Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[CH:10][C:11]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[C:2]1=[O:27].Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH:33][C:23](=[O:24])[CH:22]([O:21][C:18]1[CH:19]=[CH:20][C:11]([CH:10]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:27])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)[CH3:26]
Reactant: CC(Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Reaction time: 15 h
Yield: 44.1 %

Procedure:
To a solution of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy]propionic acid (100 mg, 0.28 mmol), L-alanine methyl ester hydrochloride (40 mg, 0.29 mmol) and triethylamine (0.4 ml) in THF (10 ml) was added N, N'-dicyclohexylcarbodiimide (60 mg, 0.29 mmol) at room temperature under stirring. The stirring was continued for 15 h, then the mixture was filtered and the filtrate evaporated under vacuum. The residue was chromatographed on silica gel using as eluant ethylacetate methanol (9:1) to give pure title compound in 44.1% yield (55 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Cl:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Cl)cn2)cc1
Yield: 84.1 %

Procedure:
According to Scheme 4 Step 1 Method A: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (1.38 mmol, 500 mg) and N-chlorosuccinimide (1.38 mmol, 184 mg) in DMF (3 mL) was stirred for 1 hour at 50° C. The reaction mixture was diluted with AcOEt (250 mL) and the organic phase was washed with a saturated solution of Na2CO3. The organic phase was dried over MgSO4, was filtered and was concentrated to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-yl)pyridin-2-amine (1.16 mmol, 460 mg, 84%) as a beige solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN1CCOCC1.[C:23]1(=[O:42])[N:27]([C@@H:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29](O)=[O:30])[C:26](=[O:37])[C:25]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:24]12.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[C:26]1(=[O:37])[N:27]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29]([NH:2][C@@H:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:30])[C:23](=[O:42])[C:24]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:25]12
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](Cc1ccccc1)NC(=O)C(CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of L-phenylalanine, ethyl ester, hydrochloride salt (998 mg., 4.3 mmol.) in dimethylformamide (10 ml.) was added 4-methylmorpholine (575 μl., 529 mg, 5.2 mmol). After stirring at room temperature for 5 minutes, the solution was cooled to 0° C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.), and ethyl-3-(3-dimethylamino)propyl carbodiimide, hydrochloride salt (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (acetone:hexanes, 1:1) Rf =0.30.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.Cl>N1C=CC=CC=1>[C:19]([O:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12]([OH:14])=[O:13])[C:6]=2[C:15]=1[CH3:16])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(C(=O)O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 25.03 g (0.1M) of 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid (described in Example 1) in 200 ml of pyridine is added 100 ml of acetic anhydride and the mixture is stirred at room temperature for 24 hours. Water and ice is added and the mixture is stirred at about 30° C. for 30 minutes. More ice and 450 ml of 6N hydrochloric acid is added and the resulting solid is collected, washed with water, and taken up in ethyl acetate. The solution is washed with 2N hydrochloric acid and water and is dried over anhydrous sodium sulfate. The residue obtained after filtration and evaporation of solvent is recrystallized from ethyl acetate to give 23.6 g (81%) of the title compound as racemate, m.p. 187°-8° C. Elemental analysis, UV, and 1H-NMR spectra confirm the structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C@H:21]([CH3:30])[C:22](N3CCOCC3)=[O:23])=[CH:15][CH:14]=1)[C:7]([CH3:31])=[C:6]2[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[O:33].C1C[O:44]CC1.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C@H:21]([CH3:30])[C:22]([OH:23])=[O:44])=[CH:15][CH:14]=1)[C:7]([CH3:31])=[C:6]2[C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)c(C(=O)c1ccc(C)cc1)c(C)n2Cc1ccc(CO[C@H](C)C(=O)N2CCOCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c(C(=O)c1ccc(C)cc1)c(C)n2Cc1ccc(CO[C@H](C)C(=O)O)cc1
Yield: 31 %

Procedure:
The compound of Example 40-1 (142 mg, 0.26 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N lithium hydroxide solution (0.5 ml), followed by stirring under reflux for 15 hours. The reaction mixture was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (39 mg, 31%).
Reaction SMILES: C(S[C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12](=[O:51])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)C.[O-:52][CH2:53][CH3:54].[Na+]>C(O)C>[CH2:53]([O:52][C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:12](=[O:51])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:54]
Reactant: CCSc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.7 %

Procedure:
A mixture of 2-ethylthio-3-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-4(3H)-quinazolinone (0.5 g) and sodium ethoxide (182 mg) in ethanol (20 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated to dryness. The residue was extracted using methylene chloride and an aqueous solution of ammonium chloride. The organic layer was washed with water, dried and evaporated to dryness. The resulting syrup was purified by column chromatography on silica gel to give a colorless oil (72 mg, 21%).
Reaction SMILES: [C-:1]#[C-:2].[C-]#[C-].[Na+].[Na+].[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>C#C>[NH2:7][C:8]1[CH:22]=[CH:21][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([OH:13])[C:1]#[CH:2])=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: [C-]#[C-]
Agent: C#C
Agent: [Na+]
Product: C#CC(O)(c1ccc(N)cc1)c1ccc(F)cc1

Procedure:
Referring now to FIG. 2, wherein one non-limiting approach to the 1-(4-aminophenyl)-1-(4-fluorophenyl)-2-propyn-1-ol is presented, 4,4′-difluorobenzophenone (7) is reacted with a secondary amine HNR′″R″″ to give the 4-amino-4′-fluorobenzophenone 8, where R′″ and R″″ may be the same as R36 and R37, respectively, as set forth and claimed herein. Acetylide anion, for example, sodium acetylide in acetylene saturated dimethylformamide, is added to the carbonyl of 4-amino-4′-fluorobenzophenone 8 to give, upon aqueous workup, 1-(4-aminophenyl)-1-(4-fluorophenyl)-2-propyn-1-ol 9.
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:7](OCC)=[O:8])C.[NH2:20][C:21]([NH2:23])=[S:22].O>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:6]1[C:5](=[O:4])[NH:23][C:21](=[S:22])[NH:20][C:7]1=[O:8]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1F
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1NC(=S)NC(=O)C1c1ccccc1F
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To absolute ethanol (200 ml), sodium (3.62 g, 157 mmol) was added at room temperature under nitrogen atmosphere. The reaction mixture as stirred until all the sodium had reacted. A solution of diethyl-(2-fluorophenyl)malonate (20 g, 78.7 mmol) in absolute ethanol (50 ml) was then added followed by thiourea (8.38 g, 110 mmol). The reaction mixture was then refluxed under nitrogen atmosphere for 17 hours. The cooled reaction mixture was then poured into water (800 ml), the reswiting mixture stirred for 15 minutes and extracted with diethyl ether (500 ml). The organic phase was extracted with brine (150 ml, ⅓ saturated) and the aqueous layers combined. Now concentrated hydrochloric acid (14 ml) was added to the aqueous phase and the resulting white suspension was stirred gently for 1 hour. The suspension was filtered and the resulting solid washed with water, followed by diethyl ether and dried in vacuo for approximately 12 hours to afford 8.59 g (46% yield) of the title compound as a white solid (melting point: >240° C.).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)([CH3:11])[CH3:10].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH:9]([N:12]1[C:16]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[N:13]1)([CH3:11])[CH3:10]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)n1cccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a cold (−78° C.) solution of LDA (prepared from n-BuLi (7.99 mL, 1.6 M, 1.1 eq) and diisopropylamine (1.82 mL, 1.1 eq)) in THF, a solution of 1-isopropyl-1H-pyrazole (1.28 g, 11.6 mmol) in THF was added dropwise while keeping the temperature below −70° C. At the end of the addition, the mixture was stirred at −78° C. for 30 min. Tributyltin chloride (3.44 mL, 1.1 eq) was then added dropwise while keeping the temperature below −70° C. At the end of the addition, the mixture was stirred for 1 h at −78° C. and for 2 h at r.t. The solvent was removed in vacuo and the crude oil was dissolved into AcOEt. The organic phase was washed with water and dried over Na2SO4. The solution was concentrated in vacuo to afford a yellow oil (3.82 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.Cl.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>O1CCCC1.C(N(CC)CC)C>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccncc1)Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Yield: 21.2 %

Procedure:
A solution of 50 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26, 26 mg of 4-pyridylacetic acid hydrochloride and 0.05 ml of triethylamine in 5 ml tetrahydrofuran was added 37 mg of 1,1′-carbonyldiimidazole as a condensing agent at room temperature. After the completion of the reaction, the reaction mixture was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 11 mg of the title compound as a colorless powder.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:12]([O-:15])(=[O:14])=[O:13].[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: CCCCCC(Br)Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCBr
Temperature: 25 °C

Procedure:
To a stirred mixture of dibromohexane (81.0 g), ethanol (120 ml) and water (50 ml) is added dropwise an aqueous solution (50 ml) of sodium sulfite (12.5 g) under reflux over 2 hours. After additional refluxing for 2 hours, the reaction mixture is allowed to cool and unreacted dibromohexane is removed and then the resulting solution is concentrated under reduced pressure. 95% Ethanol (200 ml) is added and the mixture is allowed to cool at room temperature overnight and precipitated crystals are collected by filtration to give the title compound as colorless prisms. The filtrate is concentrated and is allowed to cool overnight and precipitated crystals are collected by filtration to give additional title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1F)[NH:7][C:6](=[O:12])[C:5]2=[O:13].[S-:14][CH2:15][CH3:16].[Na+].FC1C=C2C(=CC=1SC)NC=C2>>[CH2:15]([S:14][C:10]1[CH:9]=[C:8]2[C:4]([C:5](=[O:13])[C:6](=[O:12])[NH:7]2)=[CH:3][C:2]=1[F:1])[CH3:16]
Reactant: CC[S-]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Agent: CSc1cc2[nH]ccc2cc1F
Agent: [Na+]
Product: CCSc1cc2c(cc1F)C(=O)C(=O)N2

Procedure:
6-Ethylthio-5-fluoroindole-2,3-dione was prepared from 5,6-difluoroindole-2,3-dione using sodium thioethoxide according to the method described in the synthesis of 5-fluoro-6-methylthioindole as a brown solid (2.53 g, 19%): mp 215° C.; IR νmax (Nujol)/cm−1 3286, 2926, 2855, 1766, 1712, 1619, 1467 and 1038; NMR δH (400 MHz, DMSO-d6) 1.32 (3H, t, J 7.5 Hz), 3.13 (2H, q, J 7.5 Hz), 6.77 (1H, d, J 6.0 Hz), 7.39 (1H, d, J 8.5 Hz), 10.97 (1H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[CH:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:6]=[CH:7][CH:8]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: CCCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC#Cc1cccc(OC)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Methoxyphenylacetylene [5.00 g, 0.032M, prepared by the method of E. Negishi et al, J. Org. Chem. 45 2526-8, (1980)] was dissolved in dry tetrahydrofuran (15 ml), cooled to -70° C. under nitrogen, and n-butyl lithium, 1.6M in hexane, (24.40 ml, 0.038M), added dropwise. After stirring for 0.5 h, iodohexane (8.00 g, 0.038M), dissolved in dry tetrahydrofuran, (15 ml) was added dropwise. The rection was warmed slowly to room temperature, refluxed overnight, then cooled. The solution was then quenched with water, acidified with dilute hydrochloric acid and extracted with diethyl ether (twice). The organic phases were combined, washed with water and dried, (MgSO4). Evaporation in vacuo affored 7.71 g of product as an orange oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]=2[CH3:38])=[CH:21][CH:20]=1)(C(C)(C)C)(C)C.[CH3:39]I.O>O1CCCC1>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:39])[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[C:26]=2[CH3:38])=[CH:23][CH:24]=1
Reactant: CI
Reactant: C=CCOC(=O)Cc1cccc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(C)c1cccc(-c2ccc(O)cc2)c1C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
A bis(trimethylsilyl)amide lithium-11.0M tetrahydrofuran solution (2.47 ml, 2.47 mmol) was added dropwise to a solution of allyl (4′-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-1,1′-biphenyl-3-yl)acetate (675 mg, 1.70 mmol) obtained in Example (98-2) in tetrahydrofuran (6 ml) at −78° C. After the mixture was stirred for 30 minutes, methyl iodide (512 μl, 8.22 mmol) was added thereto and the mixture was stirred at −78° C. for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was dissolved in tetrahydrofuran (5 ml). A tetra-n-butylammonium fluoride-1.0M tetrahydrofuran solution (2.04 ml, 2.04 mmol was added to the solution and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to give allyl 2-(4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl)propanoate (457 mg, yield: 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[C:13](=O)[CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:23]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[C:13]([CH3:14])[C:3]=2[CH:4]=1
Reactant: CC(C)C(=O)CBr
Reactant: COCCOc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2oc(C(=O)C(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.2 %

Procedure:
To a solution (10 mL) of 1-[2-hydroxy-5-(2-methoxyethoxy)phenyl]ethanone (0.55 g) synthesized in Example A79(1) in N,N-dimethylformamide were added potassium carbonate (1.1 g) and 1-bromo-3-methylbutan-2-one (0.56 g) synthesized in Example A75(1) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was filtered through celite, water (200 mL) was added and the mixture was extracted with diethyl ether (10 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) was added to the solution at room temperature. The reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with diethyl ether (10 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.71 g, 98%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([C:17]1[CH:18]=[CH:19][C:20]([NH2:25])=[N:21][C:22]=1[O:23][CH3:24])([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:25][C:20]2[CH:19]=[CH:18][C:17]([CH:14]([CH3:16])[CH3:15])=[C:22]([O:23][CH3:24])[N:21]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: COc1nc(N)ccc1C(C)C
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C(C)C)c(OC)n1
Temperature: 100 °C
Yield: 28.6 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (1.47 g, 6.64 mmol) in acetonitrile (7.6 mL) was added 5-isopropyl-6-methoxypyridin-2-amine (830 mg, 4.99 mmol) and the mixture heated at 100° C. in a sealed tube for 18 h. Upon completion, the mixture was concentrated onto silica gel and purified by chromatography (silica, 10% to 80% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (500 mg, 28.5%). MS (EI/CI) m/z: 351.2 [M+H].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:31]=[CH:30][C:6]2[O:7][CH2:8][O:9][C:10]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:11]=3[C:12](=CCCN3CCC[C@@H](C(O)=O)C3)[C:5]=2[CH:4]=1.ICI.CN(C)C=[O:38]>>[Cl:2][C:3]1[CH:31]=[CH:30][C:6]2[O:7][CH2:8][O:9][C:10]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:11]=3[C:12](=[O:38])[C:5]=2[CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(O)[C@@H]1CCCN(CCC=C2c3cc(Cl)ccc3OCOc3ccc(Cl)cc32)C1
Agent: Cl
Solvent: ICI
Product: O=C1c2cc(Cl)ccc2OCOc2ccc(Cl)cc21
Temperature: 105 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
(R)-1-(3-(2,10-Dichloro- 12H-dibenzo[d,g][1,3]-dioxocin-12-ylidene)-1-propyl)-3-piperidinecarboxylic acid hydrochloride ##STR7## 2,2'-Dihydroxy-5,5'-dichlorobenzophenone (12.1 g, 0.042 mol, prepared similarly as described in Journal of the American Chemical Society 77, 543 (1955)) and diiodomethane (11.9 g, 0.044 mol) were dissolved in dry N,N-dimethylformamide (226 ml). Dried and powdered potassium carbonate (8.3 g) was added and the mixture was heated at 105° C. for 5 h and left overnight at room temperature. The reaction mixture was poured on ice (220 g). The precipitate was collected by filtration after 0.5 h and dissolved in diethyl ether (500 ml). The organic layer was washed with 5% sodium hydroxide (50 ml), dried over MgSO4 and evaporated in vacuo, affording 12 g (96%) of 2,10-dichloro-12H-dibenzo[d,g][1,3]-dioxocin-12-one as a solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([OH:22])=[CH:24][C:25]=1[CH3:30])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(O)cc1C
Yield: 44.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (2.48 g, 6.63 mmol) and 4-hydroxy-2-methylaniline (1.06 g, 8.62 mmol) in acetonitrile (20 ml) was refluxed for 8 h. The reaction mixture was evaporated and the residue was chromatographed (SiO2 ; CH2Cl2 :MeOH 95:5) yielding 1.22 g (45%) of the desired product.