Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([OH:15])(=[O:14])[CH2:9][CH2:10][C:11]([CH3:13])=O.[CH2:16](S)[CH3:17]>Cl.CCOCC>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:11]([C:17]2[CH:16]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:13])[CH2:10][CH2:9][C:8]([OH:15])=[O:14])=[CH:3][CH:2]=1
Reactant: CCS
Reactant: CC(=O)CCC(=O)O
Reactant: Oc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
376 g of phenol (4 mols), 116 g of levulinic acid (1 mol) and 0.4 ml of ethyl mercaptan were condensed, while stirring and simultaneously feeding in hydrogen chloride, for about 48 hours at 30°-40° C. The viscous reaction solution was taken up in ether and the ether phase was washed first with a sodium bicarbonate solution and then with water. After the ether had been eliminated, a brittle resin-like solid was obtained, m.p. 171°-173° C.
Reaction SMILES: BrC1C=C(OC)C=C(OC)C=1.O1C2C=CC(C=O)=CC=2OC1.C([Li])CCC.[O:28]1[C:33]2[CH:34]=[CH:35][C:36]([CH:38]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[CH:41]=3)[OH:39])=[CH:37][C:32]=2[O:31][CH2:30]C1>>[O:28]1[C:33]2[CH:34]=[CH:35][C:36]([CH:38]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([O:48][CH3:49])[CH:41]=3)[OH:39])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: COc1cc(Br)cc(OC)c1
Agent: O=Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCO3)c1
Yield: 81 %

Procedure:
1-Bromo-3,5-dimethoxybenzene (0.47 g, 3.14 mmol), benzo[1,3]dioxole-5-carbaldehyde (0.75 g, 3.46 mmol), and n-butyl lithium (1.38 ml, 3.46 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give Benzo[1,3]dioxol-5-yl-(3,5-dimethoxy-phenyl)-methanol as an off-white oil (0.73 g, 81%): 1HNMR (CDCl3) 6.87-6.83 (m, 2H, Ar), 6.77-6.74 (m, 1H, Ar), 6.53 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H), 5.93 (m, 2H, CH2), 5.68 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 6H, 2OCH3), 2.15 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:24][CH3:25])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-bromobenzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH:19]([CH3:21])[CH3:20])[CH:5]=[O:6]
Reactant: CC(C)Br
Reactant: O=Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1c(F)cc(C=O)cc1F
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a suspension of 3,5-difluoro-4-hydroxy-benzaldehyde as a colourless solid (0.81 g) and K2CO3 (2.14 g; 15.4 mmol) in MeCN (15 ml) is added 2-bromopropane (1.45 ml) dropwise. The mixture is stirred at 65° C. for 24 h. After evaporation of the solvent the residue is taken-up in Et2O and water. The organic layer is separated and extracted with brine, dried over MgSO4 and evaporated to give 3,5-difluoro-4-isopropoxy-benzaldehyde (0.14 g).
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2([CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:15][C:16](=[O:25])[C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12][CH2:11][CH2:10]2)C=CC=CC=1>[Pd].[C].C(O)C>[NH2:8][C:9]1([CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:15][C:16](=[O:25])[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:24])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N)CCCC1
Yield: 88 %

Procedure:
The title compound (1.14 g; 71%) was prepared from the catalytic hydrogenation of (±)-N-[{1-[bis(phenylmethyl)amino]cyclopentyl}(phenyl)methyl]-2,6-dimethylbenzamide D34 (2.51 g; 5 mmol) over 10% Pd/Carbon (0.4 g) in 3 MHCl (8 ml) and ethanol (150 ml) in a similar manner to that described in D29. The ethanol was evaporated off in vacuo and the residual material was partitioned between DCM and sodium bicarbonate solution and dried (Na2SO4). The filtrate was reduced in volume by evaporation in vacuo and loaded onto an SCX cartridge. Washing with DCM, then methanol followed by elution with 1M ammonia in methanol afforded the title product (90 mg, 88%). 1H NMR (CDCl3) δ: 0.98-1.96 (10H, m). 2.23 (6H, s), 4.97 (1H, m), 7.0 (2H, m), 7.16 (1H, m), 7.22-7.41 (6H, m); Mass Spectrum (Electrospray LC/MS). Found 323 (MH+). C21H26N2O requires 322. Ret. time 1.69 min.
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([OH:8])[CH:7]=1.[Cl:12]C1C=CC(C2CC2)=C(C=1)N>[Hg]>[Cl:12][C:2]1[CH:3]=[CH:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: Cc1ccc(C2CC2)c(O)c1
Reactant: Nc1cc(Cl)ccc1C1CC1
Agent: [Hg]
Product: Oc1cc(Cl)ccc1C1CC1
Yield: 32 %

Procedure:
Prepared according to the method described for the 5-methyl-2-cyclopropyl-phenol of Example I, from 31.5 g (0.188 mol/g) of 5-chloro-2-cyclopropyl-aniline with a yield of 32%. B.P.=69° C.-76° C./0.1 mm mercury. m.P. 30° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CO.[Zn]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]([F:12])=[CH:5][C:6]=1[NH:9][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: Nc1c([N+](=O)[O-])cc(F)c(NCc2ccc(F)cc2)c1F
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)Nc1cc(F)c(NCc2ccc(F)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a stirred solution of compound 3 (0.062 g, 0.21 mmol, 1.0 equiv) in methanol (0.560 mL) was added zinc powder (0.068 g, 1.04 mmol, 5.00 equiv) followed by ammonium chloride solution (55.3 mg, 1.04 mmol, 5.00 equiv) drop wise. After being stirred for 4 h at RT, DIPEA (48.0 μL, 0.260 mmol, 1.25 equiv) and ethyl chloroformate (20.0 μL, 0.210 mmol, 1.00 equiv) were added to reaction mixture at 10° C. and the stirring was continued for another 2 h at RT. After consumption of the starting material (by TLC), the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2×75 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by neutral alumina column chromatography (EtOAc/Hexane 18:82) to afford to compound 4A (0.017 g, 21%) as an off-white solid. TLC: 50% EtOAc/Hexane (Rf: 0.50); 1H NMR (500 MHz, CDCl3): δ 7.30-7.27 (m, 2H), 7.00 (t, J=8.5 Hz, 2H), 6.88 (d, J=11.5 Hz, 1H), 6.26 (br s, 1H, Exc), 4.40 (d, J=6.0 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.75 (br s, 1H, Exc), 3.50 (s, 2H, Exc), 1.30 (t, J=7.0 Hz, 3H); LC-MS: m/z=340 (M++1) at RT 3.46 (94.3% purity); UPLC purity: 95.2%
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[CH:9][C:10]2[N:20]=[C:13]3[C:14]([CH3:19])=[N:15][CH:16]=[C:17]([CH3:18])[N:12]3[N:11]=2)=[N:6][C:5]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:4]1)[CH3:2]>[Pd].CO>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][C:10]2[N:20]=[C:13]3[C:14]([CH3:19])=[N:15][CH:16]=[C:17]([CH3:18])[N:12]3[N:11]=2)=[N:6][C:5]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(N2CCCC2)nc1C=Cc1nc2c(C)ncc(C)n2n1
Agent: [Pd]
Solvent: CO
Product: CCn1nc(N2CCCC2)nc1CCc1nc2c(C)ncc(C)n2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
A mixture of 2-(2-(1-ethyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (33 mg, 97.5 μmol, Eq: 1.00) and palladium on carbon 10% (10.4 mg, 9.75 μmol, Eq: 0.1) in methanol (30 ml) was stirred for 5 hours under hydrogen atmosphere at 25° C. The catalyst was filtered off and the filtrate was evaporated affording 2-[2-(2-Ethyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (32 mg 96.4%) as a yellow oil. MS: m/e=341.5 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:21])[N:15]3[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]3)=[O:10])=[C:4]([Cl:23])[CH:3]=1.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:21])[N:15]3[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]3)([OH:10])[C:25]([F:27])([F:26])[F:24])=[C:4]([Cl:23])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1ccc(=O)n2ccccc12)c1ccc(Br)cc1Cl
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n2ccccc12)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 1-[2-(4-bromo-2-chloro-phenyl)-propionyl]-quinolizin-4-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a light yellow solid. MS (m/e)=460.2 [M+H+].
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:25])[O:22][C:21](=[O:23])[C:18]2([CH2:20][CH2:19]2)[C:17](=[O:24])[O:16]1>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][CH2:19][CH:18]2[C:17](=[O:24])[O:16][C:15]([CH3:25])([CH3:14])[O:22][C:21]2=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CCN2CCC(Cc3ccccc3)CC2)C(=O)O1

Procedure:
Following the procedure described in S. Danishefsky and R. K. Singh, J. American Chemical Society, 97:3239-3241(1975), a mixture of 0.5 g of 4-benzylpiperidine, 10 mL of toluene, and 0.5 g, of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane 4,8-dione was stirred for 20 h, cooled, and, the white solid product collected by filtration and dried under vacuum. The yield of 5-[2-(4-benzyl-piperidin-1-yl)-ethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione was 0.94 g.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=O)[CH:17]=[CH:16]3.[O:25]=[C:26]1[CH2:35][C:34]2([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][NH:37][C:32]3[C:33]2=[C:28]([CH:29]=[CH:30][CH:31]=3)[NH:27]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:25]=[C:26]1[CH2:35][C:34]2([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][N:37]([CH2:22][C:18]3[CH:17]=[CH:16][C:15]4[C:20](=[CH:21][C:12]5[CH2:11][C@:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:24][C:13]=5[CH:14]=4)[N:19]=3)[C:32]3[C:33]2=[C:28]([CH:29]=[CH:30][CH:31]=3)[NH:27]1
Reactant: CCOC(=O)CC12CNc3cccc(c31)NC(=O)C2
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CC12CC(=O)Nc3cccc(c31)N(Cc1ccc3cc4c(cc3n1)C[C@]1(C4)C(=O)Nc3ncccc31)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde (339 mg, 1.08 mmol, described in Intermediate 10), ethyl (4-oxo-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl)acetate, enantiomer A (200 mg, 0.768 mmol, described in Intermediate 22), and AcOH (0.44 mL, 7.68 mmol) in DCE (5 mL) was added sodium triacetoxyborohydride (228 mg, 1.08 mmol) and the mixture was stirred for 90 min at ambient temperature. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (20 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=560 (M+1). HRMS: m/z=560.2303; calculated m/z=560.2293 for C33H30N5O4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:22][C:21]([CH3:23])=[CH2:20])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: C=C(C)CBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)COc1cc(O)cc(C(=O)OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). 1H NMR (400 MHz, CDCl3) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1H) 4.93-5.04 (m, 1H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:15]=[N:16][C:17]([Br:20])=[CH:18][CH:19]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>>[Br:20][C:17]1[N:16]=[CH:15][C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nn(-c2ccc(Br)nc2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method B using (1aR,5aR)-2-(6-bromopyridin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester and 2.0 M sodium hydroxide. LCMS m/z=320.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49 (td, J=4.7, 3.4 Hz, 1H), 1.25 (td, J=7.8, 4.8 Hz, 1H), 2.30-1.36 (m, 1H), 2.61-2.66 (m, 1H), 2.76 (d, J=16.6 Hz, 1H), 2.90 (dd, J=16.6, 6.4 Hz, 1H), 7.83 (dd, J=8.6, 0.5 Hz, 1H), 8.16 (dd, J=8.6, 2.9 Hz, 1H), 8.87 (dd, J=2.8, 0.5 Hz, 1H), 12.90 (bs, 1H).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH:5]=O.O.[NH2:16]N>C(O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:3]=[N:2][NH:16][CH:5]=2)=[CH:8][CH:9]=1
Reactant: NN
Reactant: CN(C)C=C(C=O)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2cn[nH]c2)cc1

Procedure:
To a solution of 3-(dimethylamino)-2-(4-fluorophenyl)acrylaldehyde (3.0 g) in ethanol (30 mL) was added hydrazine monohydrate (0.90 mL), followed by heating and refluxing for 3 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure until the amount of the reaction liquid was reduced to about a half. Water (20 mL) was added thereto, and the resulting solid was collected by filtration and dried under reduced pressure to obtain 4-(4-fluorophenyl)-1H-pyrazole (2.44 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O.[OH-].[Na+].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
19 g (67 mmol) of 7-methoxy-4-(4-methoxyphenyl)-2H-phthalazin-1-one are dissolved in 100 mL of phosphoryl chloride. The solution is heated at 80° C. for 2 hours. The reaction medium is cooled to room temperature and then poured slowly into 500 mL of water at 40-50° C. with stirring. The mixture is then stirred at 5° C., basified by addition of 35% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water and then with brine and dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure, 19.3 g of a beige-coloured powder are obtained (yield=96%).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH3:23])[N:3]=1.N(OCCC(C)C)=O.[ClH:32]>C(#N)C.[Cu](Cl)Cl>[Cl:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:22][CH3:23])[N:3]=1
Reactant: Cl
Reactant: COc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COc1nc(Cl)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.3 g (10.634 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-methoxypyridine-3,5-dicarbonitrile are initially charged in 300 ml of acetonitrile, 8.578 g (63.806 mmol) of copper(II) chloride and 8.59 ml (63.806 mmol) of isoamyl nitrite are added and the mixture is stirred at room temperature overnight. 1N hydrochloric acid is added, and the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 2.11 g (58% of theory) of the target compound.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([C:24]2[CH:25]=[N:26][C:27]([C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:41][CH3:42])=[CH:28][C:29]=2[O:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH3:23])[CH:14]=1>C1COCC1.CCOCC>[CH2:41]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][CH3:40])[C:33]=1[C:27]1[N:26]=[CH:25][C:24]([CH:20]([O:19][C:15]2[CH:14]=[C:13]([CH2:12][OH:11])[CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH3:23])=[C:29]([O:30][CH2:31][CH3:32])[CH:28]=1)[CH3:42]
Reactant: CCCC(Oc1cccc(C(=O)OC)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(Oc1cccc(CO)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reaction time: 2 h

Procedure:
DIBAL-H (1.5 M in Toluene, 0.3 mL) is added dropwise to a solution of 3-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butoxy}-benzoic acid methyl ester (80 mg, 0.17 mmol) in THF (3 mL) at room temperature. The reaction mixture is stirred for 2 hours, then diluted with ether (5 mL) and treated with Na2SO4.10H2O. The resulting mixture is stirred for one hour and filtered through Celite. Concentration of the filtrate at reduced pressure gives (3-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butoxy}-phenyl)-methanol. 1H NMR (CDCl3) 8.53 (s, 1H), 7.10-7.30 (m, 4H), 6.74-6.90 (m, 4H), 5.60 (m, 1H), 4.51 (s, 2H), 4.13 (q, 2H), 2.47 (s, 1H), 2.24-2.37 (m, 4H), 1.80-2.10 (m, 2H), 1.40-1.60 (m, 5H), 0.90-1.05 (m, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([NH:24][CH2:23][CH2:21][OH:22])=[N:12][C:11]1=2)[CH3:14]
Reactant: NCCO
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(NCCO)nc21

Procedure:
The title compound, m.p. 241°-244° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and ethanolamine using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 260° C. for 50 min., and the product was crystallized from chloroform/ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A solution of the compound of Example 45, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.411 g, 4.95 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was treated with triethylamine (1.38 mL, 9.89 mmol). With vigorous stirring, the solution was treated with phenyl isocyanate (0.538, 4.95 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 9:1 CH2Cl2:MeOH) gave 351 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea as a white powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[C:3]1([CH3:42])[CH3:41].C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(#N)C.C(OCC)(=O)C>[CH3:50][S:51]([O:1][CH:2]1[C:3]([CH3:42])([CH3:41])[C:4](=[O:40])[N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[CH2:34][C:35]([F:36])([F:38])[F:37])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[CH2:6]1)(=[O:53])=[O:52]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(O)C(C)(C)C2=O)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(OS(C)(=O)=O)C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (4-(4-((3-(4-hydroxy-3,3-dimethyl-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (40 mg) was dissolved in acetonitrile (2.0 mL), triethylamine (14 μL) and methanesulfonyl chloride (5.7 μL) were added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, and the mixture was washed three times with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15 mg).
Reaction SMILES: O=[Si]=O.[C:4]1(C)[CH:9]=[CH:8][C:7](S(O)(=O)=O)=[CH:6][CH:5]=1.[O-2:15].[Mg+2]>>[C:4]1([OH:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:4]=[O:15]
Reactant: [O-2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=[Si]=O
Agent: [Mg+2]
Product: C=O
Product: Oc1ccccc1

Procedure:
100 parts by weight of quartz sand were mixed with 65% aqueous-alcohol solution of paratoluenesulphonic acid amounting to 1.2% by weight of the sand, and with phenol formaldehyde resin taken in an amount of 2% by weight of the sand and produced by condensing 1 mole of phenol and 1.2 moles of formaldehyde in the presence of magnesium oxide at a condensing temperature of 70°-75° C.