Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([OH:31])=[CH:23][N:22]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[CH:23]=[N:22]2)[CH:7]=1
Reactant: Oc1cnnc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ncc(=O)c2ccccc21)C(F)(F)F
Temperature: 85 °C

Procedure:
To a suspension of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (216 mg) and cinnolin-4-ol (V. G. Chapoulaud et al., Tetrahedron, 2000, 56, pp. 5499-5507) (216 mg) in anhydrous ethanol (1.2 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 276 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (eluted with 40% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (26 mg), m.p. 122° C.-123° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:27]3[CH2:28][CH2:29][CH2:30][CH:23]2[C:24](=[CH:32]O)[C:25](=O)[CH2:26]3)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]2[CH:27]3[CH2:28][CH2:29][CH2:30][CH:23]2[C:24]2[CH:32]=[N:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:25]=2[CH2:26]3)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CC(C)c1ccc(NN)cc1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)c1ccc(-n2ncc3c2CC2CCCC3N2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
Prepared as described in Example 5 using 4-isopropylphenylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:23][C:24]1[C:29]([CH:30]=O)=[CH:28][N:27]=[C:26]([CH3:32])[C:25]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=2)=[CH:45][CH:44]=1>>[CH2:1]([O:8][C:9](=[O:41])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:23][C:24]1[C:29]([CH2:30][NH:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=3)=[CH:47][CH:48]=2)=[CH:28][N:27]=[C:26]([CH3:32])[C:25]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc(C=O)c(CN(CCCCCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1OCc1ccccc1
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2)c(CN(CCCCCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 83.3 %

Procedure:
The reductive amination of 6-[(3-benzyloxy-5-formyl-2-methyl-pyridin-4-ylmethyl)-tert-butoxycarbonyl-amino]-hexanoic acid benzyl ester (2.2 g, 3.9 mmol) and 4-amino-4′-cyanobiphenyl (2.1 g, 10.8 mmol), as described in Example 21, gave 6-({3-benzyloxy-5-[(4′-cyano-biphenyl-4-ylamino)-methyl]-2-methyl-pyridin-4-ylmethyl}-tert-butoxycarbonyl-amino)-hexanoic acid benzyl ester (44) (2.4 g, 83% yield).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[C:27](OC)(=[O:32])[C:28]([O:30][CH3:31])=[O:29].C(=O)=O>O1CCCC1>[CH3:31][O:30][C:28](=[O:29])[C:27]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[O:32]
Reactant: CC(C)(C)[Si](C)(C)OCCCn1ccc2c(Br)cccc21
Reactant: COC(=O)C(=O)OC
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cccc2c1ccn2CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
Add tert-butyl lithium (88.1 ml, 149.8 mmol, 1.7 M in hexane) to a solution of 4-Bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]-1H-indole (22.0 g, 59.92 mmol) in anhydrous tetrahydrofuran (100 ml) at −78° C. Stir the reaction at −78° C. for 20 min. Transfer the mixture into a solution of dimethyl oxalate (24.8 g, 209.72 mmol) in tetrahydrofuran (400 ml) at −40° C. via a dry-ice cooled cannula. Upon complete addition, stir the reaction at −78° C. for 15 minutes and slowly warm to room temperature. Quench the reaction with saturated aqueous ammonium chloride and extract into ethyl acetate. Combine the organic layers, dry over magnesium sulfate, and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate:hexane gradient (100% hexane to 15% ethyl acetate:hexane over 90 minutes) gives the title compound, as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-:14].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Cl:1][C:2]1[C:3]2[C:12](=[O:14])[NH:11][S:8](=[O:9])(=[O:10])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)cccc1S(N)(=O)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21

Procedure:
A mixture of 16.4 gm (80 mmols) of 3-chloro-2-methyl-benzene sulfonamide, 14 gm (100 mmols) of potassium carbonate, 33.2 gm (210 mmols) of potassium permanganate and 350 ml of water was refluxed for 1 hour. The reaction mixture was filtered while still hot, and the filter cake was washed with hot water. The combined filtrates were acidified with concentrated aqueous hydrochloric acid and cooled. The resulting crystals were suction-filtered off, washed with water and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)=[CH:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].O>CS(C)=O>[C:42]([Si:39]([CH3:41])([CH3:40])[O:38][CH2:37][CH2:36][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=1)[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)C=Cc1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc2c[nH]c3ccccc23)cc1
Temperature: 52.5 °C
Yield: 97.6 %

Procedure:
To a stirred solution of 2 (2.82 g, 8.44 mmol) and diisopropylethylamine (2.21 mL, 12.66 mmol) in anhydrous DMSO (22 mL) at room temperature under nitrogen was added (2-bromo-ethoxy)-tert-butyl-dimethylsilane (2.17 mL, 10.12 mmol). The reaction mixture was heated at 50-55° C. for 24 h, poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/CH2Cl2, 15/85, plus a few drops of NH4OH) to afford the title compound 3 (4.06 g, 8.24 mmol, 97% yield) as a dark orange oil.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]4[CH2:32][O:31]4)=[CH:23][CH:24]=3)[O:19][CH:18]=2)=[CH:13][CH:12]=1>O1CCCC1>[OH:31][CH:30]([CH2:32][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:29][O:28][C:22]1[CH:21]=[C:20]2[C:25]([C:26](=[O:27])[C:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)=[CH:18][O:19]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-c2coc3cc(OCC(O)Cc4ccccc4)ccc3c2=O)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of cuprous iodide (0.14 g, 0.74 mmol) in tetrahydrofuran (2 ml) was added phenylmagnesium bromide in tetrahydrofuran (1M, 2.22 ml, 2.22 mmol) dropwise at −40° C. After 5 minutes 3-(4-methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol) in tetrahydrofuran (4 ml) was added slowly, and stirred at −40° C. for 1 hour. The mixture was quenched with saturated ammonium chloride and water, extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by preparative thin layer chromatography, eluting with 10% methanol/methylene chloride, followed by ethyl acetate/hexane 2/3, to provide 7-(2-hydroxy-3-phenylpropoxy)-3-(4-methoxyphenyl)chromen-4-one.
Reaction SMILES: BrCCCCCC1[O:11]N=C(C)C=1.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[O:21]CCN=2)[CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=1[OH:28].BrC1C=C(C=C([N+]([O-])=O)C=1O)C(NCCO)=O.CO.[C:48]([O:51][CH:52]([CH3:54])[CH3:53])(=[O:50])[CH3:49].OC1C=CC(C(O)=O)=CC=1[N+]([O-])=O>>[Br:13][C:14]1[C:15]([OH:28])=[C:16]([N+:25]([O-:27])=[O:26])[CH:17]=[C:18]([CH:19]=1)[C:20]([OH:21])=[O:11].[C:48]([O:51][CH:52]([CH3:54])[CH3:53])(=[O:50])[CH3:49]
Reactant: Cc1cc(CCCCCBr)on1
Reactant: O=[N+]([O-])c1cc(C2=NCCO2)cc(Br)c1O
Agent: O=C(NCCO)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)C
Solvent: CO
Product: O=C(O)c1cc(Br)c(O)c([N+](=O)[O-])c1

Procedure:
Intermediates: 5-(5-bromopentyl)-3-methylisoxazole and 2-bromo-4-(4,5-dihydro-2-oxazolyl)-6-nitrophenol. The latter, a bright yellow solid, was prepared by cyclization of 3-bromo-4-hydroxy-N-(2-hydroxyethyl)-5-nitrobenzamide, yellow solid, m.p. 163°-164° C. (from methanol-isopropyl acetate). The latter was in turn prepared by bromination of 4-hydroxy-3-nitrobenzoic acid to form 5-bromo-4-hydroxy-3-nitrobenzoic acid, m.p. 233°-234° C. (yellow solid from isopropyl acetate), esterification to the corresponding methyl ester, m.p. 128°-130° C. (yellow solid from carbon tetrachloride) and reaction of the latter with 2-hydroxyethylamine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[C:15]([CH3:26])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:13]1[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][C:16]([N+:23]([O-:25])=[O:24])=[C:15]([CH3:26])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 72 %

Procedure:
In 50 ml of N,N-dimethylformamide, 3.00 g (19.97 mmol) of 3-tertbutylphenol, 4.35 g (18.16 mmol) of 4-chloro-5-trifluoromethyl-2-methylnitrobenzene and 3.26 g (23.60 mmol) of potassium carbonate are heated at 50° C. for 15 min. The reaction solution is added to water and extracted repeatedly with dichloromethane, the extracts are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. The solid is washed with water and hexane and dried under reduced pressure. (6.6 g, purity 70.0%, yield 72.0%, log P (pH 2.3)=5.68).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred solution of 4-chloroisatin (9.10 g, 50.0 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (2.20 g, 55.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, followed by the addition of bromodiphenylmethane (14.80 g, 56.8 mmol). The mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether and hexanes to afford 4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (14.20 g, 81%): 1H NMR (300 MHz, CDCl3) δ7.37-7.17 (m, 11H), 6.98-6.95 (m, 2H), 6.42 (d, J=9.0 Hz, 1H); MS (ES+) m/z 369.9 (M+23), 371.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH2:30][CH3:31])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH2:30][CH3:31])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.7 %

Procedure:
A mixture of 111c (502 mg, 1.02 mmol), dichloromethane (2 mL), and 4.0 M HCl/dioxane (4 mL) was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford crude 111d as a yellow solid (263 mg, 66%), which was used in the next step without further purification. MS: [M+H]+ 392.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCOC(C)=O.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([C:15]#[N:16])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)ncn1
Temperature: 120 °C
Yield: 21 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (3.0 g, 23 mmol), zinc (II) cyanide (5.4 g, 46 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.2 mmol) in dry DMF (50 mL) was heated to 120° C. under nitrogen atmosphere for 15 hours. EtOAc (100 mL) was added and the insoluble precipitate was removed by filtration. The filtrate was diluted with water (100 mL), and extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a pale yellow solid (0.6 g, 21% yield). LCMS (ESI) m/z: 121.2 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: COc1ccc(Cl)cc1
Reactant: CCOc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: CCOc1ccc(Nc2ccc(OC)cc2)cc1
Temperature: 110 °C
Yield: 94.1 %

Procedure:
Following general procedure E, a mixture of 4-chloroanisole (123 μL, 1.0 mmol), 4-ethoxyaniline (154 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (229 mg, 94%), mp 73-75° C. 1H NMR (300 MHz, CDCl3) δ: 6.95 (m, 4H), 6.84 (m, 4H), 5.34 (s, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 1.43 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 154.4, 153.8, 138.2, 138.1, 119.8, 119.7, 115.7, 114.9, 64.1, 55.9, 15.3 ppm. IR (neat, cm−1): 3421, 2983, 2956, 1513, 1298, 1253, 1116, 1052, 1037, 814. Anal. Calcd. for C15H17NO2: C, 74.05; H, 7.04. Found: C, 73.95; H, 7.06.
Reaction SMILES: [C:1](O)(=O)[C:2]#[C:3]C.C[N:8]([CH3:11])[CH:9]=[O:10].C(Cl)(=O)C(Cl)=O.N[C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1F)[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[N:28]=1>CN(C)C(=O)C.O1CCCC1>[C:9]([NH:8][C:11]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[CH3:19])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:36][CH2:37]3)=[O:34])[N:31]=2)[N:28]=1)(=[O:10])[C:1]#[C:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CC#CC(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 46.4 %

Procedure:
Using 2-butynoic acid (78 mg, 0.93 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (81 μL, 0.93 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 238, the title compound (47 mg, 20%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][N:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:21](Br)[CH2:22][CH2:23][CH3:24].Cl.[OH-:27].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [OH-]
Reactant: CCCCBr
Reactant: CCCCCC[C@H]1CC[C@H](c2ccc(C#N)cn2)CC1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC[C@H]1CC[C@H](c2ccc(C(=O)CCCC)cn2)CC1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
An ethyl ether solution (30 ml) of 2-(trans-4-n-hexylcyclohexyl)-5-cyanopyridine (13.2 g) of Example 16 was added to an ethyl ether solution (50 ml) of a Grignard reagent prepared from metallic Mg (2.5 g) and butyl bromide (13.8 g), followed by agitating the mixture at 35° C. for 5 hours, pouring the resulting solution in ice water containing 6N-HCl aqueous solution (100 ml), adding 2N-NaOH aqueous solution till the solution became basic, adding toluene (300 ml) to the resulting solution, washing the separated organic layer with water till the washing water became neutral, distilling off the solvent, and recrystallizing the residue from methanol to obtain 2-(trans-4-n-hexylcyclohexyl)-5-valeroylpyridine (4.3 g). This compound exhibited smectic phase between 46° C. and 66° C. To this compound were added m-chloroperbenzoic acid (4.6 g) and chloroform (50 ml), followed by agitating the mixture at room temperature for one week, filtering off the resulting precipitates, adding phosphorus oxychloride (10 ml) and toluene (50 ml) to the precipitates, heating the mixture at 80° C. for 2 hours, distilling off the solvent, adding warm water (100 ml), adding 2N-NaOH aqueous solution till the solution became basic, adding toluene (100 ml), washing the separated organic layer with water till the washing water became neutral, and distilling off the solvent to obtain 2-(trans-4-n-hexylcyclohexyl)-5-valeroyloxypyridine. To this compound were added KOH (1.5 g) and ethylene glycol (50 ml), followed by heating the mixture at 150° C. for 8 hours, cooling, adding water (100 ml), adding acetic acid till the solution became acidic, filtering off the resulting precipitates, and recrystallizing from methanol to obtain 2-(trans-4-n-hexylcyclohexyl)-5-hydroxypyridine. This compound was dissolved in ethanol (30 ml), followed by adding ethyl iodide (1.0 g), KOH (0.3 g) and water (2 ml), heating the mixture at 65° C. for 5 hours, cooling, adding water (100 ml) and toluene (50 ml), washing the separated organic layer with water till the washing water became neutral, and distilling off the solvent from the organic layer to obtain the objective 2-(trans-4-n-hexylcyclohexyl)-5-ethoxypyridine.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH:14]([CH3:31])[C:15](=[O:30])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)(C)(C)C>ClCCl>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH:15]([OH:30])[CH:14]([CH3:31])[C:13]([OH:32])=[O:12])=[CH:23][CH:22]=1
Reactant: CC(C(=O)CCc1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.2 %

Procedure:
A solution of trifluoroacetic acid in dichloromethane (20%; 10 mL) was added to 5-biphenyl-4-yl-2-methyl-3-oxo-pentanoic acid tert-butyl ester (Intermediate 7, 130 mg, 0.382 mmol) and the resulting solution stirred at room temperature for 1.5 hour. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (1:2 ethyl acetate: 40–60 petroleum ether) to give the title compound (60 mg, 56%) as a white solid, mixture of diastereoisomers. LC/MS: 3.22 min; z/e 302, calcd (M+NH4) 302. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.51 (2 H), 7.40 (2 H), 7.28 (3 H), 4.21, 4.01 3.75, 2.91, 2.76, 2.62, 1.88, 1.25.
Reaction SMILES: O1CCCC1.[CH:6]([OH:9])([CH3:8])[CH3:7].[H-].[Na+].[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39]Br>O>[Br:12][C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2[CH:17]=[N:18][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20](=[O:21])[C:15]=2[C:14]=1[CH2:39][O:9][CH:6]([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CBr)c(Br)n2COCC[Si](C)(C)C)c1=O
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To 2 ml of dehydrated tetrahydrofuran solution containing 1 ml of isopropanol was added 155 mg of sodium hydride (55% dispersed material in mineral oil), the mixture was stirred at room temperature for 20 minutes, then, 272 mg (0.48 mmol) of 2-bromo-3-bromomethyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 25-(a) was further added to the mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 176 mg of the title compound as a colorless oil. (Yield: 67%)