Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:14]([OH:42])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:15]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C=O)[CH2:21][CH2:20]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.[NH2:44][CH2:45][C@@H:46]([C:48]1[CH:57]=[CH:56][C:55]([OH:58])=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52](=[O:59])[NH:53]2)[OH:47].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[CH:36]1([C:14]([OH:42])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:44][CH2:45][C@H:46]([OH:47])[C:48]3[CH:57]=[CH:56][C:55]([OH:58])=[C:54]4[C:49]=3[CH:50]=[CH:51][C:52](=[O:59])[NH:53]4)[CH2:21][CH2:20]2)=[O:16])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: O=CCCCCCCCCCN1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Reactant: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: O=C(OCC1CCN(CCCCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)CC1)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (90 μL, 0.65 mmol) was added to a solution of (1-(10-oxodecyl)piperidin-4-yl)methyl 2-cyclohexyl-2-hydroxy-2-phenylacetate (182 mg, 0.39 mmol) and (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (100 mg, 0.39 mmol) in methanol (4 mL). The reaction mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (154 mg, 0.73 mmol) followed by acetic acid (74 μL, 1.29 mmol) were added, and the reaction mixture stirred at RT for 72 hours. The reaction was quenched with water (500 μL) and evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide and submitted to reverse phase preparative HPLC for final purification. The title compound was isolated (42.3 mg, 16%).
Reaction SMILES: [OH-].[Na+].S(Cl)(Cl)=O.[Cl:7][S:8]([OH:11])(=O)=[O:9].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH2:13][CH3:14]>ClCCl>[Cl:7][S:8]([C:22]1[CH:23]=[CH:24][C:16]([O:15][CH2:12][CH2:13][CH3:14])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])(=[O:11])=[O:9]
Reactant: CCCOc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A three-neck flask, equipped with a 5M aqueous sodium hydroxide scrub (550 ml), was charged with thionyl chloride (40 ml, 0.55 mol) and chlorosulphonic acid (150 ml, 2.26 mol) and the stirred mixture cooled to about −10° C. A solution of 2-n-propoxybenzoic acid (100 g, 0.55 mol) in dichloromethane (200 ml) was added over 20 minutes, ensuring that the reaction temperature was maintained below 5° C., then the reaction mixture was allowed to warm to room temperature. The resulting solution was added over 1 hour to stirred, ice-cold water, whilst maintaining the temperature at about 0° C., and stirring continued for a further 30 minutes. The mixture was filtered and the solid thus obtained was washed with cold water (100 ml) and dried under vacuum to give the title compound (122.2 g, 80%) as a white solid. δ (DMSOd6): 1.13 (3H, t), 2.00 (2H, m), 4.32 (2H, t), 7.23 (1H, d), 8.21, (1H, m), 8.82 (1H, d).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:38](Cl)[CH3:39])[C:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C:23]=2[C:36]=1[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:38]([C:21]3[C:22]4[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C:23]=4[C:36]([CH3:37])=[C:19]([Cl:18])[CH:20]=3)[CH3:39])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: Cc1c(Cl)cc(C(C)Cl)c2c1CN(C(=O)OC(C)(C)C)CCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C(=O)OC(C)(C)C)CCO2
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
Cesium carbonate (500 mg, 2 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.98 mmol) in N,N-dimethylformamide (30 mL) and stirred for 10 minutes. To this was added tert-butyl 7-chloro-9-(1-chloroethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (290 mg, 0.82 mmol) in N,N-dimethylformamide (1 mL) and the reaction was stirred at 80° C. for 1 hour. The mixture was diluted with ethyl acetate and washed with water and brine. The extracts were dried over sodium sulfate, filtered and evaporated. The crude was dissolved in methylene chloride and filtered to remove insoluble material (unwanted regioisomer). Purification on silica gel using ethyl acetate in hexanes (0-100%) followed by methanol in ethyl acetate (0-15%) gave the desired compound (240 mg, 62%). LCMS calculated for C23H30ClN6O3(M+H)+: m/z=473.2; found: 473.2. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.29 (m, 1 H), 6.32 (m, 1 H), 4.70 (m, 1 H), 4.40 (m, 1 H), 3.83 (m, 2 H), 3.57 (m, 2 H), 2.58 (s, 3 H), 2.48 (m, 3 H), 1.78 (m, 3 H), 1.39 (, 9H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].C(N(CC)CC)C>CCOC(C)=O.O>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7][CH2:8][CH2:9][NH:10][C:13](=[O:14])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(SCCN)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(SCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of compound 24 (1.60 g) in EtOAc (100 mL) was added benzyl chloroformate (2.0 g, 1.2 eq.) and Cs2CO3 (3.2 g, 3 eq.). The reaction mixture was stirred at r.t. for 5 h. Triethylamine (2 mL) was added and the reaction was stirred for 3 h. After addition of H2O (30 mL), the organic phase was separated and washed with 1N HCl (2×30 mL), and sat. NaHCO3 (2×30 mL). The solvent was removed by evaporation under reduced pressure to give product 25 as white solid. Yield: 2.4 g, 79.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[C:30]([Cl:37])[N:29]=1.[N-]=C=O>C(Cl)(Cl)Cl.ClCCl>[Cl:37][C:30]1[N:29]=[C:28]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [N-]=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)amine (7.79 g, 30.3 mmol) and triethylamine (2.89 g, 28.6 mmol) in chloroform (20 mL) was added dropwise over 20 minutes to a cold (ice-bath), stirred solution of 2,6-dichloro-3-nitropyridine (5.0 g, 26.0 mmol) in chloroform (25 mL). The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give an oil. The mixture was taken up in dichloromethane (120 mL) and polymer-supported isocyanate resin (1.6 mmol/g, 8.0 g) was added and the mixture was shaken at room temperature for 2 days. The mixture was filtered and the filtrate was evaporated to give the title compound (10.7 g, 100%) as a bright yellow oil.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38]>CN(C)C=O>[CH3:38][C:24]1[N:25]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[S:27][C:23]=1[CH2:22][N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]1=[O:12]
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-diphenylpyrrolidin-2-one (Example 1A) (0.062 g, 0.262 mmol) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride dispersion in oil (0.013 g, 0.314 mmol). The mixture was stirred at room temperature for 1 hour. Then a solution of 5-(bromomethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole (CAS 439134-78-8) (0.088 g, 0.262 mmol) in N,N-dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was partitioned between H2O and dichloromethane. The organic layer was separated, dried over MgSO4 and concentrated. The obtained residue was purified by silica gel chromatography eluting with 2-5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.95-8.00 (m, 2H), 7.65-7.70 (m, 2H), 7.17-7.37 (m, 10H), 4.72 (s, 2H), 3.35 (t, J=6.4 Hz, 2H), 2.76 (t, J=6.3 Hz, 2H), 2.47 (s, 3H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].C[O-].[Na+].BrCC[CH2:19][C:20]([F:23])([F:22])[F:21]>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:7])([S:8][CH2:9][CH2:10][CH2:19][C:20]([F:23])([F:22])[F:21])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Reactant: FC(F)(F)CCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCCC(F)(F)F
Temperature: 85 °C
Yield: 84.3 %

Procedure:
To a solution of 149 g (785.4 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester (prepared as described in Method C, step 1) in ethanol (1.2 L, degassed under nitrogen for 1 h) are added 169.7 g (105 mmol) of sodium methoxide, followed by a solution of 150 g (785.4 mmol) of 4-bromo-1,1,1-trifluoro-butane. The reaction is heated to 85° C. for 3 d. The solvent is removed under reduced pressure. The residue is dissolved in DCM (1 L) and washed with saturated aqueous NaHCO3 solution (2×1 L). The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to afford 171 g of 2-methyl-2-(4,4,4-trifluoro-butylsulfanyl)-propionic acid ethyl ester as a brown oil. Yield: 84%; ES-MS: m/z 259 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29 (3H, t, J=7.17 Hz), 1.51 (6H, s), 1.76-1.86 (2H, m), 2.12-2.27 (2H, m), 2.69 (2H, t, J=7.17 Hz), 4.18 (2H, q, J=7.17 Hz)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]=[CH:12]2.CCN(C(C)C)C(C)C.C1C[O:36][CH2:35][CH2:34]1>>[C:35]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2](=[O:3])[O:4][CH3:5])[CH:13]=[CH:12]2)(=[O:36])[CH3:34]
Reactant: C1CCOC1
Reactant: COC(=O)Cl
Reactant: Brc1cccc2ccc(Nc3ccccc3)nc12
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(c1ccccc1)c1ccc2cccc(C(C)=O)c2n1
Temperature: 70 °C

Procedure:
Methyl chloroformate (0.155 ml, 2.006 mmol) was added to a solution of 8-bromo-N-phenylquinolin-2-amine (Example 165c; 0.500 g, 1.671 mmol) and DIPEA (0.438 ml, 2.507 mmol) in 5 mL THF and stirred over the weekend. The reaction was then sealed and heated at 70° C. for 6 h. Additional DIPEA (0.438 ml, 2.507 mmol) and methyl chloroformate (0.155 ml, 2.006 mmol) were added and the reaction was stirred overnight at RT. The reaction was heated for several hours at 70° C. The reaction mixture was then quenched with saturated aq. NaHCO3 and diluted with DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by column chromatography (silica gel: 0-10% EtOAc/hexane). The product-containing fractions were concentrated under reduced pressure to afford a mixture of starting material and desired product (0.376 g) that was used in the next step without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[O:14]([C:16]#[N:17])[K]>CC(O)=O.O>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:16]([NH2:17])=[O:14])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: N#CO[K]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Reaction time: 14 h
Yield: 52.7 %

Procedure:
To a solution of 21.3 g (0.124 mole) of 5-aminoindole-3-acetonitrile in 400 ml of 25% aq HOAc cooled to 0° was added 10.5 g (0.13 mole) of KOCN in 30 ml of H2O. The reaction mixture was stored at 0° for 14 hours after which a beige solid was filtered and recrystallized from methanol to give 14.0 g (53% yield) of N-(3-cyanomethyl-1H-indol-5-yl)urea. Further recrystallization affords an analytical sample: m.p. 219°-220°; i.r. (Nujol) 3455, 3300, 2250 and 1650 cm-1 ; nmr (d6 -DMSO) δ(TMS) 11.06 (1,S,indole NH ), 8.46 (1,S, --NHCO--), 7.70 (1,d,Jmeta =2 Hz), 7.37 (1,d,Jortho =9 Hz), 7.30 (1,S,indole C2H), 7.18 (1,d of d,Jortho =9 Hz, Jmeta =2 Hz), 5.73 (2,S,--CONH2) and 4.00 ppm (2,S,--CH2CN).
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]2[CH:11]=[CH:10][C:9]3=[N:12][CH:13]([N:15]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH2:17][CH2:16]4)[O:14][C:8]3=[CH:7]2)[CH2:3][CH2:2]1.Cl.[CH3:34]O>>[CH:1]1([CH2:4][O:5][N:6]2[CH:11]=[CH:10][C:9]3=[N:12][CH:13]([N:15]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:34])[CH3:24])[CH2:17][CH2:16]4)[O:14][C:8]3=[CH:7]2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: C[C@@H](COC1CCN(C2N=C3C=CN(OCC4CC4)C=C3O2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(C2N=C3C=CN(OCC4CC4)C=C3O2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl [(1S)-2-({1-[5-(cyclopropylmethoxy)[1,3]oxazolo[5,4-c]pyridin-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (328 mg) was added 2M hydrogen chloride/methanol (4 mL), and the mixture was stirred at room temperature for 10 min and concentrated. Pyridine (4 mL) and acetic anhydride (0.5 mL) were added to the residue, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate). The obtained solid was washed with diisopropyl ether to give the title compound (197 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O.[ClH:18].Cl.[O:20]=[C:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:22]1.C(N(CC)CC)C>C(O)CC(C)C>[ClH:1].[ClH:18].[NH2:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:23]3[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21](=[O:20])[CH:22]=3)[CH2:30][CH2:31]2)[N:11]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC1(C)CC(=O)C=C(N2CCCNCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCCN(C4=CC(=O)CC(C)(C)C4)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 1.7 g (0.007 mol) of 2-chloro-4-amino-6,7-dimethoxyquinazoline, 2.2 g (0.007 mol) of (3-oxo-5,5-dimethyl-1-cyclohexen-1-yl)-homopiperazine dihydrochloride monohydrate, 3.55 g (0.035 mol) of triethylamine and 30 ml of anhydrous isoamyl alcohol is heated at the boiling point under reflux for 10 hours. After cooling, the triethylamine hydrochloride is filtered off with suction and washed with isoamyl alcohol. The alcohol phases are concentrated at 50° C. in vacuo and the residue which remains is dissolved in 200 ml of chloroform. After washing twice with water, the chloroform solution is dried with sodium sulphate and evaporated to dryness. The residue can be taken up in 20 ml of absolute ethanol. Hydrogen chloride, dissolved in ethyl alcohol, is added to this solution, followed by absolute ether, while cooling with ice, until the onset of turbidity. The 1-(4-amino-6,7-dimethoxyquinazolin-2-yl)-4-(3-oxo-5,5-dimethyl-1-cyclo-hexen-1-yl)-homopiperazine dihydrochloride which precipitates is filtered off with suction and washed with absolute ether. Yield: 2.1 g (60%) of melting point 259°-261° C. (decomposition). A sample recrystallised from ethanol/methanol (2:1) has a melting point of 260°-261° C. (decomposition).
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH:5]3[O:6][C:7]([O:12][CH2:13][C:14]45[CH:25]6[CH2:26][C:21]([CH:33]=[O:34])([C:22]4([C:30]([OH:32])=[O:31])[C:23]([CH:27]([CH3:29])[CH3:28])=[CH:24]6)[CH:20]4[CH:16]([CH:17]([CH3:35])[CH2:18][CH2:19]4)[CH2:15]5)([CH:10]([OH:11])[CH:3]1[O:4]3)[O:8]2.[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1>[C:39]([CH2:38][CH2:37][C:36]([O:1][CH:2]1[CH:9]2[CH:5]3[O:6][C:7]([O:12][CH2:13][C:14]45[CH:25]6[CH2:26][C:21]([CH:33]=[O:34])([C:22]4([C:30]([OH:32])=[O:31])[C:23]([CH:27]([CH3:29])[CH3:28])=[CH:24]6)[CH:20]4[CH:16]([CH:17]([CH3:35])[CH2:18][CH2:19]4)[CH2:15]5)([CH:10]([OH:11])[CH:3]1[O:4]3)[O:8]2)=[O:42])([OH:41])=[O:40]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O)C13C(=O)O
Solvent: c1ccncc1
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OC(=O)CCC(=O)O)C5O2)C4O)C13C(=O)O
Reaction time: 52 h
Yield: 16.6 %

Procedure:
20 mg of compound (2) was dissolved in 1.0 ml of pyridine and stirred together with 16.4 mg of succinic anhydride at room temperature. After 52 hours, 8.2 mg of succinic anhydride was added, and the reaction was conducted for another 20 hours. The reaction solution was concentrated in vacuo and subjected to reversed phase chromatography (Capcell Pak C18 UG-120, Shiseido, 2.0φ×25 cm, 0.05% trifluoroacetic acid-acetonitrile [6:4], flow rate 10.0 ml/min, detection 210 nm) for purification, and the desired fraction was recovered. The recovered fraction was poured into 100 ml of 0.1 M sodium phosphate buffer pH 5.5 and extracted with 100 ml of ethyl acetate. The ethyl acetate extract was concentrated in vacuo to give 4.0 mg of compound (20).
Reaction SMILES: [OH-].[Na+].[CH:3]([O:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:5])[CH3:4].[CH2:22]([O:24][C:25](=[O:28])[CH:26]=[CH2:27])[CH3:23]>CS(C)=O>[C:25]([CH2:26][CH2:27][C:7]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([OH:6])[C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O:24][CH2:22][CH3:23])=[O:28].[CH:3]([O:6][CH:7]([CH3:16])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)OC(C(=O)c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)OC(C)C
Product: CCOC(=O)CCC(O)(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
1 ml of an aqueous 4N sodium hydroxide solution is added to a solution of 25.4 g (0.1 mol) benzoin isopropyl ether in 100 ml DMSO. The blue-green solution is mixed dropwise at 20°C with acrylic acid ethyl ester until the colour turns yellow (0.104 mol). After stirring for 2 hours, the product is worked up. The crystalline crude product is recrystallised from petroleum ether; melting point 52°-53°C. 86% of theory.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C(O)C.O>C1(C)C=CC=CC=1>[CH3:3][N:2]([CH:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[OH:11])[CH3:1]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(C)C(c1ccccc1)C1CCCCC1O
Yield: 86.4 %

Procedure:
3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 (2nd stage), dissolved in 26 ml toluene, were added dropwise to 26 ml (39 mmole) diisobutylaluminium hydride (1.5 M in toluene) at RT under nitrogen. The mixture was heated under reflux for 15 hours, while stirring. For working up, 13 ml ethanol and 13 ml water were slowly added dropwise and the suspension was stored at 0° C. for several hours, filtered through a glass frit and washed several times with a little toluene. The filtrate was concentrated on a rotary evaporator (500 to 10 mbar) and residues of solvent were removed under a high vacuum (approx. 0.1 mbar). 2.62 g (86.6% of theoretical) 2-(dimethylaminophenylmethyl)-cyclohexanol were obtained.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(O)C>[OH:1][CH:2]([CH2:23][NH:27][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Yield: 73 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman (6.35g.), isopropylamine (16ml) and ethanol (16ml) was boiled under reflux for 2 days. Removal of the solvent in vacuo gave 7-(2-hydroxy-3-isopropylaminopropoxy)-2,2-dimethyl-4-phenylchroman (6.7g., 73%) isolated as the hydrochloride salt, m.p. 171-174° from ether-ethanol.
Reaction SMILES: [CH3:1][N:2]([C@@H:7]([C:9]1[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])[CH3:8])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:20]1[CH:33]=[N:32][C:23]2[NH:24][C:25](=[O:31])[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:22]=2[CH:21]=1.CCN(C(C)C)C(C)C>C(C#N)C.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:29][C:26]1([CH3:30])[C:25](=[O:31])[NH:24][C:23]2[N:32]=[CH:33][C:20]([CH:5]=[CH:4][C:3]([N:2]([CH3:1])[C@@H:7]([C:9]3[O:10][C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]=3[CH3:14])[CH3:8])=[O:6])=[CH:21][C:22]=2[O:28][CH2:27]1
Reactant: C=CC(=O)N(C)[C@H](C)c1oc2ccccc2c1C
Reactant: CC1(C)COc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: Cc1c([C@@H](C)N(C)C(=O)C=Cc2cnc3c(c2)OCC(C)(C)C(=O)N3)oc2ccccc12
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A suspension of (R)—N-methyl-N-[1-(3-methyl-benzofuran-2-yl)-ethyl]acrylamide (328 mg, 1.35 mmol), 3-bromo-7,7-dimethyl-6,7-dihydro-9H-5-oxa-1,9-diaza-benzocyclohepten-8-one (400 mg, 1.48 mmol), (o-tol)3P (1.32 mg, 0.43 mmol) and DIEA (0.3 mL, 1.6 mmol) in EtCN (10 mL) and DMF (5 mL) was deoxygenated with argon for 30 min. Pd(OAc)2 (50 mg, 0.22 mmol) was added, the mixture was deoxygenated again with argon for 20 min and the mixture was heated to reflux overnight. The mixture was cooled to room temperature and partitinned between EtOAc and water. The residue was suspended in Et2O and then sonicated to give a solid. The solid was collected by filtration. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) and sonication in Et2O gave the title compound (150 mg, 26%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ10.13 (s, 1H), 8.27 (s, 1H), 8.0.1-7.89 (m, 1H), 7.58-7.50 (m, 3H), 7.32-7.18 (m, 3H), 6.19-5.99 (m, 1H), 4.07 (s, 2H), 3.04-2.79 (m, 3H), 248 (s, 3H), 1.64-1.54 (m, 3H), 1.19 (s, 6H); MS (ESI) m/e 434 (M+H)+.