Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[S:11](Cl)(=[O:14])(=[O:13])[NH2:12].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([O:9][S:11](=[O:14])(=[O:13])[NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: CN(C)c1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)c1cccc(OS(N)(=O)=O)c1
Temperature: 15 °C

Procedure:
A solution of 3-dimethylaminophenol (6.90 g, 0.05 mole) in 30 ml of acetonitrile was added in 13 minutes to a chilled (15° C.) stirred solution of 0.10 mole sulfamoyl chloride (Preparation 19) in 30 ml of acetonitrile. This was followed by the addition of 14 ml (0.10 mole) of triethylamine. The resultant mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (~60 ml) and then extracted twice with sodium bicarbonate solution. The aqueous layers were back extracted with 1:1 ethyl acetate/acetonitrile once. The organic layers were combined, dried over sodium sulfate, charcoaled, filtered, and evaporated to a black oil weighing 7.57 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](OC)[CH:6]=1)=O.[CH:15]1([C:18]([NH2:20])=[NH:19])[CH2:17][CH2:16]1.[OH-].[Na+].[CH2:23]([OH:25])C>>[CH:15]1([C:18]2[NH:19][CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][C:10]=3[O:25][CH3:23])[N:20]=2)[CH2:17][CH2:16]1
Reactant: N=C(N)C1CC1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2c[nH]c(C3CC3)n2)c(OC)c1

Procedure:
Ex-105A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.3 g, 1.16 mmol), cyclopropanecarboxamidine (0.14 g, 1.16 mmol) and sodium hydroxide (0.18 g, 4.5 mmol) in ethanol was refluxed overnight. The solvent was removed under reduced pressure, the residue taken up to water. The aqueous solution was then extracted with dichloromethane which was subsequently washed with brine, dried over sodium bicarbonate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) then methanol (10%, v/v in dichloromethane) afforded 2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H-imidazole as white solid (0.1 5 g, 53%): 1HNMR (CDCl3) δ 9.50 (bs, 1H), 7.63 (s, 1H), 7.20 (s, 1H), 6.57–6.53 (m, 2H), 3.93 (s, 3H), 3.03 (s, 3H), 1.97–1.93 (m, 1H), 1.00–0.94 (m, 4H). MS m/z=245 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:4]=1[C:5]([OH:7])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:5](=[O:7])[C:4]2[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH2:17][CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cccc([N+](=O)[O-])c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc([N+](=O)[O-])c1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
2-Methoxy-6-nitro-benzoic acid (2.0 g, 10.1 mmol), 4-amino-1-benzylpiperidine (1.9 mL, 10.1 mmol), 1-hydroxybenzotriazole (1.43 g, 10.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.9 g, 10.1 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.3 mmol) and the reaction mixture stirred at 40° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2×), 5% sodium bicarbonate, brine (2×), dried over sodium sulfate, and concentrated to afford 3.2 g (86%) of the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.NC1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:32]1[C:41]2[C:40](=[O:42])[NH:39][CH:38]=[N:37][C:36]=2[CH:35]=[C:34]([Cl:43])[N:33]=1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:32]3[C:41]4[C:40](=[O:42])[NH:39][CH:38]=[N:37][C:36]=4[CH:35]=[C:34]([Cl:43])[N:33]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: O=c1[nH]cnc2cc(Cl)nc(Nc3ccc(N4CCOCC4)nc3)c12
Reaction time: 0.17 h

Procedure:
At 0° C., to a solution of aniline 6-morpholinopyridin-3-amine (II) (125 mg, 0.7 mmol) in THF (3 mL) was added NaHMDS (2 mL, 1M/THF). After 10 minutes, compound 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (I) (108 mg, 0.5 mmol) was added. The resulting mixture was stirred for 4 hours. The mixture was subjected to HPLC-MS, and the product 5-(6-morpholinopyridin-3-ylamino)-7-chloropyrido[4,3-d]pyrimidin-4(3H)-one was obtained as a purple solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:18][C:13]4([CH2:17][CH2:16][NH:15][CH2:14]4)[CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=2)=[N:3][CH:2]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34].[Cl-].[NH4+]>O1CCCC1>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([N:15]1[CH2:16][CH2:17][C:13]2([CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]3[NH:18]2)[CH2:14]1)=[O:34]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=c1cc(-c2ccncn2)nc2n1CCC1(CCNC1)N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cccc(F)c1)N1CCC2(CCn3c(nc(-c4ccncn4)cc3=O)N2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 0.3 g (1.055 mmol) of 8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one dissolved in 5 ml of tetrahydrofuran at room temperature were added 0.18 ml (1.27 mmol) of triethylamine and 0.152 ml (1.27 mmol) of 3-fluoro-benzoyl chloride. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2h. The reaction mixture was added to a saturated aqueous solution of ammonium chloride, extracted with a mixture of dichloromethane/menthanol in the proportions of 100/0 to 80/20, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane/menthanol in the proportions of 100/0 to 70/30 to give 0.310 g (72%) of pure product as grey solid. Mp: 296-298° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:27]1([C:33]2[N:37]=[C:36]([NH2:38])[S:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN1C(=O)CCC1>[C:27]1([C:33]2[N:37]=[C:36]([NH:38][C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)=[O:15])[S:35][N:34]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: Nc1nc(-c2ccccc2)ns1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccccc2)ns1)c1cnc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
To a suspension of 2-phenyl-pyrimidine-5-carboxylic acid (400 mg, 2 mmol) in DCM (10 mL), oxalyl chloride (0.2 mL, 2.3 mmol) is added at 0° C. followed by DMF (0.23 mL, 3 mmol). The mixture is stirred at 0° C. for 20 minutes, warmed to room temperature and stirred for 20 additional min. The mixture is concentrated in vacuo. The residue is dissolved in DCM and 3-phenyl-[1,2,4]thiadiazol-5-ylamine (248 mg, 1.4 mmol) is added followed by NMP (0.5 mL). The mixture is stirred at room temperature for two hours, and concentrated in vacuo. The residue is triturated in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (3-phenyl-[1,2,4]thiadiazol-5-yl)-amide (300 mg) as a solid. MS: 360 (M+H); IC50=30 nM.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1.C(O)C.[I-:30].[K+]>CO>[I-:30].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)c(Cl)c1
Yield: 58.1 %

Procedure:
A solution of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylamine (3.0 g) and α,3,4-trichlorotoluene (4.0 g) in methanol (15 cc) was refluxed for 2 hours, and thereto were added ethanol (40 cc) and then an aqueous solution of potassium iodide (3.0 g). The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and ether to give colorless crystals (4.0 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(3,4-dichlorobenzyl)ammonium iodide, m.p. 160°-165° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:22]([CH3:21])(=[O:24])=[O:23])=[C:7]([CH3:12])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(NS(C)(=O)=O)c(C)c1

Procedure:
A flask was charged with 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.0166 mole), triethylamine (1.83g., 0.018 mole, 2.53 ml.) and about 100 ml. of benzene. To this slurry was added methanesulfonyl chloride and after one hour at reflux the mixture was cooled and filtered. The solids were stirred vigorously with water to dissolve any residual by-product triethylamine hydrochloride. Refiltration and drying gave 2.3g. of the desired product (m.p. 167°-69° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:20])[C:5]=2[NH:4][N:3]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].ClC[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=3)[C:6](=[O:20])[C:5]=2[N:4]([C:21](=[O:24])[CH2:29][CH2:30][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)c1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: O=C(CCCl)N1CCN(c2ccccc2)CC1
Agent: [K+]
Product: CN(C)c1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5ccccc5)CC4)c3C2=O)cc1

Procedure:
A target compound (15.4 mg, 0.031 mmol, 7.8%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-6-N-(4-(dimethylamino)phenyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (110 mg, 0.405 mmol) with potassium carbonate (83.9 mg, 0.607 mmol) and 3-chloro-1-(4-phenylpiperazin-1-yl)propan-1-one (112.4 mg, 0.445 mmol).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1(C)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=C[CH:31]=1>>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([S:25]([C:22]3[C:23]([CH3:31])=[CH:24][CH:19]=[CH:20][CH:21]=3)(=[O:26])=[O:27])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: Cc1ccccc1S(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 2.39 g (1 mmole) of 1-diphenylmethyl-3-hydroxyazetidine [prepared in the manner described in J. C. S. Chem. Commun. 93 (1968) by S. S. Chatterjee and D. J. Triggle] in 30 ml of pyridine is added 3.8 g (2 equivalents) of p-toluenesulfonyl chloride, and the mixture is stirred at room temperature overnight and evaporated under reduced pressure. The residue is alkalified with an aqueous sodium carbonate solution and extracted with benzene. The extract is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The resulting brown oily residue (4.5 g) is adsorbed on a column of 20 g of silica gel and eluted with benzene. The eluate is crystallized from ether-hexane to yield 2.55 g of 1-diphenylmethyl-3-toluenesulfonylazetidine having mp. 108° to 110° C. as prisms in 64.8% yield, which is recrystallized from ether to yield the pure product having mp. 110° to 112° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:12]([N:3]1[CH:4]=[CH:5][NH:6][C:2]1=[S:1])=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: Sc1ncc[nH]1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)n1cc[nH]c1=S
Temperature: 50 °C
Yield: 92.5 %

Procedure:
2-Mercaptoimidazole (24.39 g, 0.244 mole) and butyl isocyanate (48.3 g, 0.487 mole) were combined in a round-bottom flask and heated to 50° C. for 30 min or until the reaction was complete by TLC. The reaction mixture was then cooled to room temperature and the solidified mass was triturated with 50 mL of hexane for 30 min. The beige solid was filtered, washed with a minimum amount of hexane and dried under reduced pressure to yield 44.96 g (93%) of 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione as beige crystals: mp 66°-68° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[N:4]=[C:5]([NH2:7])[S:6][C:2]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Br)s1
Product: Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
5-Bromo-4-(4-fluoro-phenyl)-thiazole-2-ylamine and morpholine (6 eq) were stirred for 30 minutes at 120 C, under microwave heat. Triturated with ethyl acetate/n-Heptane solvent mixture (1:2 ratio) to afford the title compound pure. LCMS Method A Rt=1.14 (M+1=280.0, M−1=278.1). 1H NMR (400 MHz, DMSO-D6) 2.67-2.75 (m, 4H) 3.67-3.74 (m, 4H) 6.87 (s, 2H) 7.14-7.20 (m, 2H) 8.11 (ddd, J=12.41, 5.53, 3.03 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O>[Si:20]([O:19][C:11]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:14]([C:15]([F:17])([F:18])[F:16])[NH:13][N:12]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)n[nH]c2C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
15.0 g (55.6 mmol) of 1,2-dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazol-3-one (4) (prepared by the method described in J. Med. Chem 1996, 39, 3920-3928) was dissolved in 150 ml of dimethylformamide, and cooled to 0° C. Then, 9.3 g (61.1 mmol) of t-butyl dimethylsilyl chloride was added to the above solution in small portions, and thereafter 4.2 g (61.1 mmol) of imidazole was added in small portions. The temperature of the resultant mixture was returned to room temperature and the mixture was stirred for 3 hours. After the addition of water to the reaction mixture, the reaction mixture was extracted with ethyl acetate twice. The resultant organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated, to give 21.4 g (55.6 mmol) of the intended compound (100% yield).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27]Cl)=[O:25])[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:29]([OH:37])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1.C(N(CC)CC)C>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([O:37][CH2:27][O:26][C:24]([NH:23][CH2:22][CH2:21][C:10]2[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:9]=2)=[O:25])=[O:36])[CH:31]=1
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCCl)cc1OC(=O)C(C)(C)C
Reactant: O=C(O)c1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)OCOC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C
Reaction time: 96 h

Procedure:
The chloromethyl carbamate prepared in Example 112 (1.26 g, 3.04 mmol) was combined with 10 mL of dry dimethylformamide and that mixture was added to a premixed solution of nicotinic acid (375 mg, 3.04 mmol) and triethylamine (445 mL, 5% excess) in 15 mL of dry dimethylformamide at room temperature. The reaction mixture was stirred for 4 days, then the precipitate which formed was removed by filtration. The filtrate was evaporated to dryness and the residue was taken up in 20 mL of methylene chloride. That solution was washed twice with 10 mL portions of water. Removal of the solvent in vacuo afforded the title compound of the formula: ##STR141## The identity of the product was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:10])=[O:9])[S:4][N:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>O1CCCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]([O-:10])=[O:9])[S:4][N:3]=1.[CH:11]([NH3+:14])([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: O=C(O)c1snc(Cl)c1Cl
Solvent: C1CCOC1
Product: CC(C)[NH3+]
Product: O=C([O-])c1snc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
In 10 ml of dry tetrahydrofuran, 1.0 g of the 3,4-dichloro-5-isothiazolecarboxylic acid obtained in Example 2 was dissolved. While the resultant mixture was stirred at room temperature, a solution of 0.30 g of isopropylamine in 5 ml of dry tetrahydrofuran was added dropwise. White crystals were formed concurrently with the dropwise addition. After the resulting mixture was stirred further at room temperature for 30 minutes, the crystals were collected by filtration and then washed with a small amount of dry tetrahydrofuran. The crystals were dried at 40° C. for 30 minutes under reduced pressure, whereby 1.10 g of the title compound were obtained (yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][SH:24].C([Li])CCC.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: CN(C)CCS
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A 25 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-9H-β-carboline (98 mg, 0.37 mmol) in 2 ml of anhydrous DMF. A second 10 ml round-bottom flask with magnetic stirrer was charged with 2-dimethylamino-ethanethiol hydrochloride (100 mg, 0.70 mmol) in 2 ml anhydrous DMF. To the resulting suspension was added n-butyllithium (0.43 ml of 1.6 M solution in hexanes, 0.69 mmol) via syringe and the mixture was stirred for 5 min at RT. Next, the thioanion solution was added via syringe to 6-chloro-7-fluoro-8-nitro-9H-β-carboline, and the resulting red solution was stirred at RT for 30 min. The reaction mixture was slowly added to a 5:1 mixture of H2O/saturated aqueous sodium bicarbonate (30 ml) and allowed to sit at RT for several hours. The resulting precipitated solid was collected via suction filtration and air-dried to afford 109 mg of [2-(6-chloro-8-nitro-9H-β-carbolin-7-ylsulfanyl)-ethyl]-dimethyl-amine as an orange solid (83%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[N:12]O)[CH3:11])=[CH:2]1.C(O)(=O)C.[H][H]>C(O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([NH2:12])[CH3:11])=[CH:2]1
Reactant: CC(=NO)c1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)c1c[nH]c2ccccc12
Yield: 74.5 %

Procedure:
10% palladium-carbon (water content: 50%, 12.2 mg) was added to a solution of 1-(1H-indol-3-yl)ethanone oxime (0.20 g) obtained as above and acetic acid (0.7 mL) in ethanol (7 mL) at room temperature. The reaction mixture was stirred in a hydrogen stream at room temperature for 10 hours, and then filtered on a celite. The filtrate was concentrated under reduced pressure. The residue was extracted with chloroform. The organic layer was washed sequentially with a 1 N aqueous solution of sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform-methanol system) to obtain 0.137 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[F:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[F:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(C)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(OCCCC(=O)O)cc1F
Yield: 78.2 %

Procedure:
4-(4-Acetyl-3-fluorophenoxy)butanoic acid, ethyl ester (20 mg, 0.0745 mmol) is dissolved in 1 mL of methanol/water (3:2) and treated with 30.91 mg (0.22 mmol) of potassium carbonate according to the procedure described for Example 4 to give 14 mg (82%) of 4-(4-acetyl-3-fluorophenoxy)butanoic acid as a white powder: m.p. 110°-111° C.; The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 1710, 1670, 1610 cm-1 ; MS m/e calculated for C12H13O4FNa: 263.0695, found 263.0699.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:25][NH:26][CH3:27]>C(O)C>[ClH:23].[CH3:25][N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:27]
Reactant: CNC
Reactant: O=C(c1ccc(-c2ccc(CBr)cc2)cc1)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: CN(C)Cc1ccc(-c2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)cc1
Product: Cl
Reaction time: 4 h
Yield: 51 %

Procedure:
1.0 g of 2,4-dichlorophenyl 4'-bromomethyl-4-biphenylyl ketone and 20 mL of a 33 percent solution of dimethylamine in ethanol were heated to boiling for 4 hours, whereupon the mixture was evaporated. The residue was taken up in ether and treated with an ethereal solution of hydrogen chloride. The precipitated hydrochloride was filtered off and dried. There was obtained 2,4-dichlorophenyl 4'-[(dimethylamino)methyl]-4-biphenylyl ketone hydrochloride with a m.p. of 195°-196° C. Yield 51%.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:4][CH:3]=1.C(O)COCCOCCO.O.[NH2:27][NH2:28]>O>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NN
Reactant: Clc1cccc(Nc2ccc(Cl)nn2)c1
Solvent: O
Solvent: OCCOCCOCCO
Product: NNc1ccc(Nc2cccc(Cl)c2)nn1
Temperature: 25 °C

Procedure:
(Step 1-ii) 6-chloro-N-(3-chlorophenyl)pyridazin-3-amine (88.1 g, 367 mmol) was suspended in 1:6 triethylene glycol/hydrazine hydrate and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, diluted with water and a solid filtered off. This solid was triturated with Et2O to give the product, N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine, as a brown solid (60 g, 254 mmol, 69% yield): 1H NMR (500 MHz, DMSO-d6) 9.23 (s, 1H), 8.09 (t, J=1.8 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.08 (d, J=9.4 Hz, 1H), 7.00 (d, J=9.4 Hz, 1H), 6.85 (dd, J=1.3, 7.8 Hz, 1H).