Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH:36]=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCOC(C)=O>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:17][C:2]=2[NH:1][CH:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[CH2:34][CH2:33]2)[CH3:36])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 61.5 %

Procedure:
Using a similar procedure to that described in Example 47-C, 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.7 g, 8.8 mmol) and 1-(tert-butoxycarbonyl)-piperidine-4-acetaldehyde (3.0 g, 13 mmol) afforded, after trituration with EtOAc:methylene chloride, 2.8 g (61%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:21]N1C(=O)CCC1=O>C(#N)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.900 g, 2.67 mmol) in acetonitrile (30 mL) was treated with N-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases washed with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in 0.399 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.17 (s, 1H), 6.68 (m, 1H), 3.88 (s, 3H), 3.78 (m, 1H), 3.6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MS calculated for C14H15ClF3NO2+H: 322, observed: 322.
Reaction SMILES: N#N.[C:3]1([CH3:11])[C:4]([CH:9]=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(C)C.N1CCOCC1>[C:12]([C:14](=[CH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:11])[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: Cc1ccccc1C=O
Agent: N#N
Solvent: C1COCCN1
Solvent: CC(C)O
Product: COC(=O)C(C#N)=Cc1ccccc1C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A 100-mL, 1-necked round bottom flask (with magnetic stir-bar and dry N2 adaptor) was charged with 11.6 mL (12.0 g, 100 mmol) of o-tolualdehyde, 8.8 mL (9.9 g, 100 mmol) of methyl cyanoacetate, and 50 mL of isopropanol. Morpholine (0.50 mL, 0.55 g, 6.3 mmol, 6.3 mol %) was added and the mixture was stirred at 20–33° C. for 60 minutes. This mixture was diluted with 25 mL of isopropanol. The precipitate was filtered, washed with 10 mL of isopropanol, and dried to afford 17.37 g (86.3%) of methyl 2-cyano-3-(2-mehtylphenyl)-2-propenoate as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.ClC1C(C[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]=[CH2:30])[C:20](=[O:22])[CH3:21])=CC(F)=C(Cl)N=1>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=1[CH2:9][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])[C:20](=[O:22])[CH3:21]
Reactant: ClCc1cnc(Cl)cc1Cl
Reactant: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Product: C=Cc1ccccc1N(Cc1cnc(Cl)cc1Cl)C(C)=O
Yield: 82 %

Procedure:
Compound 41C (210 mg, 82%) was prepared from 41B (157 mg, 0.8 mmol) and bb (129 mg, 0.8 mmol) using a procedure similar to the synthesis of 1C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([NH:10][S:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([OH:19])[C@@:15]2([CH3:23])[C:20](O)=[O:21])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[OH:19][C@@H:16]1[CH2:17][CH2:18][N:14]2[C@:15]1([CH3:23])[C:20](=[O:21])[N:10]([C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:24])[S:11]2(=[O:13])=[O:12]
Reactant: Cc1c(NS(=O)(=O)N2CC[C@@H](O)[C@@]2(C)C(=O)O)ccc(C#N)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@]3(C)[C@H](O)CCN3S2(=O)=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a suspension of 3D (70 mg, 0.187 mmol) in 4 mL of acetonitrile at rt was added DCC (39 mg, 0.187 mmol) followed by p-nitrophenol (53 mg, 0.374 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 50:50) to afford the title compound (48 mg) as a yellow foam. 1H NMR (CD3OD) δ 1.59, 1.64 (s, 3H), 2.14-2.18 (m, 1H), 2.33-2.39 (m, 4H), 3.62-3.68 (m, 1H), 3.98-4.07 (m, 1H), 4.29, 4.31 (d, J=3.3, 1H), 7.45, 7.52 (d, J=8.3, 1H), 7.81, 7.82 (d, J=8.3, 1H); 13C NMR (CD3OD) δ 16.11, 16.25, 22.94, 23.24, 34.60, 50.21, 50.67, 77.10, 77.26, 82.46, 82.66, 116.44, 116.55, 129.95, 131.05, 133.22, 133.35, 136.32, 138.82, 140.34, 141.02, 169.27; HPLC a) column: Phenominex LUNA C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.90 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.75 min. retention time (98%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 6.96 min retention time (98%); MS (ES) m/z 356 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[O:6][CH:7]1[C:11]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:12][O:13][N:14]=[CH2:15])[O:10][CH:9]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[CH:8]1[OH:43])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>N1C=CC=CC=1>[C:1]([Si:5]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[O:6][CH:7]1[C:11]([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:12][O:13][N:14]=[CH2:15])[O:10][CH:9]([N:35]2[CH:40]=[CH:39][C:38](=[O:41])[NH:37][C:36]2=[O:42])[CH:8]1[O:43][S:60]([CH3:59])(=[O:62])=[O:61])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=NOCC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(=O)[nH]c2=O)C(OS(C)(=O)=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
The mesylation of hydroxyl groups proceeds readily under these conditions (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 150-160 and references cited therein). Briefly, to a solution of Compound 17 in a 1:1 mixture of anhydrous dichloromethane and anhydrous pyridine is added methanesulfonyl chloride (1.2 eq.). After stirring at room temperature for several hours, this mixture is quenched with methanol, concentrated, diluted with dichloromethane, washed with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography will yield Compound 18.
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]=[CH:10][C:11]([CH3:20])=[CH:12][CH:13]=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[CH3:22][C:23]1([CH3:52])[CH2:28][O:27][CH:26]([C:29]([CH3:51])=[CH:30][CH2:31][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:25][CH2:24]1.[O-]CC.[Na+]>ClCCl.[Cl-].[Na+].O>[CH3:22][C:23]1([CH3:52])[CH2:24][O:25][CH:26]([C:29]([CH3:51])=[CH:30][CH:31]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=[C:11]([CH3:20])[CH:10]=[CH:9][CH:8]=[C:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:27][CH2:28]1
Reactant: CC(=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C1OCC(C)(C)CO1
Reactant: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C1OCC(C)(C)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.7 g (50 mmol) of the product from step b) were dissolved in 125 ml of dichloromethane. 25.7 g (55 mmol) of 3-(5,5-dimethyl-1,3-dioxan-2-yl)but-2-enyltriphenylphosphonium chloride were added. At 0° C., 20.4 g of a 20% strength ethanolic solution of sodium ethoxide (60 mmol) were added over the course of 1 hour. The mixture was stirred at 0° C. for 1 hour and then 50 ml of semiconcentrated brine were added. The organic phase was separated off, washed once with 50 ml of semiconcentrated brine, dried over sodium sulfate and concentrated in a rotary evaporator at 20° C. down to 20 mbar. The residue (38.2 g) was purified by flash chromatography on silica gel (eluent: cyclohexane/methyl t-butyl ether 4:1). 19.9 g (93.4% of theory) of the title compound were obtained. For characterization, the product was dissolved by heating in 100 ml of ethyl acetate. 50 ml of diisopropyl ether were added to the hot solution and, after cooling to 0° C., the mixture was stirred for 1 hour. The crystals which formed were filtered off, washed with cold ethyl acetate/diisopropyl ether mixture (2:1 vol./vol.) and dried in a stream of nitrogen. Yield: 8.9 g of red crystals. Melting point 157.5 to 158° C. E11 (CHCl3): 2495 (423 nm), 2243 (448 nm).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[C:15]1([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[NH:17][C:16]1=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([NH:1][C:2]3[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CCOc1cccc(C(=O)O)c1N
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cccc(C(=O)O)c1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 8 h
Yield: 26 %

Procedure:
At room temperature, 2-Amino-3-ethoxy-benzoic acid (0.59 g, 3.26 mmol), 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.21 g, 3.26 mmol) and DIPEA (0.68 ml) were mixed in about 6 ml CH2Cl2. After stirred overnight, the solution was concentrated and the crude product was purified by chromatography to obtain 400 mg solid rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid. MS: 471 (M+H)+.
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].C1(N=[CH:15][C:16]2[O:17][CH:18]=[CH:19][C:20]=2[CH3:21])C=CC=CC=1.ClC(OCC)=O>C1(C)C(C)=CC=CC=1>[CH2:6]([O:5][C:3]([C:1]1[CH:21]=[C:20]2[CH:19]=[CH:18][O:17][C:16]2=[CH:15][N:2]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C#N
Reactant: Cc1ccoc1C=Nc1ccccc1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2ccoc2cn1
Temperature: 130 °C
Yield: 52.2 %

Procedure:
Ethyl cyanoformate(21.4 g, 0.216 mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine(10.0 g, 54.1 mmol) were mixed at room temperature in xylene (50 mL) then heated to reflux at 120 to 140° C. with stirring. A xylene (30 mL) solution of 11.7 g (0.108 mol) of ethyl chloroformate was added dropwise for an hour to the resulting mixture. After all the solution had been added, the reaction mixture was heated to reflux for 2 hours, it was allowed to cool to room temperature, and the solvent was distilled off to give 14.0 g of crude product. This product was purified by column chromatography on silica gel, giving 5.40 g (52.3% yield) of 5-ethoxycarbonylfuro[2,3-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.Cl.[NH:18]1CCN=[C:19]1[CH2:23]OC1C=C(NS(C)(=O)=O)C=CC=1.NC1C=C(C=CC=1)OCC#N>>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:5]=[C:6]([CH2:8][C:9]2[NH:18][CH2:19][CH2:23][N:10]=2)[CH:7]=1
Reactant: CS(=O)(=O)Nc1cccc(OCC2=NCCN2)c1
Reactant: Cc1c(Cl)cc(CC#N)cc1NS(C)(=O)=O
Agent: Cl
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(Cl)cc(CC2=NCCN2)cc1NS(C)(=O)=O

Procedure:
N-[3-chloro-5-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-methylphenyl]methanesulfonamide hydrochloride (mp 256.2-256.7° C.) was prepared from N-(3-chloro-5-cyanomethyl-2-methylphenyl) methanesulfonamide in a manner similar to that described in Example 1 for the preparation of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)phenyl]methanesulfonamide hydrochloride from (3-aminophenoxy)acetonitrile.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=C1OCCN1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To an ice cold stirring solution of crude 3-(2-hydroxyethyl)oxazolidin-2-one (15.1 g, 115 mmol) in dichloromethane (40 mL) was added triethylamine (18 mL, 129 mmol), and 4-(N,N-dimethylamino)pyridine (0.143 g, 1.2 mmol). A slurry of 4-toluenesulfonyl chloride (25.0 g, 131 mmol) in dichloromethane (50 mL) was then added dropwise. The reaction mixture was stirred for 3 d at room temperature, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was slurried in isopropanol and filtered to give 23.88 g (73%) of a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:19]=1Cl.O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:19]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
To a solution of 2-mercapto-5-trifluoromethyl-benzothiazole (239) (470 mg, 2.0 mmol) in DMF (20 mL) was added NaH (Aldrich, 60% suspension in hexanes, 80 mg, 2.0 mmol). After the resulting mixture was stirred at ambient temperature for 20 minutes, was added 1,2,3-trichloro-5-nitrobenzene (Acros, 452 mg, 2.0 mmol). The mixture was then heated at 60° C. for 4 hours. After cooled to room temperature, the mixture was poured to water and stirred for 1 hour. The solid product was collected by vacuum filtration to give 258 as a pale yellow solid (840 mg, 99%) which was used in the next reaction without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:30][O:29][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCOCC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (37 mg) was dissolved in N,N-dimethylformamide (1 ml) to prepare a solution. Potassium carbonate (242 mg) and morpholine (0.1 ml) were added to the solution, and the mixture was stirred at 60° C. for 2 days. Water was added to the reaction solution and was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (11 mg, yield 27%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=3)[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[CH:33]/[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[N:25]=[C:24]2[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)[CH3:14]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(C=O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)c(-c1cccc(F)c1)nn2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.11 ml ethyl diethylphosphonoacetate in 5 ml N,N-dimethylformamide was added 20 mg of sodium hydride (60% oily) under ice-cooling, and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of 150 mg of tert-butyl 3-(3-fluorophenyl)-5-formyl-1H-1-indazolecarboxylate in 1 ml N,N-dimethylformamide, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.16 g of tert-butyl 5-[(E)-3-ethoxy-3-oxo-1-propenyl]-3-(3-fluorophenyl)-1H-1-indazolecarboxylate as a colorless oil. This product was dissolved in 2 ml of tetrahydrofuran, 0.1 ml of 5 N hydrochloric acid was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 0.14 g of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[O:9][C:7](=O)[CH2:6]2)[CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C1(C)C(C)=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:13]2[C:7](=[O:9])[CH2:6][C:4]3([CH2:3][CH2:2][CH2:1][CH2:5]3)[CH2:12][C:10]2=[O:11])[CH:15]=1
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1C
Product: O=C1CC2(CCCC2)CC(=O)N1c1cccnc1

Procedure:
The starting material is prepared as follows. The mixture of 16.8 g of 3,3-tetramethyleneglutaric anhydride, 9.4 g of 3-aminopyridine and 225 ml of xylene is stirred and refluxed for 48 hours while collecting the water formed. After cooling in the refrigerator the precipitate obtained is filtered off and recrystallized from 300 ml ethanol-hexane, to yield the 8-(3-pyridyl)-8-azaspiro[4,5]decan-7,9-dione melting at 153°-154°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>S(Cl)(Cl)=O>[NH:22]1[C:21]([NH:20][C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[N:5]=2)=[O:19])=[N:25][N:24]=[N:23]1
Reactant: Cc1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 66.2 %

Procedure:
In the same manner as described in Example 13-(1), 4-methyl-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (3.0 g), thionyl chloride (20 ml) and 5-aminotetrazole (1.29 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-nitrophenyl)-2-pyridinecarboxamide (2.5 g). M.P. 284°-285° C. (decomp.) (wetted from 278° C.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[C:7](Br)[CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[CH2:26][NH2:27].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[C:7]([NH:27][CH2:26][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[O:15][CH3:14])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc2ccccc2c1CN
Reactant: CC(C)n1ncc(Br)c(Br)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ccccc2c1CNc1cnn(C(C)C)c(=O)c1Br
Reaction time: 8 h

Procedure:
A mixture comprising 1.48 g of 2-i-propyl-4,5-dibromo-3(2H)pyridazinone, 1.68 g of 2-methoxy-1-naphthylmethylamine hydrochloride, 1.33 g of sodium carbonate, 30 ml of water and 30 ml of 1,4-dioxane, was refluxed under stirring overnight. Then, the solvent was distilled off under reduced pressure, and water was poured to the residue thus obtained. The mixture was extracted with ethyl acetate. The extract was washed sequentially with a 2 wt% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over sodium sulfate. Then, the solvent was distilled off. The residual solid thus obtained was crystallized from ethyl acetate/n-hexane to obtain 1.18 g of the above identified compound as colorless crystals having a melting point of from 160° to 161° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]=[C:12]=[S:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:14](O)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[C:14](=[O:22])[C:15]3[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:17][C:12]2=[S:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)Oc1cccc(N=C=S)c1
Solvent: CC(=O)O
Product: CC(C)Oc1cccc(-n2c(=S)[nH]c3ccccc3c2=O)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHC3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.