Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].[H-].[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]2=[N:8][S:12](=[O:14])(=[O:13])[CH2:11][CH2:10][N:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 3-bromopyridin-2-amine (3 g) in dehydrated THF (30 mL) was added to a mixture of 2-chloroethanesulfonyl chloride (7.07 g) and sodium hydride (60%, 3.47 g) in dehydrated THF (30 mL) at room temperature, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and THF was removed under reduced pressure. The resulting precipitate was collected by filtration, and washed with water and diethyl ether to give the title compound (3.41 g) as a white solid.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][CH:5]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4]1.CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N:8]1([CH2:7][CH:5]2[CH2:4][C:3](=[O:2])[CH2:6]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC1(OC)CC(CN2CCCC2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC(CN2CCCC2)C1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a stirring solution of 1-[(3,3-dimethoxy-cyclobutyl)methyl]-pyrrolidine (intermediate 5, general prcedure B, step B) (1.6 g, 8.0 mmol) in 3:1 acetone:H2O (100 mL) was added p-toluenesulfonic acid mono hydrate (1.5 g, 8.0 mmol). The reaction mixture was heated to 65 C for 1 hour. Both TLC and GS/MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and then the acetone was removed under reduced pressure. The resulting mixture was diluted with CH2Cl2 and washed with an aqueous solution of NaHCO3. The aqueous layer was back extracted with 3:1 CHCl3:iso-propyl alcohol. The combined organic layers were dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure to yield the title compound (0.94 g, 76% yield) as a colorless oil. This material was processed without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[CH2:12][OH:13])=[CH:4][CH:3]=1.[CH2:16]([O:20][CH:21]1[CH:23]([C:24](O)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][CH:21]1[CH:23]([C:24]([O:13][CH2:12][C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC1C(C(=O)O)C1(C)C
Reactant: OCc1[nH]ccc1Cc1ccc(Cl)cc1
Product: CC(C)COC1C(C(=O)OCc2[nH]ccc2Cc2ccc(Cl)cc2)C1(C)C

Procedure:
Using the above procedure, 3-(4-chlorobenzyl)-pyrrolylmethyl alcohol is reacted with 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylic acid to yield 3-(4-chlorobenzyl)-pyrrolylmethyl 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:30])[CH2:17][CH2:18][CH2:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:30][N:16]([CH3:15])[CH2:17][CH2:18][CH2:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][O:29][C:2]2[C:7]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CN(C)CCCc1ncccc1OCCO
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1CCCN(C)C
Yield: 58 %

Procedure:
The procedure in Example 18, Step 4, starting from 2-chloro-3-[(2R)-2-methylpiperazin-1-yl]pyrazine* (0.48 g, 2.28 mmol) and 2-({2-[3-(dimethylamino)propyl]pyridin-3-yl}oxy)ethanol (from Step 1; 0.46 g, 2.07 mmol) was followed. The crude product was purified on a column of silica (100 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (80:20:0.5; 200 mL, followed by 60:40:1) as eluent to give 0.48 g (58%) of the title compound as a colorless oil. HRMS m/z calcd for C21H32N6O2 (M)+ 400.2587. found 400.2571. *Reported in WO 00/76984, Example 192, Step 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@@H:40]([OH:44])[C@H:39]2[OH:45])[C:34]([F:46])=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C@@H:40]([OH:44])[C@H:39]4[OH:45])[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O[C@@H]1[C@H](O)CCC[C@@H]1Nc1nc(Cl)ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a deoxygenated solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.51 mmol) and (1R,2S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31b, (0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate (0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030 mmol). The reaction was sealed and heated to 120° C. for 15 minutes in the microwave. The rxn was diluted with EtOAc and filtered thru florisil. The solution was concentrated to crude and purified via silica gel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11 g) as a pink solid.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27](Cl)=[O:28]>>[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)CSCC(F)(F)F
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]2SC1

Procedure:
7-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was acylated with trifluoroethylmercaptoacetyl chloride by the procedure of Example 2. The title product was converted into its sodium salt by the procedure described above.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=1>>[CH:21]([C:18]1[S:19][CH:20]=[C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1)([CH3:23])[CH3:22]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: CC(C)c1nc(Br)cs1
Product: Cc1onc(-c2ccccc2)c1C#Cc1csc(C(C)C)n1
Yield: 15 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 4-bromo-2-isopropylthiazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 23 mg, 15%) which was obtained as a yellow oil. MS: m/e=309.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:32]([C:34]2[CH:39]=[C:38]([CH2:40][CH3:41])[CH:37]=[C:36]([O:42][Si](C(C)(C)C)(C)C)[C:35]=2[F:50])[OH:33])[N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:32]([OH:33])[C:34]2[C:35]([F:50])=[C:36]([OH:42])[CH:37]=[C:38]([CH2:40][CH3:41])[CH:39]=2)[N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 217.2 (500 mg, 0.669 mmol) in 5 mL THF at rt, was added TBAF (1M in THF, 0.669 mL, 0.669 mmol). The mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was triturated with hexanes (10 mL) to afford 3-((4-(2-bromophenyl)-1-trityl-1H-imidazol-2-yl)(hydroxy)methyl)-5-ethyl-2-fluorophenol. To a solution of this product in 5 mL DMF at rt, were added K2CO3 (111 mg, 0.803 mmol) and iodoethane (161 μL, 2.01 mmol). The mixture was stirred at rt for 15 h, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3 and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 433 mg of Intermediate 217.3 as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:24][CH:23]([C:20]3[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=3)[CH3:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=C(C)c1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(C)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-methyl-5-(prop-1-en-2-yl)pyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>ClCCl.O>[Si:21]([O:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH:6]=[O:7])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(F)c(CO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
1.6 g of 4-Fluoro-3-hydroxymethylbenzaldehyde was dissolved in 20 ml of dichloromethane, and 1.4 g of imidazole and 1.75 g of t-butyldimethylchlorosilane were added under ice-cooling, then the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (18% ethyl acetate-hexane), to give 2.6 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([SH:14])[CH3:13]>>[NH2:1][C:2]1[N:7]=[C:6]([S:14][CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCS
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)n1
Product: CCSc1nc(N)ccc1[N+](=O)[O-]

Procedure:
6-Amino-2-chloro-3-nitropyridine was allowed to react with ethanethiol to give 6-amino-2-ethylthio-3-nitropyridine (m.p. 131.5°-132° C.). The product was then treated with acetic anhydride to give 6-acetylamino-2-ethylthio-3-nitro-pyridine (m.p. 167.5°-168° C.). The nitro group of this product was reduced in a usual manner to the amino group. The amino compound, without purification, was dissolved in 42% tetrafluoroboric acid, and then diazotized by addition of sodium nitrite to give 6-acetylamino-2-ethylthio-3-pyridine-diazonium fluoroborate decomposing at 132°-133° C. The diazonium salt was subjected to Schiemann reaction under reflux in petroleum benzine. The reaction product was isolated and purified in a usual manner to give 6-acetylamino-2-ethylthio-3-fluoro-pyridine (m.p. 110°-113.5° C.). Then the product was allowed to react with ethyl ethoxymethylenemalonate to give diethyl N-(2-ethylthio-3-fluoro-6-pyridinyl)aminomethylenemalonate (m.p. 77.5°-78.5° C.), which was subjected to cyclization reaction to give ethyl 7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 280°-284° C.). The 1,8-naphthyridine derivative thus obtained was treated with 2-fluoroethyl p-toluenesulfonate to give ethyl 7-ethylthio-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 271°-273° C.), which was then oxidized with m-chloroperbenzoic acid to give ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 176°-178° C.).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: N#CCCCCBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCCC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (4.0 g, 13.5 mmol) in DMF (100 ml) was treated with caesium carbonate (4.83 g, 14.8 mmol) and 5-bromopentanenitrile (1.73 ml, 14.8 mmol). The mixture was heated at 50° C. in a nitrogen atmosphere for 19 h and then cooled. The mixture was then degassed by the repeated successive application of a vacuum and then nitrogen pressure. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.94 mmol) and morpholine (11.8 ml, 136 mmol). The mixture was stirred in a nitrogen atmosphere for 3 h and then partitioned between EtOAc and 2M aqueous hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to reveal a yellow, oily residue. This was dissolved in MeOH, divided equally into four portions and each portion applied to a 20 g aminopropyl SPE which was then washed through with MeOH. The desired product was eluted from the cartridge with a 5% v/v solution of AcOH in MeOH. The product-containing fractions were combined and concentrated to yield the title compound as a pale yellow solid (4.03 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(OCC)(=O)C.[ClH:36].[OH-].[Na+]>O>[ClH:36].[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(N)nc4ccccc4c32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2ccccc2c2c1ncn2CCC1CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.57 g of tert-butyl 4-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 40 ml of ethyl acetate solution of hydrogen chloride was stirred at room temperature for 5 hours. The reaction mixture was added with water, adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was dried, and the solvent was evaporated. The resulting residue was washed with ethyl acetate to give 1.01 g of pale brown crystals. The resulting crystals were purified by alumina column chromatography using methylene chloride—methanol (40:1 to 20:1) as eluting solvents, and washed with diisopropyl ether to give colorless crystals. Hydrochloride was prepared in a conventional method. Recrystallization from ethanol gave colorless crystals having the melting point of from 243 to 244° C. (decomposition).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>C1COCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 25 °C
Yield: 97 %

Procedure:
0.5 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 20 ml of THF and stirred at room temperature, followed by adding 0.034 g of NaBH4 and stirred for 2 hours. After the reduction was completed, 50 ml of water was added. The solution was then extracted with chloroform, dried over anhydrous Na2SO4, filtered and condensed. The yellowish powder was thus obtained and the melting point thereof was 151°-152° C. (yield was 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:14][CH:15]=[O:16])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:14][CH:15]=[O:16])=[C:6]([Br:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1Br)NC=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC=O)=C(Br)c1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A 0.4 M solution of 3-(2-bromo-phenyl)-2-formylamino-acrylic acid ethyl ester (5.3 g; 17.8 mM) in anhydrous CH2Cl2, at 0° C., is added with N-bromosuccinimide (3.48 g; 19.6 mM). The mixture is left to slowly warm to room temperature. The reaction is completed in about 5 hours 30 mm. The equivalent amount of triethylamine is added drop by drop; after 30 minutes the mixture is washed with a NaHCO3 saturated solution and then with a NaCl saturated solution. The organic phase is dried over Na2SO4, the solid is filtered off and the clear solution is evaporated under reduced pressure to a residue. The crude (brownish oil) is purified by flash chromatography, using a 6:4 v/v mixture of hexane and ethyl acetate as eluent, thereby obtaining 2.68 g of 3-bromo-3-(2-bromo-phenyl)-2-formylamino-acrylic acid ethyl ester (white-pale yellow solid). (Yield: 40%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:22]1(=O)NC(=O)C2=CC=CC=C12>C(O)C.[Ni]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(N)cc1
Agent: [Ni]
Agent: C=O
Solvent: CCO
Product: CNc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 2 h

Procedure:
A mixture of α-t-butoxycarbonylamino-p-aminophenylacetic acid (26.6 g, 0.1 mol), formaldehyde (8.1 ml of a 37% aq. solution) and phthalimide (14.7 g, 0.1 mol) in 200 ml of absolute ethanol is heated at reflux for 1 hour. After cooling to room temperature Raney nickel catalyst is added and the mixture is hydrogenated under 60 psi of H2 100° for 2 hours. The catalyst is filtered off and the solvent is evaporated in vacuo. Following chromatography on silica gel the desired product is obtained.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:6][C:3]=2[C:4]#[N:5])[CH2:24][CH2:25]1
Reactant: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccccc2)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C#N)c(N3CCOCC3)nc2-c2ccccc2)cc1

Procedure:
A solution of 2-chloro-6-phenyl-5-p-tolylnicotinonitrile (Compound 115, 124 mg, 0.4 mmol) and morpholine (36 mg, 0.4 mmol) in DMF (2 ml) was heated at 150° C. for 2 hours. The solvents was removed and the residue was purified by MPLC column chromatography (silica gel, 10% ethyl acetate in hexane) to obtain the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([CH3:3])[CH3:2].Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH2:27][CH2:28]2)=[CH:17][CH:16]=1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Reactant: CC(C)c1cc(C(=O)O)[nH]n1
Agent: Cl
Product: CC(C)c1cc(C(=O)N2CCN(CC(=O)c3ccc(F)cc3)CC2)[nH]n1
Yield: 75.7 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 3-isopropyl-1H-pyrazole-5-carboxylic acid (23.1 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (27.1 mg) as a white solid. Exact mass calculated for C19H23FN4O2: 358.2. Found: LCMS m/z=359.3 (M+H+).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.Cl.[N+:14]([C:17]1[CH:18]=[C:19]([NH2:26])[C:20](=[CH:24][CH:25]=1)[C:21](Cl)=[O:22])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]2[C:20]([C:21](=[O:22])[N:6]3[C:5]4[CH:7]=[C:8]([Cl:12])[C:9]([Cl:11])=[CH:10][C:4]=4[NH:3][C:2]3=[N:26]2)=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)Cl
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: Cl
Product: O=c1c2ccc([N+](=O)[O-])cc2nc2[nH]c3cc(Cl)c(Cl)cc3n12

Procedure:
3-Nitro-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)-one is prepared with 2,5,6-trichlorobenzimidazole and 4-nitroanthraniloyl chloride hydrochloride.
Reaction SMILES: Cl.[C:2]1([O:12][CH2:13][CH2:14][CH2:15]Br)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:2]1([O:12][CH2:13][CH2:14][CH2:15][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:27][CH2:28]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: BrCCCOc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCCOc2cccc3ccccc23)CC1)c1ccccc1

Procedure:
The title compound as its hydrochloride, m.p. 228° C (decomp.), was prepared by the method of Example 52 using 3-naphthyloxypropyl bromide (2.07 g.), 4-benzamidopiperidine (1.8 g.) and anhydrous potassium carbonate (1.24 g.). (Found: C, 70.4; H, 7.0; N, 6.6. C25H28N2O2HCl requires C, 70.65; H, 6.9; N, 6.6%).