Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].N1C=CC=CC=1.Cl[C:17]([C:19]1[C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18]>ClCCl>[C:35]([C:32]([C:33]#[N:34])=[C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=3)=[O:18])[C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)#[N:36]
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Reactant: Oc1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Oc3cc(O)cc(O)c3)cccc21
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A solution of 30.0 grams of phloroglucinol and 70 milliliters of pyridine in 300 milliliters of dichloromethane was stirred at room temperature under a nitrogen atmosphere. Thereafter, a solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dichloromethane was added thereto over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The mixture was washed three times with dilute aqueous HCl solution, twice with dilute aqueous NaHCO3 solution, and once with water. The solution was dried, filtered, and evaporated under reduced pressure to give the crude product. Recrystallization from methanol afforded 6.1 grams of (b), m.p., 255.5° to 257° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[NH:16].C[OH:22]>[Pd]>[C:18]([OH:20])(=[O:22])[CH3:19].[C:8]1([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH2:17])=[NH:16]
Reactant: CO
Reactant: CC(=O)NC(=N)Cc1ccccc1-c1ccccc1Cl
Agent: [Pd]
Product: CC(=O)O
Product: N=C(N)Cc1ccccc1-c1ccccc1
Reaction time: 18 h
Yield: 78.4 %

Procedure:
To the solution of 2-(2′-chloro-biphenyl-2-yl)-N-acetyl-acetamidine (17) (2 g, 6.623 mmol) in methanol (10 mL) was added 200 mg 10% Pd—C. The mixture was hydrogenated by balloon pressure at room temperature for 18 h. After completion of the reaction, the mixture was filtered and evaporated to afford 2-biphenyl-2-yl-acetamidine acetic acid salt (5-01) (1.4 g, 78.4%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C1CCNC1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)ccc1N1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A 100 mL round-bottom flask was charged with 5-chloro-2-fluorobenzaldehyde (2.00 g, 12.6 mmol, 1.00 equiv), pyrrolidine (1.34 g, 18.8 mmol, 1.49 equiv), potassium carbonate (4.34 g, 31.4 mmol, 1.92 equiv), and dimethyl sulfoxide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/10) to yield 1.80 g (68% yield) of 5-chloro-2-(pyrrolidin-1-yl)benzaldehyde as brown oil. 1H NMR 300 MHz (CDCl3) δ 10.05 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.267-7.31 (m, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.29-3.37 (m, 4H), 1.95-2.04 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(COC)OC>C(OCC)(=O)C.O.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>[F:30][C:31]1[CH:36]=[C:35]([C:2]2[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Brc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccncc12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccncc23)c1
Yield: 93.6 %

Procedure:
A solution of 500 mg of 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine, 131 mg of 3-fluorophenylboronic acid, tetrakis(triphenylphosphine)palladium(0) and 537 mg of barium hydroxide octahydrate in a mixed solution of 18 mL of dimethoxyethane and 3 mL of water was stirred at 80° C. for 2 hours. The solution was diluted with ethyl acetate and water, followed by filtration through Celite. The organic layer of filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:3-dichloromethane:n-hexane=1:2-1:1-dichloromethane:methanol 100:1), to afford 399 mg of the title compound as colorless crystals.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: Cc1ccc(N)cc1O
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C)c(O)c3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (14 mg, 0.1137 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 36% yield (0.028 g, 0.0521 mmol).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH3:6])[CH2:3][CH2:2]1.FC(F)(F)S([O-])(=O)=O.[N:15]1([S:20](N2C=C[NH+](C)C2)(=[O:22])=[O:21])[CH:19]=[CH:18][N:17]=[CH:16]1>>[CH:1]1([CH2:4][N:5]([CH3:6])[S:20]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)(=[O:22])=[O:21])[CH2:3][CH2:2]1
Reactant: CNCC1CC1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(CC1CC1)S(=O)(=O)n1ccnc1

Procedure:
Imidazole-1-sulfonic acid cyclopropylmethyl-methyl-amide was prepared in accordance with step A of the general method described in example 76 from cyclopropylmethyl-methylamine and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=216.5 (M+H+).
Reaction SMILES: [CH:1]1([C:8]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[Na]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:12][CH2:11][CH:10]([C:8]([CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)C1CCCCCC1)c1ccccc1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCCC2)c2ccccc2)CC1
Yield: 70.3 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cycloheptanecarbonyl-3-phenylpropionaldehyde (2.52 mmol) and 1-(2-methoxyphenyl)piperazine (2.52 mmol) with sodium triacetoxyboranehydride (3.28 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazine (770 mg) in 70% yield. The di-hydrochloric acid salt was prepared as described above.
Reaction SMILES: [H-].[Na+].[CH:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1)=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].O>O1CCCC1>[C:14]([O:13][C:12]([NH:11][C@H:8]1[CH2:9][CH2:10][C@H:5](/[CH:3]=[CH:20]/[C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6][CH2:7]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethyl phosphonoacetate (107 mg) was dissolved in tetrahydrofuran (1 mL), and 60% sodium hydride (19 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (90 mg) in tetrahydrofuran (1 mL) was added dropwise thereto, followed by stirring at room temperature for 2 hours. Ethyl acetate and water were added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-50:50) to obtain ethyl (2E)-3-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}acrylate (100 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)(=[O:5])[CH3:4].[CH3:18][S:19]([C:22]1[CH:34]=[CH:33][C:25]([CH2:26]P(=O)(OC)OC)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>COCCOC>[C:3]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:26][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:34][CH:33]=2)=[CH:12][CH:11]=1)(=[O:5])[CH3:4]
Reactant: COP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OC
Reactant: CC(=O)OCCOc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)OCCOc1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
To a stirred suspension of 3.0 g (0.075 mol) of 60% sodium hydride dispersion, 11.0 g (0.05 mol) of 4-(2-acetoxyethoxy)benzaldehyde (Example 1) and 125 mL of dry 1,2-dimethoxyethane were added, under nitrogen, 13.9 g (0.05 mol) of dimethyl 4-methylsulfonylbenzylphosphonate. The mixture was heated at reflux for 2 hr, after which time it was cooled and poured over ca. 200 g of crushed ice under nitrogen. The crude product was filtered, washed with water and air-dried to give 17.7 g (98%) of the white solid, which was used without further purification. m.p.=175°-177° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH2:12]([O:19][C:20]1[C:21]([CH3:30])=[C:22]2[N:27]([CH:28]=1)[N:26]=[CH:25][N:24]=[C:23]2Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(C#N)(C)=O>>[CH2:12]([O:19][C:20]1[C:21]([CH3:30])=[C:22]2[N:27]([CH:28]=1)[N:26]=[CH:25][N:24]=[C:23]2[O:1][C:2]1[CH:3]=[C:4]2[CH:5]=[C:6]([CH3:11])[NH:7][C:8]2=[N:9][CH:10]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(OCc2ccccc2)cn2ncnc(Cl)c12
Reactant: Cc1cc2cc(O)cnc2[nH]1
Agent: CC(=O)C#N
Product: Cc1cc2cc(Oc3ncnn4cc(OCc5ccccc5)c(C)c34)cnc2[nH]1

Procedure:
5-Hydroxy-2-methyl-7-azaindole was treated with of 6-benzyloxy-4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (see WO 0071129) by a method similar to the preparation of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (1H, br. s), 7.85 (1H, s), 7.83 (1H, s), 7.70 (1H, br. s), 7.41 (6H, m), 6.15 (1H, br. s), 5.12 (2H, s) 2.92 (3H, s), 2.42 (3H, s). m/z 386 (M+H)+, 427 (M++AcCN).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:17].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][I:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICc1ccc(OCc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (4.3 mmol) of 4-benzyloxybenzyl chloride (Fluka; Buchs/Switzerland) in 8 ml of acetone is stirred at RT with 3.13 g (20.9 mmol) of sodium iodide. According to a gas chromatrogram, the reaction is complete after 90 min. Working up as described in Example 21 F) 1) a) yields the title compound: 1H-NMR (200 MHz, CDCl3 : 4.48 (s, 2 H), 5.06 (s, 2 H), 6.85-6.95 (m, 2 H), 7.25-7.48 (m, 7 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC2C=CC=[C:26]([OH:27])C1=2.C(Cl)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].COC(Cl)Cl>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12]([CH:26]=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc2ccsc12
Reactant: c1ccc(COc2cccc3ccsc23)cc1
Agent: COC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCc1ccccc1
Product: O=Cc1ccc(OCc2ccccc2)c2sccc12

Procedure:
In analogy to the procedure described in example 2 a], 7-benzyloxy-benzo[b]thiophene (prepared from benzo[b]thiophen-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-71 and benzylchloride by treatment with potassium carbonate in N,N-dimethylformamide at room temperature) was reacted with dichloromethyl methyl ether in dichloromethane at 0° C. to give 7-benzyloxy-benzo[b]thiophene-4-carbaldehyde.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].CN(C1C=CC=CN=1)C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([NH:14][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:12]#[CH:13]
Reactant: C#CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C#CCNS(=O)(=O)c1ccccc1
Reaction time: 15 h

Procedure:
Benzene sulfonyl chloride (1.16 mL, 9.1 mmol) was added to stirred solution of propargylamine (0.62 mL, 9.1 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (5 mL) at room temperature. The resulting solution was aged at ambient temperature for approximately 15 h. The reaction mixture was diluted with ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound (i-2), which was used without further purification.
Reaction SMILES: [CH2:1]=[O:2].[C:3]12([CH2:13]O)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[ClH:15]>>[Cl:15][CH2:1][O:2][CH2:13][C:3]12[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Cl
Reactant: C=O
Product: ClCOCC12CC3CC(CC(C3)C1)C2
Reaction time: 12 h

Procedure:
Paraformaldehyde was added to adamantane-1-methanol, and a hydrogen chloride gas was injected at 2.5 equivalent amounts per this adamantane-1-methanol. Then, the reaction was conducted at a temperature of 50° C. for 12 hours. After the completion of the reaction, the product was distillated under reduced pressure so as to obtain 1-adamantylmethyl chloromethyl ether (compound 3) represented by the following chemical formula (60).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:8][C:7]=2[CH:31]=1.[Li]CCCC.[CH:37]([C:39]1[CH:40]=[C:41]([CH:45]([S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[CH:42]=[CH:43][CH:44]=1)=O>O1CCCC1.CCCCCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[CH:37][C:39]3[CH:40]=[C:41]([CH:45]([S:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[S:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH:42]=[CH:43][CH:44]=3)=[N:8][C:7]=2[CH:31]=1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=O)c1
Reactant: Clc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2nc3cc(Cl)ccc3o2)c1
Reaction time: 0.25 h

Procedure:
To a solution of phosphonium bromide (780 mg) (Step 4) in tetrahydrofuran (THF) (8 mL) at -78° was added dropwise 1 eq. of n-BuLi in hexane. The solution was stirred at -78° for 15 min. Then (545 mg) of the aldehyde (Step 1) in THF (4 mL) was added dropwise and the reaction mixture was stirred at -78° for 1 hour. The reaction mixture was poured into pH 7 buffer, extracted with ethyl acetate, dried and evaporated. The residue was chromatographed on a column of SiO2 using 10:1 toluene/ethyl acetate to afford the title compound, m.p. 66°-67° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:22]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.10 g, 3.42 mmol) in N,N-dimethylformamide (20 mL) were added diphenylmethane hromide (0.93 g, 3.76 mmol) and potassium carbonate (0.52 g, 3.76 mmol), and the mixture was stirred at 60° C. for 3 hours. This reaction mixture was diluted with ethyl acetate and water and, after phase separation, the aqueous layer was extracted with ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in acetic acid (20 mL). To this solution was added concentrated sulfuric acid (10 ml), and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled extract was washed with water, dried over MsGO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from hexane-ethyl acetate to provide 0.58 g of the title compound. Yield 37%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[NH:13][CH:12]=1)[OH:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)=[O:10]
Reactant: OC(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To (2,4-dichloro-phenyl)-(5-phenoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (33, 48 mg, 0.12 mmol) in tetrahydrofuran (15 mL), Dess-Martin periodinane (58 mg, 0.137 mmol) was added. The reaction was stirred at room temperature for 40 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The crude material was suspended in acetonitrile (1˜2 mL). The precipitated material was collected with vacuum filtration to provide the compound (P-0036, 24 mg, 50%). MS (ESI) [M+H+]+=383.1 and 385.1.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH:4]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH3:18])[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.O>[NH:4]([C:11]1[N:12]=[C:13]([CH3:18])[CH:14]=[C:15]([O:2][CH3:1])[N:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)nc(Nc2ccccc2)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
2.9 g of 28% methanolic solution of sodium methylate was dissolved in 40 ml of methanol, and thereto was added 3.3 g of 2-anilino-4-chloro-6-methylpyrimidine. After 2 hours of reaction with stirring at room temperature the reaction liquid was poured in water The solids deposited were filtered, dried, and recrystallized from n-hexane to afford 2 9 g of 2-anilino-4-methyl-6-methoxypyrimidine (yield 92 %). Melting point: 75°-76° C.
Reaction SMILES: [Na].[C:2](O)(=O)C.C[N:7]1[CH:13]2[CH2:14][C:15](=[N:17]O)[CH2:16][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2>>[CH3:2][NH:17][CH:15]1[CH2:14][CH:13]2[NH:7][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:16]1
Reactant: CC(=O)O
Reactant: CN1C2CCCCC1CC(=NO)C2
Agent: [Na]
Product: CNC1CC2CCCCC(C1)N2

Procedure:
15 g of sodium are reacted in analogous manner to that disclosed below in Example (j) with 9.69 g 10-methyl-10-azabicyclo-[4.3.1]decan-8-one oxime acetate [m.pt. 253°-253.5° C. prepared in analogous manner to that disclosed in Example A-1b] giving an oil bpt 105°/0.9, mm after working up in conventional manner.
Reaction SMILES: [CH2:1]([N:8]([C:30]1[CH:31]=[C:32]([CH:57]=[CH:58][CH:59]=1)[C:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:44][CH2:45][CH2:46][C:47]([O:49]CC2C=CC=CC=2)=[O:48])[CH:36]=1)=[O:34])[CH:9]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCOCC1.[Pd]>[CH2:1]([N:8]([C:30]1[CH:31]=[C:32]([CH:57]=[CH:58][CH:59]=1)[C:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]([CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH:36]=1)=[O:34])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cc1ccc(C(c2ccc(CC(C)C)cc2)N(Cc2ccccc2)c2cccc(C(=O)c3cn(CCCC(=O)OCc4ccccc4)c4ccccc34)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(C(c2ccc(CC(C)C)cc2)N(Cc2ccccc2)c2cccc(C(=O)c3cn(CCCC(=O)O)c4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzyl 4-[3-[3-[N-benzyl-N-[bis(4-isobutylphenyl)methyl]amino]benzoyl]indol-1-yl]butyrate (24 mg) was dissolved in a mixture of methanol 93 ml) and 1,4-dioxane (3 ml), and 10% palladium on carbon (12 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel (2 g) eluting with a mixture of chloroform and methanol (50:1) to give 4-[3-[3-[N-benzyl-N-[bis(4-isobutylphenyl)methyl]amino]benzoyl]indol-1-yl]butyric acid as (14 mg) powder.