8][C:7]1[CH:9]=[C:10]([OH:11])[CH:12]=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(O)c1

Procedure:
A mixture of 24.8 ml of 1-Bromopentane, 66.0 g of resorcinol, and 41.5 g of potassium carbonate is stirred in 400 ml of anhydrous dimethylformamide at 60° C. for 17 hours. This mixture is filtered through Celite and concentrated under vacuum. The residue is taken up in water and extracted 3 times with ether. The combined extracts are washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is flash chromatographed on normal phase silica gel eluting with a 4:1 ratio of hexane:ether to yield 3-pentyloxyphenol as a clear oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[N:15][C:14]=12.[CH3:30]I>CN(C)C(=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[N:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([N:23]3[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[CH2:27][CH2:28]3)=[N:15][C:14]=12
Reactant: OC1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reaction time: 18 h
Yield: 65.7 %

Procedure:
Sodium hydride (60% dispersion in oil) (0.044 g, 1.10 mmol) was added to a solution of 3-(2-fluorophenyl)-5-(4-hydroxypiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (Example 9) (10 g, 0.27 mmol) in N,N-dimethylacetamide (4 ml). The mixture was stirred for 30 min before addition of methyl iodide (0.17 ml, 2.8 mmol) and then stirred for a further 18 h. The mixture was diluted with water (20 ml) and extracted with CH2Cl2 (2×50 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO4 and evaporated to give a colourless oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH:NH3(c) (95:5:0.5) gave 3-(2-fluorophenyl)-5-(4-methoxypiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.067 g, 65%) as a yellow solid. δH (360 MHz; CDCl3) 1.84-1.90 (2H, m), 2.11-2.16 (2H, m), 3.36-3.41 (2H, m), 3.42 (3H, s), 3.51-3.54 (1H, m), 3.88-3.95 (2H, m), 7.19-7.29 (2H, m), 7.32-7.37 (1H, m), 7.60 (1H, ddd, J=8, 8 and 1), 7.88 (1H, ddd, J=8, 8 and 1), 8.01 (1H, d, J=8), 8.15 (1H, ddd, J=7, 7 and 2), 8.67 (1H, dd, J=8 and 1); m/z (ES+) 378 (M+H+).