Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])=[CH2:16]>Cl.NC1C=CC=CC=1>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)([CH3:17])[CH3:16])=[CH:19][CH:20]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Oc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Reaction time: 3 h
Yield: 87 %

Procedure:
Aniline (18.6 g) and 34.4 g of the same mixture of alkenylphenols and phenol as used in Example 7 were stirred at 150° C. (2 moles of aniline per mole of the p-isopropenyl phenol monomeric unit). Then, 0.0065 g of aniline hydrochloride (0.0005 mole of catalyst per mole of the p-isopropenyl phenol monomeric unit) was added as a catalyst, and the reaction was performed for 3 hours. After the reaction, the reaction mixture was analyzed by gas chromatography. It was found that 19.7 g (yield 87%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane and 0.24 g of bisphenol A were formed.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24](O)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]>>[F:28][C:29]1[CH:30]=[C:31]([CH:36]2[CH2:41][CH2:40][N:39]([C:24]([C:13]3[CH:12]=[N:11][C:10]4[N:9]([N:8]=[CH:7][C:6]=4[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]=3[NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[O:25])[CH2:38][CH2:37]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: Fc1ccc(C2CCNCC2)cc1F
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 27.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (150 mg, 0.42 mmol) obtained in step 2 and 4-(3,4-difluorophenyl)piperidine hydrochloride (WO2004/069798, 127 mg, 0.55 mmol), the title compound (63 mg, 28%) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C@@H:14]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:20]([O:21][C:22](=[O:25])[CH2:23][CH3:24])[C@H:15]3[O:16][C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH2:38].C[O-].[Na+]>CO>[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH:38][C:2]1[C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C@@H:14]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:20]([O:21][C:22](=[O:25])[CH2:23][CH3:24])[C@H:15]3[O:16][C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)CN
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(Cl)ncnc32)O[C@@H]1COC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(NCC(=O)OC)ncnc32)O[C@@H]1COC(C)=O
Temperature: 75 °C

Procedure:
The compound from Step 3 (150 mg, 0.319 mmol) was dissolved in anhydrous MeOH (3 mL). Meanwhile glycine methylester mono hydrochloride (48 mg, 0.383 mmol) was neutralized with a 0.5M solution NaOMe (766 μl, 0.383 mmol) and this mixture was added to the methanolic solution containing nucleoside and the mixture was heated to 75° C. for 1.5 hours. Concentrated reaction in vacuo and purified on flash silica gel chromatography with a 0-5.0% MeOH gradient in DCM to afford 100 mg (60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(F)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C(=O)Cl

Procedure:
A suspension of 5-fluoro-2-methyl benzoic acid (2.31 g, 15.0 mmol) in dichloromethane (30 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with oxalyl chloride (1.6 mL, 18.3 mmol). After gas evolution subsided, the reaction mixture was refluxed for an additional 10 minutes, and then evaporated to dryness. The crude acid chloride was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([CH:33]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:23][CH3:24])[C:20]([OH:22])=O)=[O:17])[CH2:12][C:11](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][CH2:9]1.C(Cl)Cl.C(C1NC=CN=1)(C1[NH:42]C=CN=1)=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[C@H:8]([CH2:7][C:6]2[CH:33]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:34][CH3:35])[CH2:9][NH:10][C:11](=[N:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12]1)=[O:17])[CH2:23][CH3:24])(=[O:22])[NH2:42]
Reactant: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(=O)O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.2 %

Procedure:
To the compound 54 (114 mg) in a methylene chloride (2 ml) solution, carbonyl diimidazole (45 mg) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was cooled to 0° C., then 28% ammonia aqueous solution (2 ml) was added, and the mixture was stirred at that temperature for 1 hour. The reaction solution was diluted with chloroform and the resultant mixture successively washed with water, 1M hydrochloric acid, and brine. The organic layer was dried over anhydrous sodium sulfate, then was concentrated. The residue was purified by flash column chromatography (silica gel, chloroform/ethyl acetate=7/3 to 1/2) to obtain the title compound (40 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:19])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CCCO3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([OH:15])[CH2:13][F:14])[C:10]#[N:11].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][F:14])[C:10]#[N:11]
Reactant: N#CC(=C(O)CF)c1cccc(Cl)c1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CF)=C(C#N)c1cccc(Cl)c1Cl

Procedure:
Alkylation of 2-(2,3-dichlorophenyl)-4-fluoro-3-hydroxy-2-butenenitrile can suitably be achieved using ethyl iodide in dimethylformamide in the presence of potassium carbonate to afford crude 2-(2,3-dichlorophenyl)-3-ethoxy-4-fluoro-2-butenenitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]=2[O:22]C(=O)C(C)(C)C)=[C:4]([CH3:29])[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C#CC)[CH2:31][CH2:32]C>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([C:30]#[C:31][CH3:32])[CH:3]=[C:4]([CH3:29])[C:5]=1[CH:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:11][C:10]1=[O:22]
Reactant: Cc1cc(Br)cc(C)c1C1=C(OC(=O)C(C)(C)C)CC(CC2CCOCC2)C1=O
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC#Cc1cc(C)c(C2C(=O)CC(CC3CCOCC3)C2=O)c(C)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
To a degassed solution of rac-2,2-dimethylpropionic acid 2-(4-bromo-2,6-dimethylphenyl)-3-oxo-4-(tetrahydropyran-4-ylmethyl)cyclopent-1-enyl ester (0.20 g, 0.43 mmol) in toluene (4 ml) under a nitrogen atmosphere is added tributyl(1-propynyl)tin (0.39 ml, 1.29 mmol) and tetrakistriphenylphosphine palladium(0) (0.10 g, 0.086 mmol). The reaction mixture is then heated at 130°C. under microwave irradiation for 45 minutes, followed by quenching with distilled water (20 ml) and extraction with ethyl acetate (50 ml×2). The combined organic fractions are washed with water, brine, dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is then dissolved in methanol (1.0 ml) and 2N sodium hydroxide solution (0.5 ml) is added followed by stirring at 25°C. for 3 hours. The solvent is evaporated in vacuo and the crude product is diluted with distilled water, acidified with 2N hydrochloric acid then extracted with ethyl acetate (50 ml×3). The combined organic fractions are washed with water, brine, dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to afford rac-2-(2,6-dimethyl-4-prop-1-ynylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][NH2:19])[CH2:3][CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1.[NH2:20][C:21]1[C:22]([C:29]([NH:31][C:32](=N)SC)=[O:30])=[N:23][C:24]([Cl:28])=[C:25]([NH2:27])[N:26]=1>CC(O)C.CS(C)=O>[OH:15][C@H:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1[CH:16]=[CH:17][C:6]([CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:18][NH:19]/[C:32](=[N:31]/[C:29]([C:22]3[C:21]([NH2:20])=[N:26][C:25]([NH2:27])=[C:24]([Cl:28])[N:23]=3)=[O:30])/[NH:1]2)=[CH:7][CH:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NC[C@H](N)CCCc1ccc(OC[C@H](O)CO)cc1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2/NC[C@@H](CCCc3ccc(OC[C@H](O)CO)cc3)N2)nc1Cl
Temperature: 90 °C

Procedure:
To a stirred solution of (R)-3-[4-((R)-4,5-Diamino-pentyl)-phenoxy]-propane-1,2-diol (Intermediate O) (32.8 mg, 0.122 mmol) in propan-2-ol (3 ml) is added 1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (45.8 mg, 0.122 mmol) and the resultant reaction mixture is heated at 90° C. for 18 hours. The reaction is allowed to cool to room temperature and diluted with DMSO (1.5 ml) and purified on a Waters 3000 preparative HPLC system (Microsorb™ C18, Water (0.1% TFA): MeCN). The fractions containing product are passed through a 1 g SCX-2 cartridge which is eluted with 1:1 Water:MeCN (20 ml), MeCN (20 ml) and 7M NH3 in MeOH (20 ml). The ammonia elutions are concentrated in vacuo to afford the title compound; [M+H]+ 464
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH:25]([CH3:27])[CH3:26])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.CCOC(C)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]3[N:17]([CH:25]([CH3:26])[CH3:27])[C:16]2=[O:28])=[CH:13][CH:14]=1
Reactant: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cnc2c(c1)n(C(C)C)c(=O)n2-c1ccc(O)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-methyl-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (283 mg) and 10% palladium on carbon (50% wet) (87 mg) in MeOH (4.2 mL) and EtOAc (4.2 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and washed with MeOH (10 mL) to remove the catalyst. The filtrate was concentrated in vacuo to give the title compound (210 mg) as a gray solid.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N:11]([Na])=[N+:12]=[N-:13]>CN(C=O)C.[Cl-].[Li+]>[C:2]1([C:1]2[NH:13][N:12]=[N:11][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=N[Na]
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A solution of benzonitrile (60.0 g, 581.9 mmol, 1.0 equiv) in DMF (anhydrous) (600 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. Ammonium chloride (40.5 g, 757.2 mmol, 1.3 equiv) was added, followed by the addition of lithium chloride (2.0 g, 47.2 mmol, 0.1 equiv). To the mixture was added azidosodium (49.4 g, 756.8 mmol, 1.3 equiv). The resulting solution was stirred overnight, while maintaining the temperature at 100° C. The solids were filtered out and washed with EtOAc. The filtrates were combined and concentrated in vacuo. The residue was dissolved in a 10% NaOH aqueous solution (350 ml). The resulting solution was extracted with EtOAc (100 mL) and the aqueous layers were combined. The pH value of the solution was adjusted to 2 with concentrated HCl. The solids were filtered out and dried over reduced pressure to yield 5-phenyl-1H-tetrazole (78.0 g) as a white solid. ES m/z: [M+H]+ calcd for C7H6N4, 147.1. Found 147.1.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26]N)=[N:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:6][NH:7]2)=[N:24][CH:25]=1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-n3ccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
233 mg (1.0 mmol, purity 90%) of the compound from Example 42A are initially introduced into 4 ml ethanol. 260 mg (1.0 mmol, purity 75%) of the compound from Example 12A and 38 mg (0.2 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, the solid which has precipitated out is filtered off and washed with a little ethanol and the solid is dried under a high vacuum. A further amount of the target compound is obtained by purifying the mother liquor of the filtration via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[CH:13]=[CH:14][C:9]([C:6]4[N:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][N:5]=4)=[CH:10][C:11]3=[O:15])[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ncc(C(F)(F)F)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(-c5ncc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 39.3 %

Procedure:
4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(1H)-one (100 mg, 0.34 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (124 mg, 0.339 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (70 mg, 39%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.11 (s, 2H), 7.86 (s, 1H), 7.59-7.53 (m, 2H), 7.38 (s, 1H), 7.28-7.26 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.89-4.63 (br m, 2H), 3.90-3.80 (br m, 2H), 3.65 (s, 3H), 2.88-2.79 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7](=[CH2:10])[CH2:8][OH:9].CN(C)C1C=CC=CC=1>ClCCl>[Br:1][CH2:2][C:3]([O:9][CH2:8][C:7]([Cl:6])=[CH2:10])=[O:4]
Reactant: C=C(Cl)CO
Reactant: O=C(Br)CBr
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: C=C(Cl)COC(=O)CBr
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of bromoacetyl bromide (51.5 g, 25.5 mmol) in dichloromethane (80 mL) kept under nitrogen atmosphere was added 2-chloroallyl alcohol (26.0 g, 28.1 mmol) over 5 minutes period and N,N-dimethylaniline (30.9 g, 25.5 mmol) at such a rate that the temperature was kept below 5° C. (30 minutes). When the addition was completed, the cooling bath was removed and, the mixture was stirred for 2 hours at 23° C. and washed with water (25 mL), 0.1N HCl (2×25 mL) and water (25 mL). The organic solution was dried (Na2SO4) and concentrated to a crude material from which the title compound was distilled; 44.8 g, 82%, bp 74°-6° C./1.25 torr; ir (neat) νmax : 1745 (C=O), 1635 (C=C) cm-1 ; 1Hmr (CDCl3) δ: 3.93 (s, BrCH2), 4.73 (s, COOCH2C(Cl)=CH2), 5.48 (m, COOCH2C(Cl)=CH2). Anal. calcd. for C5H6O2BrCl: C 28.13, H 2.83, Cl 16.61; found: C 28.49, H 2.92, Cl 16.78
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:22]12([NH2:32])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([NH:32][C:17](=[O:18])[CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]4)[CH2:2]5)=[CH:21][CH:20]=3)[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NC12CC3CC(CC(C3)C1)C2
Yield: 93.3 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and adamantan-1-amine (0.105 g, 0.69 mmol) according to the example 1, which was given N-(adamantan-1-yl)-2-(4-(adamantan-1-yl)phenoxy)acetamide as a white solid (0.27 g, 92.1% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH:47]3[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>C1COCC1>[CH3:2][O:3][CH:4]=[C:50]1[CH2:49][CH2:48][CH:47]([C:44]2[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH:36]3[CH2:35][CH2:34][CH:33]([CH2:30][CH2:31][CH3:32])[CH2:38][CH2:37]3)=[CH:46][CH:45]=2)[CH2:52][CH2:51]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC1CCC(CCc2ccc(C3CCC(=O)CC3)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(CCc2ccc(C3CCC(=COC)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
THF solution (20 ml) including methoxymethyltriphenylphosphonium chloride (2 g, 5.9 mmol) was slowly added by in solid potassium tert-butoxide (0.6 g, 5.9 mmol) for 3 minutes in a flask filled with argon gas at −10° C. and then stirred for 20 minutes with maintaining the temperature. The temperature of reacting solution was adjusted to 0° C., added slowly dropwise by THF solution (15 ml) of 4-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}cyclohexanone (1.5 g, 4.5 mmol) and then was stirred by warming to a room temperature. After the reaction termination, the resulting solution was diluted by distilled water (20 ml), extracted by ether (20 ml×3 times), washed by distilled water (10 ml×2 times) and then concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether=1:40) to obtain 1-[4-(methoxymethylene)cyclohexyl]-4-[2-(4-propylcyclohexyl)ethyl]-benzene (1.2 g, 80%).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#[N:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:15][S:12]([C:6]1[CH:7]=[C:8]([CH:9]([CH3:11])[CH3:10])[C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N
Product: CC(=O)NS(=O)(=O)c1cc(C(C)C)c(C#N)cc1C(C)C

Procedure:
A mechanically stirred mixture of 8 parts of 4-cyano-2,5-diisopropylbenzenesulfonamide and 50 parts of acetic anhydride was heated near reflux for 6 hours. The reaction was concentrated in vacuo to give a solid which was recrystallized from ethanol-water, and then exhibited a m.p. of 170°-173°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO>O=[Pt]=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CCC1CC2=Cc1ccc(Cl)c(Cl)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCC1CC2Cc1ccc(Cl)c(Cl)c1
Yield: 88.4 %

Procedure:
5-(3,4-Dichloro-benzylidene)-2-aza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (0.45 g) was stirred under 1 atm of H2 in 20 ml of 1:1 of EtOH:EtOAc in the presence of PtO2 for 20 min. The reaction mixture was filtered through celite and concentrated to give 0.4 g of 5-(3,4-dichloro-benzyl)-2-aza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (M+: 369).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:37]([O:36][CH:35]([O:39][CH2:40][CH3:41])[C@@H:34]([N:22]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:13])[CH2:43][C:44](=[O:45])[NH:46][C:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH3:42])[CH3:38]
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 56 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[N:36]=[CH:37][C:30]=12)[C:24](OC)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[C:30]2[CH:37]=[N:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=3[CH3:45])[C:31]=2[N:32]=[CH:33][N:34]=1)[C:24]([NH:53][C:50]1[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][N:51]=1)=[O:25])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:8])[CH3:2]
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(F)c1C
Product: Cc1c(F)cccc1-n1ncc2c(O[C@@H](COCCO[Si](C)(C)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21

Procedure:
Prepared using a procedure analogous to that described for Intermediate AE1 using (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AF4) and 5-chloropyridin-2-amine. 1H NMR (400 MHz, DMSO) d 0.87 (9H, s), 1.96 (3H, d), 3.75 (4H, m), 4.10-4.02 (1H, m), 4.15 (1H, m), 6.00 (1H, m), 7.38 (9H, m), 7.63-7.57 (4H, m), 7.88 (1H, dd), 8.03 (1H, d), 8.40 (1H, d), 8.52 (1H, s), 8.56 (1H, s), 11.25 (1H, s).