Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][S-:14].[K+]>>[CH3:13][S:14][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: C[S-]
Agent: [K+]
Product: CSc1cccc(CC(=O)O)c1
Yield: 17.2 %

Procedure:
Prepared in an essentially similar fashion from methyl 3-aminophenyl-acetate (11 g, 0.67 mole) and potassium methanethiolate (2.68 mole) to give 3-methylthiophenylacetic acid (21.0 g). Mp=76-77° C., 1H NMR (DMSO-d6, 200 MHz) δ: 2.44 (s, 3H, SCH3), 3.53 (s, 2H, ArCH2), 7.02-7.28 (m, 4H, Ar), 12.30 (br s, 1H, CO2H). Mass spectrum (CI-CH4): 183 (M+1, 100%). (Lit. ref.: Plant Physiol 42(11) 2596-1600 (1967).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:25]([O-])=[O:26].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 38.8 %

Procedure:
4.3 g of 1-(2-chloroethyl)-3-n-hexyl-3-D-glucopyranosylurea are dissolved in 15 ml of formic acid, and 2.4 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-hexyl-3-D-glucopyranosylurea are thereby obtained as a yellow oil.
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:14].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:2][CH:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[O:14]1
Reactant: CC=C1CCOCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1OC12CCOCC2
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 4-ethylidenetetrahydro-2H-pyran (about 500 mg, step 1) and 3-chloroperoxybenzoic acid (1.11 g, 4.49 mmol) in dichloromethane (50 mL) was stirred at 0° C. to room temperature for 1 h. Then, saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated aqueous sodium thiosulfate solution (50 mL) were added, and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo to give 337 mg of the crude title compound as a yellow oil. This was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1sccc1Cl
Product: ClCc1coc(-c2sccc2Cl)n1
Yield: 54 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-chloro-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-chloro-2-thienyl)oxazole. The yield was 54%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:64]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[N+:65]=[N-:66]
Reactant: COc1cccc(CCC(O)c2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(CCC(N=[N+]=[N-])c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the product from Step A (1.36 g, 5.6 mmol) in 20 mL of THF at 0° C. under Ar was added triphenylphosphine (1.8 g, 6.9 mmol), diethylazodicarboxylate (1.12 mL, 6.9 mmol) and diphenylphosphoryl azide (1.52 mL, 6.9 mmol). The ice-bath was removed and the reaction mixture was stirred at ambient temperature for 20 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (2% EtOAc/Hexane) to provide the desired product as a nearly colorless gum.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10](S(C3SC=CC=3)(=O)=O)[CH2:9][C:8]=2[CH:36]=1)#[N:3].[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1ccc(F)cc1)[C@H](Cc1ccccc1)CN2

Procedure:
The title compound was prepared from Compound A of Example 23 and 4-fluorophenylsulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: C(OC([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:20]=[C:19]3[N:30](C4CCCCO4)[N:31]=[C:32]([CH3:33])[C:18]=23)[CH2:10][C:9]1([CH2:41][CH3:42])[CH3:40])=O)(C)(C)C.Cl>C1COCC1>[CH2:41]([C:9]1([CH3:40])[CH2:10][N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:20]=[C:19]3[NH:30][N:31]=[C:32]([CH3:33])[C:18]=23)[C:12]([CH3:15])([CH3:14])[CH2:13][NH:8]1)[CH3:42]
Reactant: CCC1(C)CN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCC1(C)CN(Cc2cc(-c3ccc(O)cc3)nc3[nH]nc(C)c23)C(C)(C)CN1
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
19 mg of 2-ethyl-4-[6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 0.4 ml of THF and treated with 1.5 ml of hydrochloric acid (4M in dry dioxane). After stirring at rt overnight and at 40° C. for 2 h the volatiles were removed in vacuo. The residue was triturated with dioxane and the resulting solid was isolated by suction. 8 mg (57%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1Cl
Reaction time: 8 h

Procedure:
2-chloro-4-methylbenzoic acid (500 mg, 2.93 mmol) was dissolved in Methanol (7 mL) and SOCl2 (0.215 mL, 2.93 mmol) was slowly added to the mixture and the reaction was left at room temperature overnight. Next morning HPLC showed completion. Volatiles were removed under vacuum to afford 526 mg of the title compound as brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]3[C:19](=[O:29])[CH2:20][C:21]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:26][C:27]3=[O:28])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Reactant: Fc1ccc(N2CCNCC2)cc1F
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2ccc(F)c(F)c2)CC1
Temperature: 165 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A mixture of 1-(3,4-difluorophenyl)piperazine (21.5 mg, 0.109 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione(20 mg, 0.087 mmol) was heated with stirring at 165° C. for 1 hour. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (13.7 mg, 0.035 mmol, 40%): ESI-MS m/z 392 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:55])[C:32]([CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[CH2:36][CH2:35]1)=[O:33]>C1(C)C=CC=CC=1.CCO>[CH3:30][N:31]([CH3:55])[C:32]([CH:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:41]=[C:42]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]5([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:18][CH2:17][CH2:16]5)=[CH:11][CH:10]=4)[C:5]([N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=3)[CH:43]=[CH:44][CH:45]=2)[CH2:38][CH2:39]1)=[O:33]
Reactant: CN(C)C(=O)C1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)CCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1CCN(c2cccc(-c3ccc([N+](=O)[O-])c(Nc4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)n3)c2)CC1
Temperature: 100 °C
Yield: 91 %

Procedure:
To a solution of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (4.1 g, 9.8 mmol) in toluene/EtOH/saturated NaHCO3 (200/200/20 mL), were added N,N-dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carboxamide. (4.2 g, 12 mmol), Pd(PPh4)3 (563 mg, 0.49 mmol). The mixture was heated at 100° C. for 18 h. The mixture was filtered through celite, separated and evaporated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate/methanol, 85:15:1.5) to give the titled compound as a pale red solid (5.4 g, 91%)
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:24])[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[N:14][C:13]=2[CH3:15])[CH2:8][CH2:9][C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2c(c1O)CCC(=O)N2Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c1N(Cc1ccccc1)C(=O)CC2
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (96 mg, 0.29 mmol), glycine (2.94 g, 39 mmol) and NaOMe solution (59 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3 with 4M HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 100 mg of the title compound as an off-white solid. MS: (+) m/z 370.05 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=[CH2:5].C12BC(CCC1)CCC2.C[O-].[Na+].Br[C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: C=CCOC
Agent: B1C2CCCC1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(CCCOC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a THF solution (0.1 M) of allyl methyl ether (1.4 eq.) was added, at 0° C., 9-borabicyclo[3.3.1]nonane (2.4 eq.) over a period of 30 min. The solution was stirred at 0° C. for 1 h and then warmed slowly to RT over 16 h. To the resulting clear solution was then added sodium methoxide (2.4 eq.), Cl2Pd(dppf)-dichloromethane complex (5% loading) and ethyl 3-bromobenzoate (1 eq.). The now brown suspension was heated to reflux for 16 h. The reaction mixture was cooled to RT, quenched with sat. aq. NH4Cl and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→4:1 (v/v) Hex:EtOAc) afforded the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(F)cc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(bromomethyl)-2,4-difluorobenzene (0.70 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.82 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27]([NH:29][C:30](=[N:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:44]=1)OC1C=CC=CC=1)#[N:28]>>[C:27]([NH:29][C:30]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:24])=[N:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]2)[CH:44]=1)#[N:28]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(CCCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.33 g (0.9 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-(3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=657 ([M+H]+, 11), 229 (100); IR (KBr): 2164 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 58° C. (ethanol/ether).
Reaction SMILES: [Mg].[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](O)(=[O:19])[CH3:18]>O1CCCC1>[C:2]1([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Brc1cccc(CCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CCc2ccccc2)c1
Reaction time: 1 h
Yield: 92 %

Procedure:
A Grignard compound synthesized from 1.0 g of magnesium and 10.0 g of 3-(2-phenylethyl)-bromobenzene in 30 ml of tetrahydrofuran was dropped at -60° C. under stirring for 3 min into 7.6 g of anhydrous acetic acid dissolved in 20 ml of tetrahydrofuran in a nitrogen atmosphere and stirred for further one hour. Then, the reaction solution was poured into a mixture of ice and an aqueous saturated solution of ammonium chloride and extracted with toluene. After separating the solution, it was washed with an aqueous 2N-solution of sodium hydroxide and saturated saline solution successively, dried over anhydrous sodium sulfate and then concentrated to solid. The residue was purified by silica gel column chromatography, using benzene/n-hexane (1:1) as an elute, to obtain 7.9 g of 1-(3-(2-phenylethyl)-phenyl)ethanone as an oily product. Then, by using 5.0 g of the thus obtained acetophenone compound, 3.8 g of (Z)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl-ethanone oxime hydrochloride with the melting point of from 185° to 188° C. (decomposition) and 0.5 g of (E)-2-(4-methylpiperazin-1-yl)-1-(3-(2-phenylethyl)-phenyl)-ethanone oxime with the melting point from 133° to 134° C. were obtained in the same manner as in Example 33.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(O)=O)[CH:15]=2)[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:22]([Cl:24])=[O:23]>ClCCl.CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:20])([C:22]([Cl:24])=[O:23])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)c2cc(C(=O)O)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C(=O)Cl)NN(Cc2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 1-benzyl-3-methyl-indazole-6-carboxylic acid in dichloromethane (20 ml) was treated with dimethylformamide (2 drops) then with oxalyl chloride (1.69 ml). After stirring for 2 hours the reaction mixture was evaporated and the residue was dried under high vacuum to give the title compound (0.16 g) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[CH3:25][C:26]1([CH3:33])[O:30][CH:29]([CH:31]=O)[CH2:28][O:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:31][CH:29]3[CH2:28][O:27][C:26]([CH3:33])([CH3:25])[O:30]3)[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Reactant: CC1(C)OCC(C=O)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cccc(NCC4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and 2,2-dimethyldioxolane-4-carboxaldehyde (0.38 mmol) (prepared as described in Kumont, von R., et al. Helv. Chim. Acta., 66, 814, (1983)) in dichloromethane (12 mL) was stirred at room temperature for 10 min., and then Na(OAc)3BH (120 mg, 0.57 mmol) was added. The reaction mixture was stirred overnight and then partition between EtOAc and H20. The organic layer was separated, washed with water and concentrated. The crude product was purified by preparatory TLC with 3/1 hexanes/EtOAc to give 3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyldioxolan-4-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione (32.6 mg, 24%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl>C(#N)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:13]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CCl)CCl
Solvent: CC#N
Product: ClCc1coc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
A mixture of benzamide (0.8 g, 6.60 mmol) and 1,3-dichloropropan-2-one (1.00 g, 7.92 mmol) was heated at 130° C. stirring under nitrogen atmosphere for 1 hour (UPLC/MS complete conversion). The obtained brown solution was cooled to room temperature, and the brown solid was suspended in acetonitrile (25 ml) and heated to reflux. The white insoluble solid was eliminated by filtration, and the solution was allowed to cool to room temperature. The formed precipitate was collected by filtration and washed with acetonitrile (8 ml), dissolved in EtOAc (20 ml) and washed with aq. NaHCO3 (15 ml). The organic phase was dried (Na2SO4), filtered and evaporated to obtain 4-(chloromethyl)-2-phenyloxazole (315 mg, 24.7% yield).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([NH2:19])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:3][CH2:4][CH3:5].[CH3:20][C:21]([CH3:23])=O>C(O)(C)C>[CH2:2]([C:6]1[N:7]([N:19]=[C:21]([CH3:23])[CH3:20])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCCCc1nc2cnc3ccccc3c2n1N
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1nc2cnc3ccccc3c2n1N=C(C)C
Temperature: 55 °C

Procedure:
A solution of 2-butyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride (520 mg, 2.17 mmol) in 10 mL of isopropanol was treated with 2 mL of acetone and 200 mg of DOWEX W50-X1 acid resin. The reaction mixture was heated to 55° C. overnight. The reaction mixture was treated with an additional 10 mL of isopropanol and 5 mL of acetone and heated to 70° C. for 2 h. The reaction mixture was filtered and the filtrate was treated with 0.5 mL of triethylamine and concentrated under reduced pressure. Chromatography (SiO2, 3% MeOH/CHCl3) gave N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (421 mg) as a brown oil.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N[C:6]1[CH:19]=[CH:18][C:9]2[C:10](=O)O[C:12]([O:14][CH2:15][CH3:16])=[N:13][C:8]=2[CH:7]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>O>[S:20]([OH:24])([OH:23])(=[O:22])=[O:21].[CH2:15]([O:14][C:12]1[O:3][C:1](=[O:4])[C:2]2[C:18]([CH2:9][CH3:10])=[CH:19][CH:6]=[CH:7][C:8]=2[N:13]=1)[CH3:16]
Reactant: CCOc1nc2cc(N)ccc2c(=O)o1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1nc2cccc(CC)c2c(=O)o1

Procedure:
7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one acetate (1.0 g) is dissolved in 50 ml water containing a stoichiometric equivalent of sulfuric acid, and the solution evaporated to dryness. The product is suspended in ether and filtered, air dried and recrystallized from methanol/acetone to yield 2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one sulfate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:46])[N:31]([CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:27]=[C:26]([Cl:47])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:47][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:25]=1)[C:30]([N:31]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45]1)[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:46]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCN2CCOCC2)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCN1CCOCC1)C1CCCC1
Reaction time: 2 h
Yield: 111.1 %

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-morpholin-4-yl-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.060 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.034 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.