Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39]Cl>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CN(C)CCCCl
Product: Cc1ccccc1N1C(=O)N(CCCN(C)C)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and 3-dimethylamino-1-propyl chloride.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[CH:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([OH:29])[CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[OH-].[Na+].[Na]>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([O:29][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[CH:4]=1)[CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: Oc1cc(CBr)c2ccccc2n1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1cc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c2ccccc2n1

Procedure:
7.2 g of 4-bromomethyl-2-hydroxyquinoline (0.03 mol), 7.7 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.03 mol), 30 g sodium hydroxide (0.75 mol) in 30 ml of water, 0.5 g benzyltrimethylammonium chloride and 45 ml of tetrahydrofuran are reacted in a manner as described in Example 1. After work up of the reaction mixture the sodium salt of the title compound is dissolved in 400 ml of water and acidified with acetic acid. After standing overnight, the solution is filtered and then neutralized with aqueous ammonia. The deposited oil is extracted with chloroform, the chloroform layer washed with water, dried with sodium sulfate and evaporated. The residual oil (8 g) is dissolved in 100 ml of ethyl acetate, charcoaled and allowed to stand overnight in the refrigerator. The crystallized 4-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]methyl]-2-quinolinol melts at 190°-192° C.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)N(CCCC#Cc1cccs1)C(=O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 300 mg of 2d in 6 ml of dioxane was added a solution of 200 mg of KOH in 2 ml of water. The mixture was stirred at 50° C. for 1 hr. After cooling to RT, 25 ml of water was added and the reaction mixture was acidified to pH3 by addition of 0.5N HCl. The product was extracted into ethyl acetate. The organic layer was washed once with water, dried and concentrated, to provide 240 mg of 2e as colorless oil;
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: O=C(C=Cc1ccc(O)c(Cl)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(3-Chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 3-chloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][NH:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:32](I)[CH3:33].C(O)(=O)C>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH2:32][CH3:33])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: CCOC(=O)c1ccc(CNCc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(CN(CC)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.05 g, 50% dispersion in oil) in DMF (100 ml) at 0° C. was added a solution of ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)aminomethyl]benzoate dropwise. The mixture was stirred at 0° C. for 1 hour, ethyl iodide (3.43 g) added and the mixture stirred at ambient temperature for 18 hours. The mixture was acidified with acetic acid, poured into water (300 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water (3×100 ml), dried and evaporated. The residue was purified by chromatography eluting with 4% ethyl acetate/CH2Cl2 to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylaminomethyl]benzoate (yield 6.61 g).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH2:15][OH:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[O-2].[O-2].[Mn+4]>[C:24]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:9]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1cc(CO)n(Cc2ccncc2)cc1C(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: O=Cc1cc(=O)c(C(c2ccccc2)c2ccccc2)cn1Cc1ccncc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 2.391 g of 3-diphenylmethyl-6-hydroxymethyl-1-(4-pyridyl)methyl-4-pyridone in 150 ml of methanol is added 14.0 g of active manganese dioxide at room temperature, and the mixture is stirred for 30 minutes. After insolubles are removed by filtration, the filtrate is subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound (2.043 g) is obtained as colorless foam.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=[O:15])[C:11]([Cl:17])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Zn]>[C:1]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([NH:14][OH:15])[C:11]([Cl:17])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc2cc(Cl)c(NO)cc2o1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
200 g of 2-tert-butyl-5-chloro-6-nitrobenzoxazole was dispersed in a mixture of 600 ml of ethanol and 300 ml of water and to the mixture was added 42 g of ammonium chloride and then was gradually added zinc powder. The temperature rose to 70° C. due to generation of heat. The mixture was stirred for one hour and then, the inorganic substances were removed by filtration. To the filtrate was added 1.8 liters of water, and the crystals thusdeposited were collected by filtration. The crystals were dried to obtain 153 g of the desired compound.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(OCC)(=O)C.[Zn]>[OH:22][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 8 g of zinc powder (122 mmol) in 47 ml of ethyl acetate. After 1.9 ml of trimethylchlorosilane (15 mmol) had been added, the mixture was heated to 60° C. for 15 min, then allowed to cool to 55° C. and 22 g of undiluted tert-butyl bromoacetate (113 mmol) were subsequently added dropwise within 5 min, and the temperature was maintained at 65° C. by external cooling. The mixture was then stirred at 50° C. for 10 min. After cooling to 0° C., 10 g of undiluted benzaldehyde (94 mmol) were added, and the temperature was maintained at 10° C. by external cooling. After stirring had been continued at 25° C. for 90 min and 35° C. for 15 min, 40 ml of ethyl acetate were added, the mixture was cooled to 15° C., acidified with 17 ml of 20% hydrochloric acid to a pH of 1-2 and the mixture was stirred for 10 min, during which excess zinc dissolved. The organic phase was then removed. The organic phase was then stirred with 15 ml of concentrated ammonia solution at 25° C. for 10 min. After the phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure. Tert-butyl 3-hydroxy-3-phenylpropionate was obtained in a yield of 20.3 g (97% of theory) and had a boiling point of 102° C. (1.5 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13])[CH:3]=1
Reactant: C[C@H](CCl)CBr
Reactant: Oc1cccc(Cl)c1
Product: C[C@H](CCl)COc1cccc(Cl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cccc(Br)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-bromoaniline to yield 2-[(3-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[NH:12][CH2:11]3)[C:9](=[O:16])[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]2=[CH:6][CH:7]=1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:12]1[C:13](=[O:15])[CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]2=[O:16])[CH2:11]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CNC(=O)C2)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2)c2cc(Cl)ccc21
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (5-chloro-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 32 (175.00 mg; 0.50 mmol) in dry THF (5 mL), sodium hydride (24 mg; 0.60 mmol) was added. The reaction mixture was stirred 15 minutes then benzyl bromide (71.10 μl; 0.60 mmol) was added. After stirring for 10 min, the solvent was evaporated and the residue redissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and removed in vacuo to give a residue which was purified by chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate (20 to 50%) to give the title compound was obtained (220 g, 52.1%, HPLC purity 96.7%). MS (ESI+): 441.4; MS (ESI−): 439.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>C(#N)C>[Si:20]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (5.0 g, 40.9 mmol) was dissolved in acetonitrile (10.0 mL). Subsequently, potassium carbonate (11.3 g, 81.9 mmol), and then tert-butyldimethylchlorosilane (7.4 g, 49.1 mmol) were added thereto, and the resultant mixture was stirred at room temperature. After completion of reaction, ethyl acetate was added thereto, followed by washing sequentially with water and brine, and drying over anhydrous sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (9.1 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C@@H:24]([CH3:27])[CH2:25][OH:26]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CO)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
A 1-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirrer, thermocouple, and condenser was charged with 4-bromo-1-fluoro-2-nitrobenzene (46 g, 209 mmol), DMF (230 mL), potassium carbonate (31.8 g, 230 mmol), and (S)-2-aminopropane-1-ol (17.9 mL, 230 mmol). The reaction mixture was heated to 60° C. for 6 h and then cooled to rt and stirred overnight. The mixture was slowly diluted with water (690 mL), and the resulting slurry stirred at rt for 3 h and was then filtered. The solids were washed with water (120 mL) and dried under house vacuum (ca 17 Torr) overnight to afford (S)-2-(4-bromo-2-nitrophenylamino)propane-1-ol (72.98 g) as a yellow-orange solid which contained excess water, and was used in next step without further drying or purification. MS (ESI, pos. ion) m/z 275 [M+1]+.
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10]([CH3:13])(=O)=O)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:29]1[C:30]([C:35]([F:38])([F:37])[F:36])=[N:31][O:32][C:33]=1[CH3:34]>CN(C)C=O.O>[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10][CH2:13][C:29]2[C:30]([C:35]([F:38])([F:37])[F:36])=[N:31][O:32][C:33]=2[CH3:34])[CH2:6]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Cc1onc(C(F)(F)F)c1CBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
0.4 g of sodium hydrosulfide hydrate (purity: 70%, 4.6 mmoles) was added to a solution of 0.4 g (2.3 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. Thereto were added 0.3 g (2.3 mmoles) of potassium carbonate, 0.4 g (2.3 mmoles) of Rongalit and 0.5 g (1.8 mmoles) of 4-bromomethyl-5-methyl-3-trifluoromethylisoxazole. The resulting mixture was stirred at room temperature for 14 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (yield: 70.0%) of 5,5-dimethyl-3-(5-methyl-3-trifluoromethylisoxazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][CH:15]=[CH:16][Sn])[CH3:13]>CN(C)C=O>[CH2:15]([O:14][C:12]([C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[CH2:13])[CH3:16]
Reactant: CCOC=C[Sn]
Reactant: COC(=O)c1ccc(Cl)nn1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc(C(=O)OC)nn1
Temperature: 80 °C
Yield: 71.8 %

Procedure:
A solution of methyl 6-chloropyridazine-3-carboxylate (1.5 g, 8.7 mmol), ethoxyvinyl tin (3.2 g, 8.7 mmol), trans-bis(triphenyl-phosphine)palladium (200 mg) and N,N-dimethylformamide (50 mL) were combined. The mixture solution was heated to 80° C. for 10 hours under nitrogen gas protected. N,N-dimethylformamide was concentrated to dry in vacuo. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=4:1) to give methyl 6-(1-ethoxyvinyl)pyridazine-3-carboxylate as a white solid (1.3 g, 72%). 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=9 Hz, 1H), 7.98 (d, J=9 Hz, 1H), 4.98 (d, J=2.4 Hz, 1H), 4.68 (d, J=Methyl 6-acetylpyridazine-3-carboxylate. A solution of methyl 6-(1-ethoxyvinyl)pyridazine-3-carboxylate (1.3 g, 7.2 mmol) in hydrochloric acid (6 mol/L, 20 mL) was stirred at room temperature for 4 hours. The mixture solution was neutralized with potassium carbonate, extracted with ethyl acetate (100 mL). The organic layer was concentrated to dry to give methyl 6-acetylpyridazine-3-carboxylate as a white solid (0.9, 81%). 1H NMR (300 MHz, CDCl3): δ 8.36-8.40 (m, 1H), 8.36-8.40 (m, 1H), 4.00 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1F
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 53 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-3-methylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.07 g, 0.14 mmol) obtained in step 2 and ethanesulfonamide (0.074 g, 0.7 mmol), the title compound (0.044 g, 53%) was obtained.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][C@H:44]3[CH2:49][CH2:48][C@H:47]([NH2:50])[CH2:46][CH2:45]3)=[CH:40][CH:41]=2)[CH:36]=[N:35]1.[OH-].[Li+]>CN(C)C=O.O>[NH:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][C@H:44]3[CH2:49][CH2:48][C@H:47]([NH:50][C:1](=[O:4])[CH3:2])[CH2:46][CH2:45]3)=[CH:40][CH:41]=2)[CH:36]=[N:35]1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](Oc2ccc3[nH]ncc3c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 8 h

Procedure:
Acetic acid (0.033 g, 0.58 mmol), triethylamine (0.12 ml, 0.86 mmol), 1-hydroxybenztriazole (0.088 g, 0.65 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.124 g, 0.65 mmol) were added to a solution of the trans-4-(1H-indazol-5-yloxy)cyclohexanamine (0.100 g, 0.44 mmol) obtained in Example 384 in N,N-dimethylformamide (5 ml) and stirred overnight. A 2N-aqueous lithium hydroxide solution (2 ml) was added thereto and stirred for some time, and the resulting mixture was added to water and extracted three times with toluene/ethyl acetate=1/1. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the solid precipitated was suspended in a hexane/ethyl acetate mixed solvent and stirred to be washed. The solid was collected by filtration and dried under reduced pressure to obtain trans-N-[4-(1H-indazol-5-yloxy)cyclohexyl]acetamide (0.097 g, 82%).
Reaction SMILES: C(S(N1CCC(C2[C:20]3[C:15](=[C:16](C(N)=O)[CH:17]=[C:18](C4SC(CNCC(C)CC)=CC=4)C=3)[NH:14]C=2)CC1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.CC(N)CCC.[BH3-]C#N.[Na+]>>[CH3:20][CH:15]([NH:14][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)[CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: CCCC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCC(C)NCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (1-methylbutyl)amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 35.2 mg of the title compound (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccc(Cl)cc1Cl

Procedure:
To a suspension of 2,4-dichlorobenzaldehyde (462.1 mg, 2.64 mmol), 1,1-dimethylnitroethane (543.1 mg, 5.27 mmol) and zinc (514.8 mg, 7.88 mmol) in ethanol (3.0 ml) was added acetic acid (944.8 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. Zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/1).